Brain Research Reviews 23 Ž1997.

79–133

Full-length review

The role of adrenocorticoids as modulators of immune function in health

and disease: neural, endocrine and immune interactions
Bruce S. McEwen a,) , Christine A. Biron b, Kenneth W. Brunson c , Karen Bulloch a ,
William H. Chambers c , Firdaus S. Dhabhar a , Ronald H. Goldfarb c , Richard P. Kitson c ,
Andrew H. Miller d , Robert L. Spencer a,1, Jay M. Weiss d
a
Laboratory of Neuroendocrinology, Rockefeller UniÕersity, 1230 York AÕenue, Box 165, New York, NY 10021, USA
b
DiÕision of Biology and Medicine, Brown UniÕersity, ProÕidence, RI, USA
c
Pittsburgh Cancer Institute, UniÕersity of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
d
Department of Psychiatry and BehaÕioral Sciences, Emory UniÕersity School of Medicine, Atlanta, GA, USA
Accepted 9 July 1996

Contents

1. Introduction . . . . . . . . . ............................................................... 80
1.1. Perspective . . . . . . . ............................................................... 80
1.2. Historical background . ............................................................... 80

2. Components of the neuroendocrine-immune axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

2.1. Nature of the immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.2. Hypothalamo-pituitary-adrenal axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.3. Autonomic nervous system–hypothalamo-pituitary-adrenal interactions that affect immune system function . . . . . . . . . . . . . . . . . . 83

3. Behavioral influences on hypothalamo-pituitary-adrenal activity and immune function ................................ 84

3.1. Behavior and individual differences . . . . . . . . . . . . . . . . . . . . . . . . ................................ 84
3.2. Stress effects on immune processes and mechanisms . . . . . . . . . . . . . . . ................................ 85

4. Mechanisms of action of adrenal steroids on the immune system . ........................................... 91

4.1. Adrenal steroid receptors in immune cells and tissues . . . . ........................................... 91
4.2. Immunologic mechanisms . . . . . . . . . . . . . . . . . . . ........................................... 95

5. Disease models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

5.1. Glucocorticoids and immune responses to viral infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
5.2. Role of glucocorticoids in tumor establishment and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
5.3. Glucocorticoids, autoimmune and inflammatory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.4. Genetic differences in hypothalamo-pituitary-adrenal-axis responsivity — effects on resistance to autoimmune disease, infection and cancer. 118

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................ 119

6.1. A new view of adrenal steroid effects on immune function ............................................ 119
6.2. An important role for other immune modulators . . . . . . ............................................ 120

)
Corresponding author. Fax: q1 Ž212. 327-8634; E-mail:
mcewen@rockvax.rockefeller.edu
1
Present address: Department of Psychology, University of Colorado,
Boulder, CO, USA.

0165-0173r97r$32.00 Copyright q 1997 Elsevier Science B.V. All rights reserved.

PII S 0 1 6 5 - 0 1 7 3 Ž 9 6 . 0 0 0 1 2 - 4
80 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
Acknowledgement ......................................................................
References ..........................................................................
1. Introduction
1.1. PerspectiÕe
Glucocorticoids are powerful regulators of immune
function. Their role in reducing inflammation and autoim-
mune responses is well known, as is their ability to induce
apoptosis in immature thymocytes. However, much of the
story of glucocorticoid effects on immunity has been de-
rived from in vitro studies on immune cells, as well as
from the in vitro and in vivo actions of synthetic glucocor-
ticoids, both of which may not represent the complex
effects manifested by endogenous adrenal steroids in vivo.
As a result, the picture of glucocorticoid actions on im-
mune function has been biased towards the immuno-
suppressive actions of these hormones. A more accurate
view of endogenous glucocorticoids is that they are subtle
and complex modulators of immune function, not only
containing the exuberance of inflammatory and autoim-
mune responses, but also both enhancing and inhibiting
host immune responses and thereby influencing disease
susceptibility and progression.
This article will summarize our current knowledge of
glucocorticoid physiology in relation to immune function
in health and disease. This is an important task because,
while glucocorticoids are powerful regulators of immune
function, much of the work on this topic has been fragmen-
tary with regard to the specificity and diversity of gluco-
corticoid actions within diverse immune cell types and
organs. As will be seen, the distribution of adrenal steroid
receptors is different among immune cell types; and so are
the effects of adrenal steroids on the response to or produc-
tion of immune modulators. Finally, all of this must be
viewed in the context of disease, in order to determine the
range of glucocorticoid effects that are beneficial to the
host response during an immune challenge and to ascertain
the levels of stress or exposure to glucocorticoids that
exacerbate disease processess.
1.2. Historical background
In his Nobel Lecture delivered in 1950, Philip Hench
w197x described the discovery of an endogenously derived
substance which had a significant impact on disease ex-
pression in individuals suffering from rheumatoid arthritis
w197x. His work stemmed from clinical observations that a
variety of concurrent conditions including jaundice, preg-
nancy, typhoid vaccination, surgical operations and short
periods of starvation could significantly alter the course of
rheumatoid arthritis and other immunologic disorders such
120
120
as hay fever and asthma. Ultimately, he developed the idea
that the concurrent conditions somehow stimulated the
release of an endogenous substance which was both anti-
allergic as well as anti-rheumatic. Discovery that the en-
dogenous compound was the adrenal steroid, cortisone
ŽKendall’s Compound E or 17-hydroxy-11-dehydrocorti-
costerone., ushered in the era of glucocorticoid therapy as
a cornerstone of the treatment of autoimmune and inflam-
matory diseases. Since Hench’s discovery w197x, tremen-
dous strides have been made regarding the clinical use of
adrenal steroids. Moreover, numerous studies have re-
vealed the basic biochemical and molecular mechanisms
by which adrenal steroids influence specific immune re-
sponses.
Concurrent with the early work of Hench and Kendall,
Hans Selye w393x introduced experimental data demonstrat-
ing that a wide variety of stressors were associated with
enlarged adrenal glands and involution of the thymus,
providing an important connection between endogenous
hormones and the immune system. However, Selye be-
lieved that glucocorticoids enhanced disease resistance by,
for example, lysing lymphocytes and releasing antibodies
w394x. He suggested that rheumatoid arthritis might be a
disorder caused by an overproduction of adrenocortical
hormones during stress and therefore represented a disease
of adaptation. When the anti-inflammatory and immuno-
suppressive effects of glucocorticoids were discovered in
the late 1940s, Selye’s notion of glucocorticoid enhance-
ment of immune system function was abandoned.
In an effort to resolve the contrasting roles of glucocor-
ticoids as both critical facilitators of the adaptive response
to stress and powerful immunosuppresive agents, it was
suggested that the inhibitory effects on immune function
were primarily a result of pharmacologic effects of these
hormones whereas the more positive effects of glucocorti-
coids in orchestrating the adaptive response to stress were
physiologic in nature. A decade ago, based on work that
all effects of adrenal steroids, whether occuring at physio-
logic or pharmacologic concentrations, were mediated
through the glucocorticoid receptor, a new model for glu-
cocorticoid–immune interactions was proposed. Incorpo-
rating the anti-inflammatory and immunosuppressive ef-
fects of glucocorticoids, Alan Munck suggested that adrenal
steroids were functioning to protect the body by preventing
or ‘containing’ a potential overshoot of immune responses
w327,328x: e.g., containing or preventing immunologic re-
sponses to ‘self’ antigens released during tissue damage
that would cause further tissue injury and possibly the
development of autoimmune disorders. These notions of
glucocorticoid containment of the immune system were
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
further developed by Hugo Besedovsky who suggested
that glucocorticoid elevations following administration of
non-specific immune activators represented the role of
endogenous glucocorticoids in fine-tuning immune re-
sponses, antigen–antibody interactions in particular, after
an immune challenge w40x. Munck presented the contain-
ment of the immune response in the broader context of
glucocorticoid containment of a host of other physiological
responses, ranging from edema after trauma to neurochem-
ical responses to stressors w328x. This notion has been
further developed for the brain and provides a basis for
understanding how neural and behavioral responses to
stressful challenges are buffered and regulated by the same
agents which contain immune function w295x.
More recently, it has become apparent that glucocorti-
coids, as originally suggested by Selye, do enhance certain
aspects of the response to an immune challenge. Therefore,
considerable interest has been shown in developing alter-
native models of glucocorticoid–immune interactions that
incorporate both the facilitative as well as the inhibitory
effects of endogenous glucocorticoids w29,110,220,481x. In
other words, models are needed wherein glucocorticoids
guide and shape the immune system rather than either
enhance or contain immune responses. The data upon
which such a revision might be based is the topic of this
review.
2. Components of the neuroendocrine-immune axis
The tissues and organs of the immune system are
innervated by the autonomic nervous system ŽANS. and
bathed by endocrine and paracrine hormones. They are
dynamic structures which develop and mature under the
influence of these hormonal and neural regulators, in addi-
tion to their own internal regulators, cytokines. In order to
understand the immunologic influence of glucocorticoids,
it is necessary to understand something about the organiza-
tion of the immune system, its function and its develop-
ment, as well as the basic plan of the hypothalamic-pitui-
tary-adrenal axis.
2.1. Nature of the immune response
In mid-to-late embryogenesis, pleuripotential hemato-
poietic stem cells, which are precursors to immunocytes
Žlymphocytes and other cells of the immune system.,
migrate from blood islands of the yolk sac to the fetal
liver, the spleen and the bone marrow. There, they are
exposed to extrinsic and local microenvironmental factors
including those of the nervous and endocrine systems that
commit them to a granulocytic, an erythrocytic, lympho-
cytic or a monocytic developmental pathway. Prelympho-
cytes then travel either to the thymus or to the bursa of
Fabricius in birds or bone marrow in other vertebrates,
where T cells and B cells undergo development, selection
81
and maturation. These antigen-sensitive T and B lympho-
cytes are distributed to strategically located lymphoid tis-
sues, where they monitor the pathways Žwet membranes,
tissue fluids, lymphatics and blood. by which an invasive
agent enters the body and is transported to its various
targets w189x.
The functions of the immune system can be divided into
two separate categories: Ž1. non-adaptive or innate immu-
nity; and Ž2. adaptive or specific immunity. Non-adaptive
immunity lacks fine specificity, although selectivity in
recognition is apparent. It also lacks memory, i.e., no
enhanced response upon secondary exposure and it is
frequently thought to provide an initial means of defense.
Adaptive immunity shows specificity in responsesm, as
well as an ability to distinguish self from non-self. It is
also characterized by the ability to establish immunologic
memory and by an enhanced response upon secondary
exposure. However, these distinctions are for the ease of
discussion of components of the immune system and there
are clear instances of overlap and substantial interaction
between these two categories.
The mobile, functional cellular, and soluble elements of
the immune system are organized and distributed in order
to provide the capacity for both systemic and regional
reponsiveness to challenge w351x. The cells mediating
non-adaptive immunity such as myeloid and cytolytic cells
Žnatural killer ŽNK. cells. are involved in non-adaptive
responses and do not require prior activation to be func-
tional. Therefore they can provide an important first line of
defense against infectious agents during the early stages of
an immune response. The complement system provides an
important humoral element of the non-adaptive immune
system.
The cells with primary responsibility for adaptive im-
munity are T and B lymphocytes w253,451x. B cells pro-
duce immunoglobulins. T cell subsets function as
helperrinducers of responses, i.e. T helper 1 ŽTh1. and T
helper 2 ŽTh2., and effectors, i.e., cytolytic T lymphocytes
ŽCTL., mediating direct lysis of target cells.
An effective, specific immune response includes three
separate phases: an induction phase, in which the presence
of an infectious agentrimmunogen is detected and relevant
antigens are presented to T cells; an activation or expan-
sion phase, which includes the proliferation and mobiliza-
tion of immune cells important for the erradication of the
infectious agentrimmunogen, largely regulated by the re-
lease of intrinsic modulators such as cytokines Žsee below.;
and the effector phase in which the infectious agentrim-
munogen is neutralized and eliminated by humoral or
cellular elements or by an interaction of both.
2.2. Hypothalamo-pituitary-adrenal axis
The major goal of the immune system, namely, to
protect against the invasion and destruction of tissue by
pathogens, is conducted within an organism whose life
82 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
Fig. 1. Innervation of immune system organs by the autonomic nervous
system.
support mechanisms are governed by the neuroendocrine
system and the ANS. These systems work together to
modulate immune activation as well as provide checks and
balances to contain the potentially destructive properties of
this activation. In order to understand the influence of
glucocorticoids, it is necessary to briefly review the basic
plan of the hypothalamic-pituitary-adrenal axis and some
of its interactions with the autonomic nervous system.
The hypothalamo-pituitary-adrenal ŽHPA. axis consists
of three components: the hypothalamus, particularly the
paraventricular nucleus ŽPVN., the anterior pituitary, and
the adrenal cortex Žsee Fig. 1.. Within these three tissues
are specialized cells that synthesize and secrete three
molecules that act as the primary signals of the HPA axis:
corticotropin releasing hormone ŽCRH., adrenocorti-
cotropin hormone ŽACTH., and glucocorticoid hormone
Žcortisol in humans and corticosterone in rats.. CRH is
produced by a subset of parvocellular neurons in the PVN
of the hypothalamus and CRH is probably an obligatory
and primary stimulus for ACTH production and secretion;
norepinephrine, angiotensin II, vasopressin and oxytocin
can potentiate these effects w9x. ACTH is produced by a
subset of anterior pituitary cells Žcorticotrophs. and is the
primary stimulus for glucocorticoid synthesis and secretion
from cells in the adrenal cortex. The glucocorticoids are
the final end product of activation of the HPA axis and are
the primary effector molecule of this neurohormonal cir-
cuit. Glucocorticoid receptors are found in both the PVN
and the anterior pituitary and glucocorticoids have a well
documented negative feedback effect on CRH and ACTH
synthesis and secretion at the levels of the pituitary, hypo-
thalamus, and limbic brain w244x. Thus, the HPA axis is a
closed-loop circuit.
When considering the effects of glucocorticoid hor-
mones on the immune system it is important to bear in
mind that glucocorticoid levels vary considerably through-
out the day. There are two modes of glucocorticoid secre-
tion. One mode is phasic, as in the stress response, whereas
the second mode is cyclic, as in the circadian rhythm; both
modes operate more or less independently, in that the
timing of the circadian rhythm is not affected by the stress
response except under extreme conditions Žfor a review,
see w296x..
Whether linked to stress or to the circadian rhythm,
glucocorticoids are part of a complex signalling system
between the external environment, the brain and the rest of
the body. This system links waking and sleeping states,
food seeking and cognitive behaviors with a variety of
physiological processes, such as metabolism of food and
movement of cells of the immune system throughout the
body w176,276,296,347,363x. Events are often stressful be-
cause they violate expectations w276,345x and the stress-in-
duced secretion of glucocorticoids is regulated, at least in
part, through the activity of the hippocampal formation
w222x. The hippocampus is a brain structure that is associ-
ated with aspects of learning and memory, especially those
aspects related to spatial memory and ‘working’ memory
w129x. The hippocampus plays an important role in the
‘cognitive’ aspects of the response to stress and operates
together with the amygdala, hypothalamus, periaqueductal
gray matter and other brain structures to regulate the
behavior of the animal under conditions that, by reason of
many internal and external factors, may be perceived as
stressful w270,294x.
Although the focus of this review will be upon the
modulation of the immune system by glucocorticoids, at
times consideration will also be given to possible immuno-
modulation by another adrenal steroid, aldosterone. Aldos-
terone is the principal mineralocorticoid in humans and
rodents and plays an important role in regulating sodium
and water retention. Regulation of aldosterone secretion is
largely under the control of the hormone, angiotensin II.
Aldosterone becomes relevant to our discussion because
the receptor, for aldosterone Žreferred to as the Type-I
adrenal steroid receptor or mineralocorticoid receptor; see
subsection 4.1. has an equally high affinity for the endoge-
nous glucocorticoids, cortisol or corticosterone. Whether
aldosterone or corticosteroids are the primary endogenous
hormone for these Type-I receptors appears to often de-
pend on the location of these receptors and the local
presence of an enzyme Ž11-b-hydroxysteroid dehydroge-
nase. that preferentially metabolizes corticosteroids. Thus,
in the kidney, where 11-b-hydroxysteroid dehydrogenase
is localized, aldosterone is the principal hormone for Type-I
adrenal steroid receptors w151x. Overall the circulating
levels of corticosteronercortisol are much higher than
aldosterone, so that in many regions of the brain, where
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
11-b-steroid dehydrogenase does not appear to be a factor,
corticosteroids appear to be the principal hormone for
Type-I receptors. It still remains to be determined whether
aldosterone has an important immunomodulatory role that
is mediated by Type-I receptors located in immune cells.
2.3. Autonomic nerÕous system–hypothalamo-pituitary-
adrenal interactions that affect immune system function
The ANS is divided into three components: the
parasympathetic, with cranial and sacral connections; the
sympathetic, with central nervous connections in the tho-
racic and lumbar segments of the spinal cord; and the
enteric nervous system w67x. Sensory afferents are impor-
tant sources of input to the ANS w132x.
Experimental work now indicates that a direct and
significant influence on immune development and function
is mediated through ANS innervation of the major lym-
phoid tissues involved in the production, education, and
function of the lymphocyte as well as through independent
and interdependent endocrine system hormones secreted
by the cells of the pituitary, adrenals, gonads, thyroid and
the immune tissues. Virtually every organ of the immune
system receives innervation from the ANS Žsee Fig. 2; for
reviews, see w45,67,228,406x.. The distribution and density
of nerves and their neurotransmitters varies greatly within
lymphoid tissues. This is also true for the expression of the
corresponding receptors on the surfaces of the immuno-
cytes w190,292,358x.
Many neurotransmitters and their receptors of the sym-
pathetic, parasympathetic, enteric and sensory nervous sys-
tems have been detected and mapped within the tissues
Fig. 2. Schematic diagram of the dual regulation of immune system
activity by the HPA axis and the autonomic nervous system.
83
Table 1
Glucocorticoid effects on immune cells
Increases:
Insulin receptors human lymphocytes
ß-Adrenergic receptors human lymphocytes
High-affinity VIP receptors human monocytes
Ig E stimulation by Il-4 human lymphocytes
IgG, IgA, IgM human lymphocytes
IgA levels in serum intact rats
Decreases:
Il-1, 2, 6, 8, 12 production various species
TNF, granulocyte colony stimulation factor various species
MHC-1 or MHC-2 or both
Fc receptor on granulocytes human granulocytes
Eicosanoid biosynthesis macrophages
Proenkephalin mRNA rat B cells
Low to moderate concentrations of adrenal steroids enhance the humoral
immune response by increasing helper T cell production of IL-4 w105x and
enhancing IL-4 actions to increase immunoglobulin E production by B
lymphocytes w144,475x. Adrenal steroids also increase ß-adrenergic recep-
tor density on lymphocytes w91,423x and this effect may be able to
potentiate the stimulation via ß-adrenergic receptors of the differentiation
of precursor B lymphocytes in to IgM-secreting cells w382x. However, not
all inductive effects of glucocorticoids result in immunoenhancement. For
example, adrenal steroids also increase receptors for VIP on immune cells
w469x and VIP inhibits T cell mitogenesis w346x. Glucocorticoids also
induce insulin receptors on lymphocytes, but the functional implications
of this induction are not clear at present w133x. At the same time, adrenal
steroids have many effects which reduce immune responses w98x. These
include inhibiting the production and responses of lymphocytes to the
cytokines, IL-1 and IL-2 w328x and suppressing the expression of
proenkephalin mRNA w32x. Not only is T cell differentiation suppressed
by glucocorticoids, but also early events in B cell activation are sup-
pressed w60x as well as monocyte to macrophage differentiation w369x. The
inhibition of the MHC I expression by glucocorticoids appears to be
another of the repressive function of the glucocorticoid receptor w73x.
and organs of the immune system. They include but
are not limited to: substance P, VIP, somatostatin,
acetylcholine, CGRP, endorphins, enkephalins, NPY,
CCK, norepinephrine, dopamine. For reviews, see
w43,45,69,288,292,383,406,471x.
The neurotransmitters and hormones of the ANS and its
various components are released as a result of stimuli from
an immune response and they act upon receptors that are
developmentally regulated or expressed in response to
another chemical signal, such as a circulating hormone.
Because we focus on adrenal steroids in this review, only a
few examples will be cited where interactions occur be-
tween the immune system, the adrenal steroids and various
components of the ANS Žsee Table 1.. For other aspects of
this topic, the reader should consult recent reviews
w43,288,383x.
Glucocorticoids modulate the expression of parasympa-
thetic Že.g., muscarinic acetylcholine receptors. on mature
thymocytes w292x and adrenergic receptors on the mono-
cytesrmacrophages w358x. Furthermore, the activation of
acetylcholineesterase has been shown to be influenced by
glucocorticoids w16,68x. Glucocorticoids also modulate
sympathetic activity, which in turn has powerful effects on
84 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
immune function ŽFig. 2.. Studies now show that the
activation of release of catecholamines from nerve termi-
nals is negatively regulated or ‘contained’ by glucocorti-
coids w266x.Furthermore, the suppression of cellular im-
mune responses commonly caused by stress, of which
activation of the sympathetic nervous system and release
of glucocorticoids is a major component, was reversed by
pharmacological blockade of adrenergic receptors w95,96x.
Diminution of stress effects by sympathetic blockade was
greater when splenic lymphocytes were examined as op-
posed to peripheral blood lymphocytes, indicating that the
sympathetic nervous system has a greater role in modulat-
ing stress-induced effects on splenic than on peripheral
blood lymphocytes w265x. Thus compartmentation of the
role of autonomic and hormonal modulators of immune
function is an important aspect of neuro–endocrine–im-
mune interactions.
Finally, the enteric nervous system is an important and
often neglected aspect of the immune defense mechanism.
The ability of the gut to clear pathogenic invasion has
recently been shown to be compromised by stress hor-
mones such as the glucocorticoids w58,406x. This might
well take place through either a primary direct interaction
or through modulation the release of neuropeptides of the
intestinal tract.
3. Behavioral influences on hypothalamo-pituitary-
adrenal activity and immune function
3.1. BehaÕior and indiÕidual differences
Before considering the role of glucocorticoids in detail,
we shall summarize what is known about behavioral influ-
ences on immune function and consider the influence of
stressful events on immunity. It is important to discuss
stress effects on immunity as an initial reference point
because stressful experience are not simply mimicked by
elevating stress hormone levels, as will be discussed later
in this review. Indeed, many stressors activate autonomic
and HPA activity as well as behavioral responses, but
whether this activation or these responses occur and to
what extent they take place depends on individual traits
w459x. Whether a situation is perceived to be stressful
depends on prior experience and developmental history,
which combine to sensitize or protect the individual from
particular challenges w375x. The responses to the challenge
are also individualized: e.g., behaviors chosen may involve
aggression or submission or may result in humiliation or
adaptation. These responses, in turn, may further increase
or decrease vulnerability to other challenges. Furthermore,
there will be individual differences in the extent of en-
docrine and autonomic responses that accompany these
different types of response. Internal neurochemical features
have been associated with different responses; e.g., low
brain serotonin is linked in animals to aggression and in
humans to hostility, substance abuse, impulsive behavior
and suicide w19,64,324x.
Long-term aspects of stress responsiveness are also
highly individualized and are related, in part, to environ-
mental influences on genetic make-up. In animal studies,
diabetes-prone rats respond to repeated stresses in adult-
hood with an accelerated expression of the diabetes w245x.
In humans, juvenile Type-I diabetes incidence is increased
in children exposed between ages 5 and 9 to threatened or
actual losses within the family w185x. The stressful early
life experience of separation from the mother in a non-hu-
man primate model promoted a behavioral disturbance
later in life, namely, alcohol abuse w225x.
These early experiences can also lead to long lasting
effects on the HPA axis w89,301x. For example, studies on
early maternal separation in rats indicate that short periods
of separation from the mother accompanied by gentle
handling lead to facilitated termination of the glucocorti-
coid response to stress in adulthood w301x. These changes
are in part secondary to increased expression of hippocam-
pal glucocorticoid receptors which are believed to subserve
feedback inhibition on hypothalamic neurons which re-
lease CRF. In contrast, more prolonged separation experi-
ences Ž3 h. lead to impaired shut-off of the stress response
in adulthood and the resultant increased glucocorticoid
response to stress is believed to exacerbate neuronal de-
generation in later life. Early immune activation can also
lead to increased glucocorticoid responsiveness and im-
paired feedback inhibition in adult animals w301x. In in-
frahuman primates, adverse early experiences have been
reported to elevate cerebrospinal fluid levels of CRF later
in life w89x.
Stress may have other consequences for disease: e.g.,
increasing susceptibility to infection by and expression of
the common cold w85x as well as of other viral infections
w249,250x; and promoting asthmatic attacks w323x and my-
ocardial infarction w325x. Stress elevates both glucocorti-
coid and insulin levels and the combination of these
hormones leads to hyperlipidemia and increases
artherosclerosis w64x. In rats, repeated stress increases ab-
dominal fat deposition w369x; and, in rhesus monkeys,
social stress increases atherosclerosis in dominant animals
fed a moderately atherogenic diet w293x.
All of these examples serve to illustrate that stressful
events have both acute and chronic consequences for the
expression of disease. The long-term effects of stress
responsiveness influence the expression of inherited pre-
dispositions and no doubt help to account for the large
influence of the environment in a variety of disease states,
including Type-I diabetes, depression, schizophrenia,
asthma and Alzheimer’s disease, in which the genetic
component results in only 40–60% concordances among
identical twin pairs w21,103,323,354x.
As far as the immune system is concerned, it has been
recognized for some time that stress increases susceptibil-
ity to, as well as severity of, disease processes in which
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 85

Table 2
Stress-associated changes in the immune system of humans
Representative effects Stressor Reference
Increased number of neutrophils spaceflight w252x
Decreased lymphoproliferation following mitogen stimulation bereavement w22x
Reduced lymphocyte cytotoxicity life change w178x
Increased interferon production noise, sleep deprivation w350x
Decreased interferon production medical school final examination w165x
Decreased phagocytosis life change w87x
Decreased natural killer cell activity medical school final examination w251x
Decreased helper and suppressor T cell percentages and helper-to-suppressor ratio medical school final examination w163x
Decreased salivary IgA academic striving w224x
Increased antibody titers to herpes viruses medical school final examination w248x

immune defense mechanisms are prominently involved,
such as responses to infectious pathogens w86,249x as well
as the development and progression of cancers w18,150x.
The data supporting the influence of stress on such disease
processes derives from both epidemiologicalrobserva-
tional studies Že.g., w27,163,390x. and experimental studies
Že.g., w85,400x.. Also, the conclusion that stress affects
disease processes is indicated not only by studies in which
stressful conditions have been found to exacerbate disease
processes, but also recently by data suggesting that the
removal or diminution of stress can decrease the normal
progression of disease w139,418x.
3.2. Stress effects on immune processes and mechanisms
3.2.1. Description of effects of stress
Stressful conditions affect immune defense mecha-
nisms. Tables 2 and 3 list a variety of immune responses
that have been measured in humans and experimental
animals after exposure to stressful conditions. These tables
list the particular immune-related response found to be
changed by exposure to a stressor and the initial reference
showing that the particular immune parameter is affected.
3.2.1.1. Suppression of immune responses. As indicated in
Tables 2 and 3, the most-reported consequence of stress is
suppression of immune responses. An illustration of the
effects of exposure to a stressful environment on a variety
of cellular immune responses is shown in Fig. 3 w446x. The
stressor in this case was exposure of rats to a tail-shock
environment for 19 h. Lymphocytes taken from either the
blood or spleen of animals that underwent this stressful
experience Ži.e., ‘stress’ subjects. showed, in comparison
to responses of lymphocytes taken from animals that had
simply remained in their home-cage prior to being killed
Ži.e., ‘home-cage’ subjects., marked decreases in vitro in:
Ža. responsivity Žproliferation. to the mitogen phytohemag-
glutinin-P ŽPHA.; Žb. NK cell activity; Žc. production of
IL-2 and interferon when stimulated by mitogen; and Žd.
expression of IL-2 receptors. The measurements shown in
Fig. 3 were made using the same number of lymphocytes
from each animal and consequently do not reflect differ-
ences in the total number of lymphocytes present in blood
or spleen of stressed compared to non-stressed animals.
However, it should be noted that the stress schedule uti-
lized in these studies reduces the number of lymphocytes
in both blood w242x and spleen w112x of rats, causing a
stress-induced lymphopenia w393x.

Table 3
Stress-associated changes in the immune system of mice and rats
Representative effects Stressor Reference
Involution of the thymus restraint Žrat. w393x
Leukopenia noise Žrat. w314x
Decreased lymphocyte proliferation to mitogenic stimulation noise Žmouse. w314x
Decreased lymphocyte proliferation to antigenic stimulation isolation Žrat. w228x
Increased lymphocyte proliferation by antigenic stimulation crowding Žrat. w228x
Reduced lymphocyte cytotoxicity noise Žmouse. w314x
Decreased interferon production avoidance learning task-shock Žmouse. w225x
Decreased macrophage cytotoxic activity restraint Žmouse. w341x
Decreased natural killer cell activity uncontrollable shock Žrat. w397x
Diminished delayed-type hypersensitivity ambient heat Žmouse. w353x
Delayed allograft rejection avoidance learning task-shock Žmouse. w472x
Decreased antibody response to challenge overcrowding, uncontrollable shock Žrat. w412x
Decreased IL-2 production uncontrollable shock Žrat. w464x
Decreased expression of IL-2 receptors uncontrollable shock Žrat. w464x
 86
B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133

Fig. 3. In vitro responses of lymphocytes harvested from stressed and non-stressed animals. ‘Stress’ animals were exposed to intermittent tail shocks over a period of 19 h whereas non-stressed animals
Ž‘home cage’. were simply remained in the home-cage. Measures were ŽA. response to mitogen, ŽB. natural killer ŽNK. cell activity ŽC., interferon and interleukin-2 ŽIL-2. production and ŽD. IL-2 receptor
expression. Means and standard errors are shown. For all measures, an equivalent number of lymphocytes from each animal was tested. Response to mitogen was measured by the incorporation of
w 3 Hxthymidine into phytohemagglutinin ŽPHA.-stimulated cells. NK cell activity was measured by release of radioactively labeled Cr from target ŽYAC. cells w366x. IL-2 was assessed in the supernatant of
PHA-stimulated lymphocytes by measuring incorporation of w 3 Hxthymidine into IL-2-dependent cytotoxic T lymphocyte line cells w160x. Interferon production was assessed by determining the dilution of
supernatant of stimulated lymphocytes that would protect mouse L cells from vesicular stomatitis virus w143x. IL-2 receptor expression was assessed by determining the amount of IL-2 binding to lymphocytes
at 08C w264x.
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
The effects shown in Fig. 3 were produced by acute
exposure to a stressor, although the stress session used to
generate these data was of moderately long duration. How-
ever, suppression of cellular immune responses is found
when the acute stressful condition is brief in duration and
also when stress has been induced by learned fear. As
examples, Rabin, Lysle, Cunnick and colleagues w96,284x
found that when animals were exposed to a foot-shock
session lasting 64 minutes, there was reduced NK cell
activity and lymphocyte responsivity to the mitogens PHA
and concanavalin A ŽConA. compared to splenic cells
extracted from animals that were handled but not shocked.
These investigators also showed that brief exposure to a
fear-producing environment decreased the same cellular
immune responses as were altered by exposure to shock
w281,282x. When animals were simply placed for 40’ into a
shock chamber where they had received footshocks 6 days
earlier, their splenic lymphocytes showed decreased mito-
genic responses to PHA, ConA and the B-cell mitogen
lipopolysaccharide ŽLPS., in relation to two other groups:
Ža. ‘baseline’ animals that had never been handled but
were simply taken from their home cage and killed; and
Žb. animals that had been given foot-shock 6 days earlier
but then were not re-exposed to the shock chamber prior to
being killed.
The immune responses described above were all mea-
sured in vitro. However, as indicated in Table 2, suppres-
sion of immune responses by acute stressors is also seen
when responses are examined in vivo. For example, inves-
tigators have found that stressful conditions decrease anti-
body titers in response to antigenic challenge in vivo
w145,269,322x. Also, under certain conditions, delayed-type
hypersensitivity measured in vivo has been found to be
suppressed by stress w341,353x and by exogenous doses of
synthetic and natural glucocorticoids w113x. Finally, tumor
development and cancer, especially in response to stimuli
that are subject to immune surveillance Že.g., viruses., are
increased in animals exposed to acute stressors, which is
indicative of decreased immune surveillance of the tumor-
producing agent w233,408x. These topics are discussed in
detail later in this review.
3.2.1.2. Enhancement of immune responses. (i) Chronic
stress. The effects described above occur from acute expo-
sure to a stressor. In experimental studies with animals,
chronic Žlong-term or repeated. exposure to stressors is
often found not to cause suppression of immune parame-
ters. A seminal finding in this regard was reported by
Monjan and Collector w314x when these investigators first
reported that exposure of animals to stressful events could
suppress cellular immune responses. Using loud sound as
the stressful stimulus, Monjan and Collector found that
mitogen-induced lymphocyte proliferation, as well as cyto-
toxicity, were enhanced after animals had been exposed to
the stressor for 4–6 weeks. The results, shown in Fig. 4,
illustrate how initial suppression of a cellular immune
87
Fig. 4. Mitogenic response of splenic lymphocytes from animals exposed
to a loud sound Žapproximately 100 dB for 5 s every minute during a 1-
or 3-h period around midnight. for different numbers of days. For
mitogenesis Žresponse to lipopolysaccharide ŽLPS. and concanavalin A
ŽconA., incorporation of w 3 Hxthymidine in vitro was measured. Data from
Monjan and Collector w314x.
response was replaced by enhancement after the animals
have been exposed to the stressor for a prolonged period of
time. Other investigators have reported similar findings
w216,226x.
Additional support for the ability of chronic Žor long-
term. exposure to a stressor to diminish initial inhibitory
effects can also be gleaned from studies of tumor develop-
ment, in which long-term exposure to a stressor produces
enhanced resistance to the development of the tumor
w367,368,408x. Although such evidence shows that chronic
exposure to a stressor can diminish stress-induced suppres-
sion of cellular immune responses, it is important to
exercise caution in assuming that this will be the case in
any particular instance. First, the number of studies that
have demonstrated enhancement of immune responses as
the result of chronic stress are, at present, few in number.
Second, the precise amount andror type of exposure to
stress that is needed for development of enhanced immune
responses requires further elucidation. For example,
Aarstad et al. w1x reported that exposure of rats to a brief
swim in cold water produced suppression of NK cell
activity when animals had been repeatedly subjected to
this stressor for 8 days. Ghoneum et al. w158x reported that
8 days of individual housing Ž‘isolation’. had the same
effect. Thus, the precise parameters of chronic Žor re-
peated. exposure to a stressor that will reverse suppression
of immune responses produced by acute stressors remain
to be clarified.
88 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
(ii) Acute stress. In addition to chronic stress, certain
acute stressful conditions may also enhance immune re-
sponses, although these conditions not yet been studied in
any detail. Such findings have been described in a small
number of reports w37,93,464x. Recently, Dhabhar and
McEwen w114x have shown that acute, moderate stress
induces a significant enhancement in an antigen-specific,
cell-mediated immune response in vivo.
The acute manipulations that have enhanced immune
responses appear to be relatively mild in intensity in
comparison to the sorts of manipulations used in conven-
tional ‘stress’ experiments. One of these studies w464x
assessed the impact of a range of environmental stimuli on
cellular immune parameters, examining conditions known
to suppress immune responses as well as much milder
conditions than are generally studied. The conditions ex-
amined in that study, in descending order of stressor
intensity, were: Ža. exposure to a tail shock regimen previ-
ously shown to profoundly depress immune responses Ži.e.,
19 h in the tail shock environment.; Žb. a briefer exposure
to the tail shock condition Ž2 h.; Žc. gentle handling Ž1-min
duration. daily for 4 days, exposure to a novel environ-
ment for 10 min and three mild, brief shocks; and Žd. only
handling daily for 4 days. One hour after each of these
treatments was completed, lymphocytes were harvested
and various responses measured in vitro. All responses
examined ŽNK cell activity, response to PHA stimulation
and IL-2 production. exhibited a similar pattern of effects.
In comparison to the responses of lymphocytes obtained
from animals that were not treated at all Ži.e., ‘home-cage’
subjects., simply handling animals caused significantly
decreased responses; exposure to the novel environment
that included three brief, mild shocks in addition to the
handling caused significantly increased responses; and ex-
posing the rats to long-duration Ž19 h. tail-shock condition
produced, as expected, profoundly decreased responses.
The 2-h shock condition did not differ from the non-stressed
condition.
Fig. 5 shows all of the individual observations made for
two measures, NK activity Ž100:1 ratio of effector to target
cells is shown. and IL-2 production. As illustrated in this
figure, the study was carried out by conducting four repli-
cations of the basic experiment, each consisting of two
animals under each of the five conditions described above.
In each replication, it can be seen that the relationship
between intensity of the stressful condition and the im-
mune measure was the same. That is, as the stressfulness
of the condition to which the animal was exposed in-
creased Ži.e., progressing from ‘handling’ to ‘19 hours’.,
suppression of in vitro immune responses was observed
initially, followed by enhancement, followed by marked
suppression. Even in the one replication where the groups
did not show precisely the same effects as seen in the other
replications Ži.e., replication 1, where ‘three shocks’ was
not elevated relative to non-stressed and ‘2 h’ was not
similar to non-stressed., the basic relationship between
stress intensity and magnitude of cellular immune response
was the same: first decreased, then increased and then
decreased again. In summary, very mild stimulation Že.g.,
handling. and intense stimulation Že.g., 19 h of tail shock.
both produced suppression of cellular immune responses,
while stimulation of moderate intensity Že.g., usually three
shocks in the study described. produced enhancement of
these immune responses. These data indicate that, whereas
a variety of stressful conditions apparently cause suppres-
sion of cellular immune responses, there exists a ‘zone’ in
which stressful conditions of moderate intensity can en-
hance these responses.
3.2.2. Mechanisms mediating effects of stress on immune
responses
Stress-induced changes in immune responses are pro-
duced via physiological mechanisms involving the activa-
tion of the ANS and the HPA axis. Historically, the
physiological response most commonly associated with
stress-induced alterations of immune responses has been
the elevation of adrenal steroids. Early in his investiga-
tions, Selye w393x observed that adrenal steroids were
capable of affecting immune-related organs Žthymus, lymph
nodes. and, when elevated by stressful conditions, that
glucocorticoids produced lymphopenia. Subsequent studies
demonstrated and it is now well known, that steroids can
have immunosuppressive effects w83,140,159x. Also, dis-
ease processes, such as viral infection, are promoted by
pharmacological doses of glucocorticoids w298x. The asso-
ciation between stress, elevated glucocorticoids and sup-
pression of immune function seemed so clear that a decade
ago it was assumed that stress-induced elevation of circu-
lating steroids accounted for stress-related immunosuppres-
sion w368x.
However, reliance on steroid elevation as the sole medi-
ator of stress-induced suppression of immune responses is
overly simplistic. Although suppression of immune-related
responses of both T and B lymphocytes are readily pro-
duced in vitro w130,146,152x, stressful events that elevate
circulating adrenal steroids in vivo do not necessarily
cause suppressed immune responses of T andror B cells
w146,340,341x. Moreover, stress-related changes in certain
immune parameters have been found to correlate poorly
with elevations of adrenal hormones w215,318x. Further,
continued elevation of steroids by chronic stress does not
result in continuing effects on cellular immune responses
w256x.
These data indicate that the link between steroid eleva-
tion and immune changes is less clear than was initially
thought. Perhaps the most convincing demonstration that
stress-induced changes in immune-related responses can
occur independently of adrenal steroids was presented by
Keller et al. w243x, who showed that stress-induced sup-
pression of the mitogenic response of blood lymphocytes
in vitro occurred in animals whose adrenal glands had
been surgically removed. Weiss et al. w463x, using the same
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 89

Fig. 5. Natural killer ŽNK. cell activity ŽA. and interleukin-2 ŽIL-2. production ŽB. by splenic lymphocytes from animals that were exposed to a range of
increasingly stressful conditions. Five different conditions were studied: undisturbed Žno stress. in home-cage Žhome-cage., handled Ž1 min. daily for 4
days Žhandled., handled and exposed briefly Ž10 min. to a novel environment in which three mild foot shocks were given Žthree shock., 2 h in an enclosure
where tail shock was given Ž2 h. and 19 h in the tail shock condition Ž19 h.. Conditions are placed on the abscissa in order of increasing stressfulness Žleft
to right.. Values for all animals in this study are shown above; the study consisted of four replications Ž1–4. with each replication composed of two
subjects in each of the five different conditions. Values in ŽA. are the percentage of 51Cr released from radiolabeled YAC-1 target cells Žratio of effector to
target cells shown is 100:1.; in ŽB. interleukin-2 ŽIL-2. production was measured by the ability of IL-2-containing supernatant from mitogen-stimulated
splenic lymphocytes to support growth of cytotoxic T lymphocyte line ŽCTLL. cells; shown are counts per min of w 3 Hxthymidine incorporated into the
CTLL cells.
90 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
stressor as employed by Keller and colleagues showed that
a variety of cellular immune functions ŽNK cell activity,
response to mitogen, IL-2 and interferon production. of
splenic lymphocytes were markedly suppressed by expo-
sure to the stressor regardless of whether animals were
normal Žintact., adrenalectomized, sham-operated or
adrenalectomized with a corticosteroid pellet implant that
produced a constant, low-level of circulating cortico-
sterone.
But while it is now clear that effects of stress on
immune responses and on diseases that are affected by
immune processes, cannot be explained simply by the
influence of stressful events on circulating glucocorticoids,
recent data indicate that stress-induced changes in circulat-
ing steroids do influence a number of immune responses
and that such changes consequently may play a significant
role in disease processes. First, there are certain changes in
immune parameters, particularly responses of blood lym-
phocytes, that are highly correlated with stress-induced
changes in circulating glucocorticoids. For example, Lysle
et al. w282x observed that suppression of mitogen-induced
proliferation of blood lymphocytes correlated well with the
steroid levels resulting from various environmental manip-
ulations. Also, it has been reported recently that mitogene-
sis in vitro of splenic lymphocytes is enhanced by brief
exposure to low levels of corticosterone via interaction
with the mineralocorticoid receptors w468x. This could
relate to the mechanism underlying the elevation in cellu-
lar immune parameters produced by brief, mild stress as
reported by Weiss et al. w464x. Second, investigators have
found that, by using adrenalectomy or chemical blockade
of glucocorticoid receptors, certain effects of stressful
conditions do appear to be mediated through action of
adrenal hormones. Okimura et al. w340x found that circulat-
ing IgG generated in response to a T-independent antigen
was enhanced in mice by restraint and this effect was
blocked by adrenalectomy. Chemical blockade of b-adren-
ergic receptors had no effect on this response, thereby
indicating that this effect of stress was occurring through
adrenal steroids removed by the adrenalectomy.
One immune parameter that seems to be particularly
influenced by adrenal steroids is trafficking of lympho-
cytes among various compartments in the body, which will
be discussed in detail elsewhere in this review ŽSection 4..
Suffice it to say here, that the early study of Keller et al.
w243x, which showed that PHA-induced proliferation of
blood lymphocytes could be suppressed by stress in the
absence of the adrenal gland, also found that the number of
lymphocytes circulating in blood was dependent on the
plasma–steroid level seen in each of the conditions, thereby
indicating that reduction in circulating lymphocytes that is
observed in stressful conditions is the result of stress-in-
duced elevation of corticosteroid levels. Dobbs et al. w119x
has recently found that long-term restraint stress blocked
the accumulation of cells in popliteal lymphocytes in
animals inoculated in the foot pads with herpes simplex
virus; this stress-induced reduction in cell influx into re-
gionally infected lymph nodes was completely blocked by
the glucocorticoid receptor antagonist RU486, thereby in-
dicating that the stress-induced elevation of glucocorti-
coids was responsible for preventing the influx of cells
into draining lymph nodes. Fleshner and colleagues also
recently reported using RU486 to block stress-induced
suppression of antibody ŽIgG. production to the antigen
KLH w289,290x. Since development of IgG to KLH deliv-
ered intraperitoneally may depend on lymphocyte migra-
tion to the mesenteric lymph nodes w145x, these findings
may parallel those of Dobbs et al. w119x wherein stress
appears to produce effects by preventing appropriate lym-
phocyte migration via elevated stimulation of glucocorti-
coid receptors. Lymphocyte migration is dealt with below
in subsection 4.2.3.
Although not the focus of the review, other mechanisms
that have been found to mediate effects of stressful condi-
tions on immune responses are worth mentioning here.
First, stress-induced activation of the sympathetic nervous
system influences immune-related functions. In stress-in-
duced suppression of immune responses produced by acute
exposure to stressors, activation of sympathetic nerves has
been shown to mediate certain aspects of this effect,
particularly influencing lymphocytes in sympathetically
innervated organs Že.g., spleen. w15,96x. Second, opioid
peptides have been shown to mediate stress-induced sup-
pression of NK cell activity w397xand do so by influencing
opiate receptors in the brain w457x. Third, also at the level
of the brain, intracranially administered corticotrophin re-
leasing factor ŽCRF. has been implicated in the pathways
by which stress reduces immune responses w215,217x, as
has interleukin-1 administration into the brain w434x, which
appears to act via stimulation of CRF w384,435x. Further-
more, peptides, as yet uncharacterized, that are released
into circulation as a result of stress also have been found to
influence cellular immune responses w313,463x.
3.2.3. Summary of stress and stress mediators
Stressors generally have been found to increase disease
and tumor growth and to suppress a variety of immune-re-
lated responses. However, there are instances in which
repeatedly applied stress has been reported to attenuate the
suppression of immune responses that is produced by acute
stressors; and even acute stressors of mildrmoderate inten-
sity, which may act to stimulate or excite the animal, have
been found to enhance certain immune responses. How-
ever, studies of this kind are not numerous and discrepant
results have been reported w283,473x which await clarifica-
tion. These seemingly diverse and contradictory results
regarding the effects of stress are perhaps not too surpris-
ing, when one realizes that stress-induced changes in im-
mune function are mediated by multiple mechanisms and
mediators functioning simultaneously and often in opposi-
tion to one another. This includes the adrenal steroids with
their multiplicity of actions on immune cells and functions.
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 91

Nevertheless, studies of stress effects on immune func-

tion have not systematically tried to separate effects of
acute stress from those of chronic stress. In particular, it
will be useful to look at implications for immune function
of the recently introduced notion of ‘allostatic load’, the
wear and tear produced on the body by the body’s own
coping with environmental demand by maintaining a dy-
namic equilibrium called allostasis as opposed to the older
term, homeostasis w297x. Allostatic load implies that medi-
ators of the autonomic and HPA axis are chronically
elevated or fail to shut off promptly after a stressful
experience or are repeatedly elevated by repeated chal-
lenges to the organism. The same situation may apply to
cytokine production.
In what follows, we will consider the impact of adrenal
steroids on the immune system under normal circum-
stances and during viral infections, tumor metastasis and
inflammatory and autoimmune disorders.

4. Mechanisms of action of adrenal steroids on the

immune system
Whereas there are multiple regulators of immune func-
tion, it is the actions of adrenal steroids that are among the
most powerful and pervasive, as well as somewhat misun-
derstood. In general, many of the adrenal steroid effects
involve inhibition of immune function, but in quite a few
instances glucocorticoids may actually enhance both the
availability and activity of specific immune cells Žsee
Table 1.. We now consider the receptors for adrenal
steroids and their actions on immune cells and processes.
4.1. Adrenal steroid receptors in immune cells and tissues
4.1.1. Adrenal steroid receptor types and distribution
The majority of the immunologic effects of adrenal
steroid hormones are mediated through hormonal activa-
tion of intracellular receptors w183,391x. Therefore, exami-
nation of the expression and activation of adrenal steroid
receptors in immune cells and tissues has been an impor-
tant component of understanding the mechanisms of adrenal
steroid effects on the immune response.
There are two receptor subtypes for adrenal steroids:
Type-I receptors, which are also referred to as mineralo-
corticoid receptors and Type-II receptors, which are com-
monly known as glucocorticoid receptors w11,30,365x.
Type-I receptors have a higher affinity for naturally occur-
ring adrenal steroids Žsuch as cortisol in humans and
corticosterone in rodents. and are therefore occupied and
activated at lower concentrations of endogenous hormone
w11,30,365,417x than Type-II receptors which have a high
affinity for the synthetic glucocorticoid, dexamethasone,
but a 6–10 fold lower affinity for corticosterone w11,417x.
Both Type-I and Type-II receptors are expressed in the
immune system. However, there is considerable hetero-
Fig. 6. Distribution of type-I and type-II receptor binding in immune
tissues, pituitary and hippocampus. Mean"S.E.M. for Bma x values of
3–5 separate determinations on tissue from adrenalectomized rats. For
pituitary, single point assays were performed at a saturating radioligand
concentration Ž ns 4.. Reprinted from w311x, by permission.
geneity among immune cells and tissues in the expression
of adrenal steroid receptor subtypes. This no doubt reflects
the heterogeneity of cell types and their differential expres-
sion of receptors, although it has not been possible thus far
to quantify adrenal steroid receptor levels in individual cell
types Žsee Fig. 6.. For example, consistent with the well-
known sensitivity of the thymus to elevations in adrenal
steroids, this tissue expresses one of the highest amounts
of Type-II receptors in the body w311x. Whereas the thy-
mus does not express Type-I receptors, the spleen ex-
presses both Type-I and -II receptor subtypes w311x. De-
spite the fact that Type-I receptor expression is low in the
spleen, Type-I receptors appear to play a tonic inhibitory
role in Type-II receptor expression in this tissue w309x. At
the cellular level, we have found peripheral blood mono-
cytes to exhibit some of the highest levels of Type-II
receptors, however, there is considerable variability in
receptor expression between cells in a given sample of
monocytes. In contrast, neutrophils exhibit a relatively low
number of Type-II receptors and minimal variability in
receptor expression between cells. Lymphocytes fall in
between monocytes and neutrophils and are characterized
by a moderate level of Type-II receptor expression and
variability between cells w310x. Type-I receptors have been
identified in isolated lymphocytes using whole cell binding
assays; however, no differences between lymphocyte sub-
sets ŽB cells versus T cells. have been described w10x.
92 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133

Since a number of in vivo and in vitro studies have

found a good correlation between adrenal steroid receptor
e x p r e s s io n a n d s e n s itiv ity to h o r m o n e
w52,59,63,214,312,326,411,449,461x, heterogeneity in re-
ceptor expression among immune cells and tissues sug-
gests that different immune compartments andror cell
types may have different responses and sensitivity to
adrenal steroid hormones. Our recent studies examining
the effects of selective Type-I and -II adrenal steroid
receptor agonists on immune cell distribution in the periph-
eral blood and spleen support this notion that receptor
expression is related to glucocorticoid sensitivity. More-
over, the two adrenal steroid receptor subtypes appear to
mediate different effects on the immune system in several
instances. For example, in a recent study examining the
effects of selective adrenal steroid receptor agonists on
immune cell distribution, the Type-I receptor agonist, al-
dosterone, was found to significantly reduce the number of
circulating neutrophils and NK cells, whereas significant
increases in neutrophil number and percentage and NK cell
percentage were seen following administration of the
Type-II receptor agonist, RU28362 w308x.

4.1.2. ActiÕation of adrenal steroid receptors by endoge-

nous and exogenous steroids
In order to influence cellular function, glucocorticoids
must enter the cell and bind to and activate intracellular
receptors. Therefore, aside from receptor expression, a
second major avenue of investigation regarding adrenal
steroid receptors in the immune system has been the
determination of which variables are important in the
activation of these receptors by hormone in immune tis-
sues. Prior to the discussion of the results, it is important
Fig. 8. Diurnal comparison of available type-I and type-II receptor levels,
to briefly describe the biochemical features of adrenal
respectively, in no-stress condition or after acute stress Ž1 h restraint. in
steroid receptors which allow the estimation of adrenal rats killed at the beginning of their light Žmorning, AM. or dark Ževening,
steroid receptor activation. Prevailing models of adrenal PM. period. Receptor binding was measured in the thymus Ž ns18., in
steroid action propose that once bound by hormone, the spleen Ž ns12., in peripheral blood mononuclear cells ŽPBMC; ns9.
adrenal steroid receptor-hormone complex undergoes a and in lymph nodes Ž ns6.. ) Significantly different from the AM no
stress group Ž P - 0.05 by Tukey test.; q Significantly different from PM
conformational change called activation w326,453x. The
no stress group Ž P - 0.05 by Student’s t-test.. Reprinted from w414x, by
permission.

activated form of the receptor has a high affinity for DNA

Fig. 7. As available type-II receptor binding sites are occupied by
dexamethasone in spleen in vivo, Concanavalin A-stimulated T cell
proliferation is inhibited in proportion. Reprinted from w312x, by permis-
sion.
and is found almost exclusively in the cell nucleus where it
is responsible for directly regulating gene transcription.
A key distinguishing feature of adrenal steroid receptors
is that the activated form of the receptor is not capable of
rebinding steroid and thus cannot participate in an in vitro
cytosolic exchange Žor binding. assay where the amount of
receptor is determined by the relative amount of radiola-
belled steroid bound w73,75,305,417x. Therefore, only un-
activated adrenal steroid receptors can be measured in a
binding assay and the amount of adrenal steroid receptor
activation that occurs in vivo can be estimated by the
relative disappearance of measurable receptors
w302,311,312,417x. The greater the receptor activation, the
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
fewer the measurable receptors. This ability to estimate
adrenal steroid receptor activation provides a truly unique
opportunity to predict steroid action in target tissues that is
not available for other steroid hormones, small molecule
neurotransmitters or peptides. Aside from the studies de-
scribed below, assessments of receptor activation have
been used to investigate the sites of steroid action in a
variety of experimental paradigms w307,416x. In addition,
evidence of adrenal steroid receptor activation highly cor-
relates Ž r s 0.89. with the inhibitory effects of adrenal
steroids on immune function w312x Žsee Fig. 7.. It should
be noted that data in Fig. 7 is from the administration of
dexamethasone, a steroid that bypasses the protective
mechanism afforded tissues like the spleen by cortics-
terone binding globulin Žsee below..
One of the most important findings which has devel-
oped from studies on adrenal steroid receptor activation in
the immune system is that following a given hormone
exposure there is a marked heterogeneity in the degree of
receptor activation among immune tissues which depends
on a variety of conditions including the time of day, the
length of hormone exposure and the type of hormone,
synthetic vs. naturally occurring w414x. For example, in a
study examining the influence of time of day on receptor
activation following restraint stress in rats, acute stress-in-
duced elevations in corticosterone were found to activate
Type-II adrenal steroid receptors in the thymus and lymph
nodes regardless of the time of day w414x. In contrast, no
matter when stress was applied, Type-II receptors in the
spleen were not activated. Interestingly, activation of
Type-II receptors in peripheral blood immune cells only
occurred if stress was applied during the rat’s dark or
active period Žsee Fig. 8.. As opposed to endogenous
glucocorticoids, in animals treated with the synthetic glu-
cocorticoid dexamethasone, which does not bind cortico-
steroid binding globulin Žsee below., all immune tissues
exhibited equal and substantial Type-II receptor activation
depending on the dose w414x.
These findings of differential access of corticosteroids
to their receptors in different immune compartments are
consistent with functional studies which have examined
the neuroendocrine mechanisms of the effects of stress on
the immune system. As previously noted, a number of
studies have demonstrated stress effects on immune func-
tion which are independent of glucocorticoids. For exam-
ple, in keeping with the relatively reduced access of gluco-
corticoids to their receptors in the spleen following stress,
several studies examining 19 h of tail shock have failed to
find stress-induced changes in mitogen-induced splenocyte
proliferation. Moreover, in studies which have demon-
strated stress-induced decreases in splenocyte function, the
mechanisms appear to be independent of glucocorticoids
and have involved both catecholaminergic and opioid path-
ways w462x. In contrast to the spleen, as mentioned earlier,
the effects of stress on peripheral blood lymphocytes often
appear to be glucocorticoid dependent. In fact, in one
93
recent study in rats, peripheral blood lymphocyte responses
were reduced by stress only in the rats’ dark period; a
result which may be directly related to the findings that
receptor activation in peripheral blood lymphocytes by
stress-induced elevations in corticosterone occur at this
time w473x. Diurnal alterations in the distribution of periph-
eral blood immune cells which parallel changes in circulat-
ing levels of corticosterone are also consistent with the
increased access of glucocorticoids to this immune com-
partment w376x.
4.1.3. Role of corticosteroid binding globulin (CBG)
An important regulator of the amount of circulating
corticosteroid that is biologically available to adrenal
steroid receptors in the various immune tissues is the
liver-derived plasma protein, corticosteroid binding globu-
lin ŽCBG. w372x. It is important to emphasize that dexa-
methasone and many other synthetic corticosteroids are not
bound by CBG. The low affinity of CBG for synthetic
glucocorticoids is a major factor that contributes to the
high in vivo potency of these synthetic steroids relative to
cortisol or corticosterone, since, under basal conditions
over 90% of circulating corticosteroid is bound to CBG
w407x. Only the unbound or free form of corticosteroids are
able to diffuse into cells and interact with their intra-
cellular receptors. It has been found that the level and
distribution of CBG appears to play a key role in regulat-
ing the access of endogenous hormones to adrenal steroid
receptors and thus receptor activation. Because synthetic
glucocorticoids such as dexamethasone are not bound by
CBG, these steroids are very potent in gaining access to
immune compartments such as the spleen w312x.
Since CBG does not cross the blood brain barrier, there
is a much higher level of CBG associated with peripheral
tissues w115x, especially the pituitary, than is associated
with brain w108x. This exclusion of CBG from the intersti-
tial spaces in brain tissue may account for the finding that
for a given circulating level of corticosterone there is a
greater proportion of adrenal steroid receptor activation in
brain tissue than in peripheral tissue w307,311,314x. A
heterogeneous distribution of CBG associated with periph-
eral tissues may further contribute to the heterogeneity
seen in adrenal steroid receptor activation between im-
mune tissues for a given hormone condition w117x.
Changes in CBG production may importantly modulate
corticosteroid action. Several factors are known to substan-
tially alter CBG levels. Estrogens upregulate CBG produc-
tion which, is evident during pregnancy and may serve to
largely offset the elevated cortisol production present at
this time w62x. Glucocorticoids Žboth endogenous and syn-
thetic. have an inhibitory effect on CBG production and
recently it has been found that this inhibition can occur
under conditions of chronic stress, with consequent effects
on adrenal steroid receptor activation. In a recent study on
rats exposed to chronic social stress, stressed animals
exhibited a significant decrease in plasma CBG which was
94 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
highly correlated with available corticosteroid receptors in
the spleen; the lower the CBG, the lower the amount of
available receptors, suggesting that there was greater acti-
vation of receptors in stressed animals w415x. Since all
animals in this study had similar total corticosterone levels
at the time of being killed, the greater corticosteroid
receptor activation in the spleens of rats with low CBG
levels probably reflected the greater free corticosterone
levels present in those animals. Therefore, prolonged expo-
sure to stress-induced elevations in glucocorticoids can
decrease CBG and thereby facilitate hormone access to
immune tissues including the spleen.
CBG levels vary between different strains of rats w115x.
These strain differences in CBG levels appear to modify
the impact of strain differences in stress-induced cortico-
sterone levels on receptor activation in immune tissues
w117x. For example, Fischer 344 rats exhibit a much greater
HPA axis response to various stressors than do Sprague–
Dawley or Lewis rats w115,427–429x, but interestingly,
Fischer 344 rats also have significantly higher plasma
CBG levels. Consequently, although there is a much greater
stress-induced activation of corticosteroid receptors in brain
tissue of Fischer 344 rats compared to these other two
strains, in the immune tissues the levels of corticosteroid
receptor activation are very similar between Fischer 344
and Sprague–Dawley rats. Lewis rats exhibit the lowest
levels of receptor activation, probably because of a rela-
tively low corticosterone response to stress w117x.
CBG located in interstitial tissue may also provide a
local supply of corticosteroids which can be utilized in
evolving immune responses. For example, neutrophils have
been found to release serine proteases which are capable of
cleaving the CBG molecule at a specific site resulting in
the local release of bound hormone w339x. Elevated temper-
ature, such as at a site of active inflammation, might also
influence local levels of free cortisol w409x.
4.1.4. Cytokine interactions with adrenal steroid receptors
Recently, studies in our laboratories and others have
indicated that the immune system may be able to alter
glucocorticoid–immune system interactions by directly in-
fluencing adrenal steroid receptor expression andror func-
tion through the local release of cytokines
w204,205,430,431x. One of the first studies to examine the
direct effect of cytokines on adrenal steroid receptor ex-
pression reported a significant decrease in cytosolic gluco-
corticoid receptors in the liver of adrenalectomized mice 6
h after endotoxin treatment w430x. The cytokine responsible
for these receptor changes appears to have been IL-1, since
similar cytosolic receptor decreases were found in the liver
of adrenalectomized and adrenal intact mice 4 h following
administration of this cytokine w204x. In addition, both
IL-1a and -b were found to significantly decrease the
binding maximum Ž Bmax . of adrenal steroid receptors in
the Reuber hepatoma cell line after 4 h of in vitro exposure
w205x. In a related study, a crude fraction of IL-6rIFN-g2
and recombinant IL-6 reduced glucocorticoid receptor
binding in rat hepatoma cells w431x. Our own preliminary
data also suggest that cytokines are capable of altering
Type-II adrenal steroid receptor expression andror func-
tion. Injection of the IFN inducer, poly I:C, not only
stimulated the secretion of adrenal steroids but also led to
a significant decrease in spleen cytosolic Type-II receptors,
even in the absence of hormone Žie in adrenalectomized
animals. w306x.
Consistent with the studies that have found decreased
receptor binding following treatment with IL-1 and endo-
toxin, several investigators have demonstrated that these
same treatments can decrease the ability of dexamethasone
to influence cellular function including the induction of
phosphoenolpyruvate kinase ŽPEPCK. activity w202,203x.
In contrast to IL-1 and endotoxin, IL-4 has been shown to
augment the inhibiting effect of dexamethasone on the in
vitro synthesis of IL-1 and TNF after LPS stimulation
w191x.
Although the majority of studies have shown decreased
Type-II Žglucocorticoid. receptor binding following cy-
tokine treatment, three studies Žall using the whole cell
binding technique. have found increased receptor binding
following treatment with the cytokines, IFN-g and IFN-b
and the cytokine-inducer, endotoxin w379,380,402x. The
descrepances in results from the previously described stud-
ies showing decreased receptor binding may be secondary
to the manner in which receptors were measured or may
represent the fact that specific cytokines may have specific
effects on receptor expression and function which depend
on the treatment conditions and the cell type studied.
4.1.5. Summary
There are two major factors which confer selectivity of
action on systemically released glucocorticoids thereby
determining the effects of endogenous glucocorticoids on
specific immune cells and their functions. One factor
involves the relative cellular expression of Type-I andror
Type-II adrenal steroid receptor subtypes and the other
involves whether or not endogenous glucocorticoids are
able to access and activate the receptors within a given
cell. This latter process is especially dependent on the
microenvironment of the immune compartment within
which the cell is located. Specific factors which deserve
special consideration in this regard are the local concentra-
tion of free hormone Žas determined by the circulating
concentration of corticosteroid in relation to the concentra-
tion of its binding protein, CBG. and the relative local
presence of cytokines. Since synthetic glucocorticoids like
dexamethasone do not bind to CBG and therefore have
equal access to all immune compartments, the subtle speci-
ficities afforded endogenous hormones are lost. Considera-
tion of the multiple factors which regulate steroid action
on target tissues and cells is critical for interpreting the
effects of hormones on the immune system and serves to
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
provide a framework for understanding how during stress
or disease glucocorticoids can influence some immune
processes but not others, thereby achieving marked selec-
tivity and specificity of action.
4.2. Immunologic mechanisms
4.2.1. Introduction
As discussed above, the immune system is highly regu-
lated and integrated and in some ways overlapping and
repetitious. This is, of course, a necessary evolutionary
development to inhibit self-reactivity but allow for effec-
tive defense against a constantly changing environmental
assault. Given these facts, it seems likely that there would
be numerous points at which the manifestations of an
immune response could be controlled. Adrenal steroids act
on many processes in the immune system and many of
their effects involve inhibition of immune function. How-
ever, in a number of instances glucocorticoids may actu-
ally enhance both the availability and function of specific
immune cells Žsummarized in Table 1.. In this section,
current data available on the effects of adrenal steroids on
the immune system will be reviewed and the significant
regulatory capacity of these hormones on both the inductor
and effector phases of non-adaptive and adaptive immunity
will be described.
4.2.2. DeÕelopment and maturation (apoptosis)
Adrenal steroids are capable of affecting both cellular
development in the bone marrow as well as cellular matu-
ration, especially T cells in the thymus. For example,
adrenal steroids have been shown to shift the balance of
macrophage progenitors to granulocyte progenitors by sup-
pressing the development of macrophage forming colonies
by 75% to 90% while enhancing the formation of granulo-
cyte colonies by 50% to 100% w401x. In addition, cortisol
has been found to block PMA-induced differentiation of
the human monocytic cell line, U-937, from a monocyte to
macrophage phenotype w28x.
One of the most intriguing aspects of the effects of
adrenal steroids on immune cells is their ability to induce
programmed cell death or apoptosis w82x. Like the majority
of the effects of adrenal steroids previously discussed,
glucocorticoid-induced cell death is believed to be caused
by glucocorticoid stimulation of the synthesis of a specific
geneŽs. that in turn regulates a death pathway. Coincuba-
tion of cells with glucocorticoids and inhibitors of protein
or mRNA synthesis can significantly delay cell death w82x.
Yet the stimulation of apoptosis appears to be linked to the
repressive activity of the glucocorticoid receptor, since a
mutant of the glucocorticoid receptor that is deficient in
gene activation is as effective as the wild type in carrying
out repression w196x. Cells undergoing programmed cell
death are characterized by cell shrinkage, nuclear collapse,
condensation of chromatin and DNA fragmentation w82x.
The ladder of bands Žin multiples of 180–200 base pairs.
95
observed following gel electophoresis of DNA from apop-
totic cells is diagnostic of this process.
Programmed cell death is believed to be one of the
mechanisms by which T cell selection occurs in the thy-
mus. Upon entering the thymus, T cells undergo the
process of positive and negative selection which leads to
MHC restriction and self-tolerance w2,351x. The majority
of immature T cells in the thymus do not survive the
selection process and thus do not enter the peripheral
circulation. There are several reasons to think that endoge-
nous adrenal steroids may induce programmed cell death
during T cell selection. Immature cells, particularly thymo-
cytes Žwhich are CD4 q CD8 q double positive., are
exquisitely sensitive to glucocorticoid-induced cell death
Žbeing lysed at physiologic concentrations of glucocorti-
coids., whereas mature T cells Žwhich are either CD4 q or
CD8 q . are relatively glucocorticoid resistant w82,84x. In
addition, the thymus, which is made up primarily of
immature T cells, has one of the highest glucocorticoid
receptor content of any tissue in the body w311x. The
thymus is also well known for its sensitivity to adrenal
steroids. It is known to undergo marked involution follow-
ing stress or exogenous administration of glucorticoids and
a marked expansion following adrenalectomy w82x. Fur-
thermore, plasma corticosteroid concentrations, consistent
with those found at the diurnal peak of this hormone are
capable of inducing cell death in thymocytes in vitro w460x.
Finally, transgenic mice with an impairment in glucocorti-
coid receptor expression show a marked increase in CD4
q CD8 q double positive cells in the peripheral circula-
tion w317x.
Yet the cell death induced by glucocorticoids is very
much interdependent on activation of immune cells by
other regulators. For example, the activation-induced cell
death in immature thymocytes that is stimulated by anti-
TCR antibodies in vivo can be attenuated by concurrent
administration of the glucocorticoid receptor antagonist,
RU38486, suggesting that there are shared or convergent
signal transduction cascades in these two pathways to
apoptosis w232x. However, the concept of convergent path-
ways between activation-induced cell death and glucocorti-
coid-induced cell death is complex, and, depending on the
models studied, these pathways can be mutually ant-
agonistic as opposed to complementary. For example, for
germinal center B cells, cross-linking of cell surface im-
munoglobulin will rescue them from apoptosis and this
rescue is blocked by glucocorticoids as well as by trans-
forming growth factor b w210x. Moreover, in human thy-
mocytes as well as pre-B leukemia cells and monocytes,
pertussis toxin blocks activation-induced apoptosis but it
fails to block glucocorticoid-induced cell death of thymo-
cytes or pre-B cells or IL-4-induced cell death of mono-
cytes w360x. Finally, in immature B cells, glucocorticoid-in-
duced apoptosis is inversely related to the expression of
Bcl-2, a gene that protects cells against programmed death
w304x.
96 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133

4.2.3. Adrenal steroids and immune cell trafficking

Adrenal steroids also play an important role in the
regulation of immune cell distribution or trafficking. In
order to launch an appropriate response to immune chal-
lenge, leukocytes have to be present in the right place and
at the right time. The appropriate distribution of immune
cells in different tissues in the body is crucial to immune
surveillance as well as effector functions of the immune
system. Interactions between adhesion molecules on leuko-
cytes and endothelial cells determine the location of leuko-
cytes in the body. The three major families of adhesion
molecules include the selectins, members of the immuno-
globulin supergene family such as CD56 and the integrins.
Adhesion molecules mediate three important steps Žrolling,
anchoring and extravasation. which are involved in captur-
ing leukocytes from the circulation. Adrenal steroid-in-
duced changes in the function andror expression of adhe-
sion molecules may mediate some of the observed effects
of adrenal steroids on leukocyte trafficking.
Adrenal steroids have profound effects on the distribu-
tionrtrafficking of leukocytes. These effects are observed
with pharmacological as well as physiological changes in
adrenal steroids w342x. It is important to note that while
pharmacological changes in glucocorticoids exert a potent
influence on the distribution of leukocytes in different
body compartments, in the case of the diurnal and stress-
induced changes observed in vivo, other mediators such as
the catecholamines, neuropeptides, sex hormones, AVP,
CRF and ACTH, may also exert an important influence
w347x.

4.2.3.1. Pharmacologic manipulations of adrenal steroids

and resulting changes in leukocyte distribution. Numerous
investigators have reported large changes in leukocyte
distribution induced by the administration of pharmaco-
logic doses of natural andror synthetic adrenal steroids in
humans as well as rodents w135,173x. These changes in-
volve a pronounced decrease in lymphocyte, monocyte,
and eosinophil numbers in the blood. This is accompanied
by a significant increase in numbers of neutrophils in the
blood. These changes in blood leukocyte numbers could be
the result of leukocyte redistribution to other immune Fig. 9. Corticosterone-induced changes in peripheral blood leukocytes. A
timecourse of changes in plasma cortiosterone Ž12A. and peripheral blood
compartments or of changes in leukocyte turnover. It has
WBC counts, lymphocyte number and neutropihl number Ž12B. are
been previously suggested there might be ‘steroid-re- shown. Corticosterone Ž5 mgrkg. was administered to previously
sistant’ and ‘steroid-sensitive’ species and that glucocorti- adrenalectomized animals via subcutaneous injection. Blood samples
coid-induced changes in blood leukocyte numbers repre- were collected repeatedly by the tail-clip method Ž ns 5. at each time
sent changes in leukocyte redistribution in ‘steroid-re- point Ž0, 0.5, 1, 2 and 4 h.. Plasma corticosterone was measured by RIA.
WBC counts were obtained on a Coulter counter. Lymphoycte and
sistant’ species Žhumans and guinea pig. and leukocyte
neutrophil numbers were obtained from smears of peripheral blood
lysis in ‘steroid-sensitive’ species Žmouse and rat. Žmodified Wright–Giemsa stain.. Statistically significant differences are
w134,135x. However, a large body of evidence indicates indicated: ) P - 0.05, ) ) P - 0.005, significantly different from pre-in-
that even in species previously labelled ‘steroid-sensitive’, jection baseline Ž0 h..
changes in adrenal steroids produce changes in leukocyte
distribution rather than an increase in leukocyte destruction
w8,81,194,315,316x. such as is shown for corticosterone administration to rats
Glucocorticoid administration to humans and animals ŽFig. 9.. The observed lymphopenia is transient and nor-
results in a rapid and profound lymphopenia in the blood, mal lymphocyte counts are observed 24 h after steroid
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 97

administration w136–138,456,479x. This lymphopenia in creased release of monocytes from the bone marrow w443x.
the blood is thought to involve the redistribution of leuko- Redistribution of monocytes from blood to other body
cytes to other body compartments Žespecially to the bone compartments has also been suggested as a possible mech-
m a rro w . in h u m a n s a s w e ll a s ro d e n ts anism w135x. Glucocorticoid administration produced a sig-
w81,134,137,138,194,316,456,479x. Although, in rodents, T nificant reduction in eosinophil and basophil numbers in
cells, B cells and NK cells and monocytes seem to be
affected by glucocorticoid treatment, in humans, T cells
seem to be selectively depleted w134,136,479x. In rats,
however, B cells, NK cells and monocytes seem to show a
greater susceptibility than T cells to glucocorticoid-in-
duced decreases in cell number in the blood
w31,111,194,308x.
Zatz w482x has reported that labelled lymphocytes from
untreated donor mice, survive normally when adoptively
transferred to corticosterone-treated recipients. However,
their accumulation in the spleen and lymph nodes is
decreased, whereas their accumulation in the bone marrow
is increased w482x. Spry w419x has reported that anesthesia
stress, as well as the infusion of ACTH and prednisolone
in rats, resulted in decreased numbers of labelled lympho-
cytes in the thoracic duct. Cessation of drug infusion
results in normal circulation of labelled lymphocytes. This
suggests that ACTH and prednisolone may cause the reten-
tion of circulating lymphocytes in different body compart-
ments, thus resulting in a decrease in lymphocyte numbers
in the thoracic duct and peripheral blood w419x. It has also
been reported that a single injection of ACTH or pred-
nisolone results in increased numbers of lymphocytes in
the bone marrow w92x. It is important to note that in all
these studies, a return to normal glucocorticoid levels was
followed by a return to normal lymphocyte circulation
patterns, further supporting glucocorticoid-induced redistri-
bution rather than glucocorticoid-induced cell death as a
mechanism for the observed changes.
Studies conducted by Dhabhar et al. w112,116,118x
demonstrate that corticosterone is an important mediator of
the stress-induced changes in leukocyte distribution in rats
and that these changes are mediated by the Type-II Žgluco-
corticoid. adrenal steroid receptor. Hormone replacement
studies conducted with specific Type-I and Type-II gluco-
corticoid agonists, revealed that injection Ž2 h. of cortico-
sterone Žwhich activates Type-I and Type-II adrenal steroid
receptors. or of RU 28362 the specific Type-II adrenal
steroid receptor agonist, reproduces most of the changes in
blood leukocyte distribution which are observed with stress.
On the other hand, acute injection of the Type-I adrenal
steroid receptor agonist, aldosterone, normalizes the Fig. 10. Plasma corticosterone response during 2 h restraint stress and
stress-induced increase in leukocyte numbers observed in subsequent return of hormone levels to baseline after cessation of the
stressor ŽFig. 4A.. Time course of stress-induced changes in WBC count
adrenalectomized animals w118x. and lymphocyte and neutrophil number in peripheral blood and recovery
With respect to other immune cell types, administration after cessation of stress ŽFig. 4B.. The experiment was conducted during
of glucocorticoids results in a significant monocytopenia in the light phase of the diurnal cycle. Total WBC counts were obtained on
the blood at 4–6 h after administration of the steroids with a Coulter counter and lymphocyte and neutrophil numbers were obtained
a return to basal levels by 24 h w134,442x. This monocy- from smears of peripheral blood Žmodified Wright–Giemsa stain.. The
percent change in leukocyte numbers after 120 min stress relative to
topenia is similar in kinetics and magnitude to glucocorti- baseline Ž0 min., is shown in Fig. 4B. Statistically significant differences
coid-induced lymphopenia w77,134,136,186,442x. One of are indicated: ) P - 0.05; ) ) P - 0.005, significantly different from 0 h
the mechanisms for the observed monocytopenia is de- baseline. P - 0.05, significantly different from 2 h stress timepoint.
98 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133

the blood which is thought to be the result of redistribution
of cells out of the blood and into the spleen w413x and other
compartments w125,126,245x. Interestingly, while glucocor-
ticoids induce a reduction in the number of immune cell
subpopulations in the blood, neutrophil numbers exhibit a
marked increase in response to treatment with glucocorti-
coids. The increase in blood neutrophil number induced by
adrenal steroids is thought to be the result of three pro-
cesses: increased egress of neutrophils from the bone
marrow, decreased egress of neutrophils from the blood
and an increase in the half-life of circulating neutrophils
w13,99,100x.
4.2.3.2. Stress-induced changes in adrenal steroids and
resulting changes in leukocyte distribution. The effects of
different stressors on blood leukocyte numbers have been
reported in conjunction with several studies describing
stress effects on various immune parameters in humans
w 1 3 1 ,1 6 5 ,3 3 2 ,4 2 0 x , m ic e w 3 6 8 x a n d r a ts
w111,116,223,242,243x. Stress-induced changes in leuko-
cyte numbers in the blood are similar to the changes
observed with pharmacological steroid treatment. While
pharmacologically induced changes in leukocyte distribu-
tion have been extensively investigated, changes in leuko-
cyte distribution induced by physiological manipulations
Ždiurnal and stress-induced changes in adrenal steroids.
need further investigation.
Studies conducted by Dhabhar et al. w116,118x have
shown a significant lymphopenia and monocytopenia, ac-
companied by a significant neutrophilia in rat peripheral
blood following a single session of restraint, a mild acute
stressor ŽFig. 10.. The observed lymphopenia was largely
accounted for by a relatively greater stress-induced de-
crease in B cells, monocytes and NK cells than T cells Žsee
Fig. 11.. Furthermore, kinetic studies have shown that the
stress-induced changes in blood leukocytes are rapid Žef-
fects observed within 30 min. and are rapidly reversible
Žrecovery begins within 1 h. upon cessation of the stressor
w116,118x. These changes are independent of time of day,
since similar changes are observed when animals are
stressed during either their active period Ždark cycle. or
their inactive period Žlight cycle. w111,112,116,118x. The
stress-induced changes in blood leukocytes are greatly
diminished in adrenalectomized animals w116,118,310x.
Hormone replacement studies in adrenalectomized animals
indicate that corticosterone is the major mediator of the
stress-induced changes w116,118,229,310x. Stress-induced
changes in leukocyte numbers in the blood are similar in
leukocyte subpopulation specificity to changes induced by
pharmacological steroid treatment. However, the magni-
tude of the stress induced changes is lower than that seen
with the pharmacological administration of steroids. Fur-
ther studies need to be conducted to investigate stress-in-
duced redistribution of leukocytes to other body compart-
ments.
4.2.3.3. Diurnal changes in adrenal steroids and resulting
changes in leukocyte distribution. It has been reported that
the diurnal peak in corticosterone levels coincides with a
diurnal trough in peripheral blood lymphocyte numbers

Fig. 11. Subpopulation specificity of stress-induced changes in peripheral blood leukocyte numbers and recovery after cessation of stress, during the light
phase of the diurnal cycle. Changes in numbers of T cells ŽFig. 5A., B cells ŽFig. 5B. and NK cells and monocytes ŽFig. 5C. in peripheral blood during a
2-h stress session and a 3-h recovery session are shown. The percent change in leukocyte numbers after 120 min stress relative to baseline Ž0 min., is
indicated for each subpopulation in each panel. Leukocyte subpopulations were measured using two-color flow cytometry with the following monoclonal
antibodies: cytotoxic ŽCTL.rsuppressor ŽTs. T cells ŽOX19 q , W3r25y ., Helper T cells ŽOX19q , W3r25q ., B cells ŽOX33q ., NK cells ŽOX19 y ,
OX8 q . and monocytes ŽOX19 y , W3r25q .. Statistically significant differences are indicated: ) P - 0.05; ) ) P - 0.005, significantly different from 0
h baseline. P - 0.05, significantly different from 2-h stress timepoint.
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 99

and that the diurnal trough in corticosterone levels coin-
cides with a diurnal peak in peripheral blood lymphocyte
numbers. This has been shown in humans w3,23,441,444x,
non-human primates w320x, mice w241x and rats w181x.
Furthermore, Thompson, Mcmahon and Nugent w444x have
reported circadian variations in peripheral blood lympho-
cytes in healthy adults and have shown that patients with
adrenal insufficiency lack this circadian pattern. These data
also indicate that administration of cortisol to these pa-
tients causes a dose-dependent lowering of lymphocyte
levels in the blood w444x. In addition, Kawate et al. w241x
have demonstrated in mice, that adrenalectomy abolishes
the circadian rhythm in lymphocyte numbers and that a
single injection of prednisolone produces a reversible de-
pression of circulating lymphocyte number soon after drug
administration w241x.
We have observed a significant lymphopenia accompa-
nied by a neutrophilia in peripheral blood in conjuction
with the diurnal corticosterone rise in the rat w111x Žsee
Fig. 12.. The observed changes in blood leukocytes are
similar in magnitude and in leukocyte subpopulation speci-
ficity to the stress-induced changes reported by us Žsee
above.. However, in the case of the diurnal changes, a
significant reduction in helper T cell numbers is observed
in addition to the reduction in B cells, NK cells, and
monocytes which is similar to that seen with the stress-in-
duced changes w111x.
Diurnal changes in leukocyte distribution may mediate
some of the observed circadian changes in immune respon-
sivity. Kaplan et al. w199x have reported striking circadian
variations in area of induration at the intradermal site of
IL-2 injection in patients with lepromatous leprosy w235x.
Other researchers have reported circadian variation in re-
sistance to endotoxins w187x, rejection of allogeneic mouse
skin grafts w188x, rejection of rat and human kidney allo-
grafts w257x and human lymphocyte responses to phyto-
hemagglutinin w441x.
4.2.3.4. Effects of glucocorticoids on leukocyte distribution
in the context of an ongoing immune reaction. In addition
to their effects on leukocyte distribution during normal
Žuninfected or uninflammed conditions., glucocorticoids
severely inhibit the infiltration of neutrophils, eosinophils
and monocytesrmacrophages into sites of inflammation.
This is thought to be a critical mechanism for glucocorti-
coid-induced suppression of inflammation w61,127,285x.
Norris et al. w338x studied the effects of epicutaneous
administration of varying concentrations of methylpred-
nisolone in human volunteers and found a significant
inhibition of monocyte and neutrophil chemotaxis. Further,

Fig. 12. Comparison of rat peripheral blood leukocyte numbers measured during the inactive period and the active period Ž n s 6 for each group.. Total
white blood cell ŽWBC. counts were obtained on a Coulter Counter and total lymphocyte and neutrophil numbers were obtained from Wright–Giemsa
stained smears of peripheral blood. Leukocyte subpopulations were measured using two-color flow cytometry with the following panel of antibodies: total
T cells ŽOX19 q ., cytotoxic ŽCTL.rsuppressor ŽTs. T cells ŽOX19 q , OX8 q ., Helper T cells ŽOX19 q , W3r25q ., B cells ŽOX33q ., NK cells
ŽOX19y , OX8 q . and monocytes ŽOX19 y , W3r25q .. Percent reduction in leukocyte numbers in the active period compared to the inactive period is
shown below the abscissa. Statistically significant differences are shown: ) P - 0.005, t-test; P - 0.05, t-test.
100 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
monocyte chemotaxis was inhibited for a longer period
than neutrophil chemotaxis w338x. It has also been reported
that glucocorticoid administration inhibited T cell migra-
tion into the bronchial mucosa of asthmatic patients w331x.
Chung et al. w76x have reported that glucocorticoids inhibit
the localization of sensitized effector cells at sites of active
inflammation w76x. However, Cox and Ford w92x have
suggested that prior antigenic challenge can completely
override the prednisolone-induced inhibition of lympho-
cyte migration into certain lymph nodes w92x. The studies
discussed above deal with pharmacological steroid manip-
ulations, further studies need to be conducted to investigate
diurnal and stress-induced changes in leukocyte trafficking
during an ongoing immune reaction.
4.2.3.5. Possible mechanisms inÕolÕed in glucocorticoid-
induced changes in leukocyte distribution. Pharmacologi-
cal as well as physiological changes in glucocorticoids
result in a decrease in lymphocyte, monocyte and
eosinophil numbers and an increase in neutrophil numbers
in the blood. A large body of evidence indicates that these
changes are the result of changes in leukocyte distribution
between various body compartments and are not the result
of leukocyte death. It may be hypothesized that glucocorti-
coid-induced changes in cell surface adhesion molecules
on leukocytes andror endothelial cells, may cause the
observed changes in leukocyte distribution. Changes in cell
surface adhesiveness may result in retention of some
leukocyte subpopulations, andror an extrusion of other
leukocyte subpopulations from specific body compart-
ments. Unlike the active recruitment of leukocytes by
chemotactic factors seen during an active immune re-
sponse, glucocorticoid-induced changes in leukocyte distri-
bution may be the result of a passive process. Leukocytes
may be transported by blood flow through different body
compartments in a random manner with specific subpopu-
lations being retained in those compartments in which they
find appropriate ligands.
Support for this hypothesis comes from several studies.
It has been shown that infusion of prednisolone into rats
results in several changes in the distribution of adoptively
transferred labelled lymphocytes w92x: these changes were
not the result of prednisolone-induced leukocyte death.
The most profound effect of prednisolone was to cause the
retention of recirculating lymphocytes within the bone
marrow, spleen and some lymph nodes. Prednisolone treat-
ment inhibited entry of lymphocytes into other lymph
nodes. Further, lymphocytes of prednisolone-treated ani-
mals took longer to cross high endothelial venules in
lymph nodes. The effects of prednisolone on lymphocyte
migration into lymph nodes were completely abrogated by
previous antigenic stimulation. Finally, prednisolone treat-
ment increased the rate of lymphocyte entry across sinu-
soidal epithelium and into the bone marrow. It has been
suggested that glucocorticoid-induced changes in leuko-
cyte distribution are mediated by glucocorticoid-induced
changes in endothelial cell adhesion properties w76x. Beer
and Center w31x have demonstrated that hydrocortisone
sodium succinate ŽHCS. inhibits the migration of human
as well as rat lymphocytes measured in an in vitro migra-
tion assay w31x. They show in the same study, that rat B
lymphocytes are more sensitive to glucocorticoid-induced
inhibition than rat T lymphocytes. Eguchi et al. w128x have
shown that IFN-g and dexamethasone inhibit adhesion of
T cells to endothelial cells and synovial cells.
Studies on glucocorticoid effects on cell adhesion
molecules also lend support for the hypothesis proposed
above. Cronstein et al. w94x have shown that the synthetic
glucocorticoid, dexamethasone, markedly inhibits the
LPS-induced increase in expression of endothelial-leuko-
cyte adhesion molecule 1 ŽE-selectin. and intercellular
adhesion molecule 1 ŽICAM-1. w94x. However, Kaiser et
al. w234x have failed to observe any effects of the glucocor-
ticoid Budesonide on adhesion or on the expression of
E-selectin, ICAM-1 or vascular cell adhesion molecule 1
ŽVCAM-1. in cultured human umbilical vein endothelial
cells w234x. It may be mentioned here that cytokines like
IFN-g w478x, IL-2, IL-4 w434x, IL-8 w373x IL1, IFN-arb
and TNF-arb w219x have potent effects on leukocyte-en-
dothelial cell adhesion. Thus, glucocorticoids may indi-
rectly influence leukocyte-endothelial cell adhesion inter-
actions, since glucocorticoids have been shown to affect
the cytokine w105,328x and lipocortin Žarachidonic acid
derivatives. w206x secretion patterns of leukocytes. Further
investigation of the effects of glucocorticoids on changes
in expressionractivity of cell surface adhesion molecules
and on leukocyte-endothelial cell adhesion is necessary.
4.2.3.6. Glucocorticoid modulation of immune cell distri-
bution between body compartments. Based on our findings
as well as those of others, we suggest that glucocorticoids
play an important role in regulating the distribution of
leukocytes in the body under physiologically relevant con-
ditions. Such regulation could be achieved by modulation
of immune cell trafficking or by modulation of immune
cell turnover Žproduction andror destruction.. Leukocyte
redistributionrtrafficking as opposed to altered turnover
seems to be a more plausible explanation for the observed
circadian and stress-induced reductions in leukocyte num-
bers in the peripheral blood. For example, it is unlikely
that 40–50% of the circulating immune cells of an animal
would be destroyed daily at the beginning of the active
cycle, a time when maximal immune preparedness is re-
quired, since this is the time when immune challenges are
most likely to occur via the gastro-intestinal tract Žas the
result of ingesting microorganisms or toxins with food. or
via wounding in an encounter with a predator. Similarly, a
40–60% loss of circulating leukocytes in response to a
mild, acute stressor, which could result from an encounter
with a predator, does not seem to be adaptive, since such
encounters often result in wounding.
Thus, neural and endocrine factors released during stress
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
may signal specific leukocytes to exit the peripheral blood
and enter other immune compartments, Žlymph nodes,
Peyers patches, bone marrow, lung, skin, mucosa, spleen,
and other tissues.. It is possible that some leukocytes,
migrate to certain compartments in order to be protected
from potential deleterious effects of stress. Alternatively,
leukocytes may migrate to immune compartments which
serve as ‘battle stations’ where leukocytes are likely to
encounter antigens, pathogens, or other activated immune
cells. In either case, stress-induced redistribution of im-
mune cells may have significant consequences for the
ability of the immune system to perform its surveillance
and effector functions. We hypothesize that an important
function of endocrine mediators released under conditions
of acute stress may be to ensure that appropriate leuko-
cytes are present in the right place and at the right time, to
respond to an immune challenge which might be initiated
by the stress-inducing agent Že.g. attack by a predator,
invasion by a pathogen, etc... Thus, endocrine mediators
released during stress may serve to enhance immune pre-
paredness for potential Žor ongoing. immune challenge.
4.2.3.7. In ÕiÕo consequences of changes in leukocyte
distribution. The results described above suggest that the
circadian and stress-induced changes in leukocyte distribu-
tion may serve to increase immune surveillance and that
such changes may enhance an immune response directed
against an immunologic challenge administered to a com-
partment that was relatively enriched in leukocytes as a
result of the stress-induced leukocyte redistribution. We
hypothesized that the skin, which is the major defence
barrier of the body, may be one compartment to which
leukocytes migrate during stress and where such a stress-
induced enhancement of immune function may be ob-
served w113,114x.
Experiments were designed to test this hypothesis using
a model for an important class of immune reactions, which
are known as delayed type hypersensitivity ŽDTH. reac-
tions. This class of immune responses mediates important
beneficial Žresistance to bacterial and viral infections and
tumors. as well as harmful Žallergies, poison ivy, arthritis
and other autoimmune diseases. aspects of immune func-
tion w193,262,303,438,439,452x. Experiments were con-
ducted to examine the effects of stress on the DTH re-
sponse. The results showed that moderate stress adminis-
tered immediately before the administration of an antigenic
challenge, induced a significant enhancement of the ensu-
ing DTH response w114x. The DTH response of stressed
animals occurred at a faster rate, attained a higher peak
and remained significantly higher than that of controls for
over 6 days following challenge. Moreover, histological
examination of the skin of unstressed and stressed animals
showed that as hypothesized, the skin was also a target
compartment for the stress-induced redistribution of blood
leukocytes w114x. Stressed animals showed significantly
higher numbers of leukocytes in the skin both before and
101
after, antigenic challenge. This suggested that a stress-in-
duced redistribution of leukocytes to the skin Žand draining
lymph nodes. may be one of the factors mediating the
observed stress-induced enhancement of immune function
w114x.
4.2.3.8. Summary. Adrenal steroid secretion during the
diurnal rhythm and following stressful experiences causes
a redistribution of immune cells from the blood into
various tissues and organs, such as bone marrow, spleen
and lymph nodes.
These effects are of varying magnitude and even direc-
tion for different immune cell types and there appear to be
different roles for Type-I and Type-II receptors. It is
important to recognize that although peripheral blood im-
mune cells represent a small portion of total body leuko-
cytes, the blood is an important compartment serving as a
conduit by which leukocytes travel between different im-
mune tissues. Furthermore, human blood is the only easily
accessible immune compartment and provides the substrate
for numerous experimental and diagnostic measures which
often involve monitoring changes in immune cell numbers.
The changes in blood leukocyte numbers described in our
animal model may provide important information about
the kinetics and hormone dependency of leukocyte redistri-
bution in the body. Moreover, these changes in leukocyte
distribution may serve an important functional role when it
comes to immune system challenges such as inflamma-
tions, viral infections and tumors and initial evidence in
this direction has been obtained in studies of the DTH
reaction. Future research should be directed towards eluci-
dating the mechanisms whereby adrenal steroids and other
mediators such as catecholamines affect cellular adhesion
andror retention by various tissues and organs. It will also
be very important to determine what effect these changes
in leukocyte trafficking have on the surveillance and effec-
tor functions of the immune system.
4.2.4. Natural immunity
We have noted above and in Table 1 that adrenal
steroids have both positive and negative effects on immune
function. In doing this they produce effects on a variety of
target cells and processes and affect such diverse cellular
processess as expression of cell surface receptors and
production of cytokines.
Adrenal steroids have been shown to influence the
production Žsee below., distribution Žsee above. and func-
tion of phagocytic cells Žneutrophils and macrophages.
w155,173,327x. While many of these effects are the result
of indirect actions of adrenal steroids on the release of
soluble mediators Žincluding chemoattractants. from other
cell types, there also appears to be direct effects of adrenal
steroids on phagocytic function. For example, a 3-day
course of glucocorticoid administration inhibited the abil-
ity of mononuclear phagocytes to kill Staphylococcus au-
reus in the majority of patients examined w370x. Moreover,
102 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
culture of purified human macrophages with relatively low
concentrations of dexamethasone has been shown to su-
press elimination of bacteria and fungi w395x. Interestingly,
the macrophage-activating factor, IFN-g, was capable of
attenuating these inhibitory effects of glucocorticoids on
phagocytosis w395x, thereby possibly explaining why in
vitro inhibition of phagocytosis by adrenal steroids is more
marked than in vivo inhibition, where factors such as
IFN-g are available w184x. As for neutrophils, the direct
effects of adrenal steroids on neutrophil function is less
clear. While some early studies demonstrated inhibitory
effects of high doses of adrenal steroids on neutrophil
responses, a more recent study using doses of hormone
sufficient to saturate the majority of neutrophil glucocorti-
coid receptors and allowing sufficient time for steroid-in-
duced protein synthesis failed to find any effect of dexa-
methasone on a variety of neutrophil functions including
degranulation, chemotaxis, binding to vascular endothe-
lium and formation of leukotriene B 4 w389x. These findings
are consistent with recent studies in our laboratories which
indicate that neutrophils exhibit low levels of Type-II
adrenal steroid receptors. In addition, the findings empha-
size that many of the effects of adrenal steroids on neu-
trophils Žand maybe phagocytic cells in general. are largely
mediated indirectly through the effects of adrenal steroids
on other cell types and their release of cytokines and other
inflammatory mediators.
Although high doses of adrenal steroids have been
shown to inhibit the level of complement proteins in the
blood of laboratory animals, there is little evidence to
support a similar effect in humans w78x. Nevertheless,
based on studies using human umbilical vein endothelial
cells, it is possible that local effects of adrenal steroids on
the expression of complement proteins may modulate the
functioning of the complement system w102x.
4.2.5. Antigen presentation — induction
In addition to affecting the ability of immune cells to
infiltrate the site of antigenic challenge, adrenal steroids
can interfere with the response to antigen by altering the
effectiveness of antigen presentation w207,263x. The induc-
tion of a T cell response depends on the ability and
effectiveness of MHC molecules to bind and present anti-
gen and adrenal steroids have been shown to downregulate
Class II major histocompatibility ŽMHC. antigens on
macrophages and reduce interferon ŽIFN.-induced in-
creases in Class II MHC expression in mice w273x. Of
significance to the role of endogenous adrenal steroids in
immune regulation is the exquisite sensitivity of antigen
specific responses to inhibition by glucocorticoids both in
vitro and in vivo. For example, T lymphocyte proliferation
in response to the antigens streptokinase-streptodornase
and tetanus toxoid is much more supressed by in vivo
administration of glucocorticoids than T cell responses to
mitogen w136x. Moreover, the autologous mixed lympho-
cyte reaction, in which non-T cells stimulate the prolifera-
tion of autologous T lymphocytes, is profoundly supressed
by glucocorticoids in vitro at concentrations that are read-
ily achieved in vivo w186x. Nevertheless, the relevance of
these adrenal steroid effects to endogenous immune
surveillance Žantigen presentation. and autoimmunity re-
mains to be determined.
4.2.6. Cytokine elaboration
One of the most well-established and important effects
of adrenal steroids on the immune system is adrenal
steroid inhibition of cytokine production. Inhibition of
cytokine production has been shown to be a major compo-
nent of the well-known effects of adrenal steroids on
lymphocyte proliferation and likely explains why adminis-
tration early following cell stimulation Žduring the period
of cytokine elaboration and cytokine receptor induction. is
so much more effective than late administration w327x.
There are numerous reports that adrenal steroids inhibit the
production of IL -1 a and IL -1b w 7 x , IL -2
w12,104,175,246,339,349x, IL-4 w70,476x, IL-6 w7x, IL-8
w466x, IFN-g w246x, tumor necrosis factor ŽTNF. w39x and
granulocyte-colony stimulating factor w246x. These effects
have been found to occur at virtually every point in the
synthesis of cytokine protein ranging from the transcrip-
tion and stability of cytokine messenger RNA ŽmRNA.
w7,12,175,339,349x to the translation of cytokine protein
from mRNA w70x. Although the exact mechanism of inhibi-
tion of these processes has not been completely estab-
lished, there are reports that the effects of adrenal steroids
on IL-2 production, for example, are mediated in part by
interference with the binding of the transcription factor,
AP-1 Žor an AP-1-like factor., which induces IL-2 mRNA
w339,349x. It has also been found that many of the genes
for the above noted cytokines contain hormone response
elements to which adrenal steroid receptors can bind di-
rectly and thus influence gene transcription w6x.
While adrenal steroids clearly alter cytokine production,
there is also evidence that they can influence the expres-
sion of receptors for the various cytokines. For instance,
glucocorticoids have been found to inhibit expression of
the IL-2 receptor a and b chains at both the trancriptional
and postranslational levels w26x. This is further substanti-
ated by the fact that induction of IL-2 driven proliferation
of lymphocytes is inhibited by glucocorticoids w299x. Inter-
estingly, glucocorticoids have been shown to enhance the
receptors for IL-1 and IL-6 w329x.
4.2.7. Glucocorticoid role in regulating the class of the
immune response
One of the most intriguing findings which supports the
notion of a comprehensive role of glucocorticoids in the
modulation of the immune response via cytokines is the
existence of subsets of T helper cells which secrete spe-
cific profiles of cytokines that appear to be differentially
affected by glucocorticoids. These T helper ŽTh. subsets
have been best characterized in the mouse. Th1 cells
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
secrete IL-2 and IFN-g, resulting in the enhancement of
cell mediated immune responses such as cytolytic T cell
activity and Th2 cells secrete IL-4, IL-5 and IL-6 which
primarily enhance B cells and humoral immune responses
w321x. Both responses appear to be mutually antagonistic,
as Th1 derived cytokines can inhibit Th 2 derived cy-
tokines and vice versa. Interestingly, whereas glucocorti-
coids supress cytokines derived from Th1 cells Žespecially
IL-2., these hormones appear to enhance the production of
cytokines derived from Th2 cells ŽIL-4. w105x. Moreover,
when IL-4 and adrenal steroids are added together they
have a significantly greater inhibitory effect on the synthe-
sis of IL-1, TNF-a and PGE2 than either agent alone
w192x.
4.2.8. Effector function
In addition to effects on the induction and proliferation
of immune responses, adrenal steroids have been reported
to directly inhibit a variety of immune effector functions.
In the case of NK cells, it has been reported that steroid
treatment can both suppress and potentiate NK cell activ-
ity. For example, adrenal steroids have been found to
interfere with NK cell lysis of tumor cells and antibody
dependent cellular cytotoxicity ŽADCC. w154,330x. In addi-
tion, cortisol has been shown to reduce the enhancement of
NK cell activity by IFN-g w153x, although IFN-g has also
been shown to partially reverse glucocorticoid effects on
NK cell function w209x. While the exact mechanisms of
inhibition of cytotoxicity have not been fully elucidated, it
has been reported that the cytolytic activity of cloned
human NK cells can be directly inhibited by glucocorti-
coids without influencing proliferation w71x. It has also
been reported that similar inhibitory effects on a cytolytic
T cell hybridoma are probably the result of inhibition of
production of lytic granule components such as BLT-
esterase w4x. Interestingly, potentiation of natural killer cell
responses has often been seen after in vivo administration
of glucocorticoid hormone and appears to reflect adrenal
steroid effects on cell distribution rather than altered indi-
vidual cell function w240x.
A number of studies have demonstrated that cytotoxic T
lymphocytes ŽCTL. can be inhibited by adrenal steroids.
For example, investigators have found that CTL generation
following the administration of polyclonal T cell stimuli
including Staphylococcus aureus enterotoxin B was inhib-
ited by dexamethasone w262x. Moreover, adrenal steroids
have been shown to be involved in stress-induced suppres-
sion of CTL generation following herpes simplex virus
ŽHSV. infection w55,265x. We have also found that CTL
activity is sensitive to inhibition by dexamethasone, much
more so than NK cell activity, for example w345x.
There are still some unresolved issues regarding the
identification and function of a population of suppressor
cells among the T cell population. Recent reports indicate
that there are T cells and T cell clones with suppressive
activities such as antigen-specific inhibition of prolifera-
103
tion of peripheral blood lymphocytes w107,333,348x.
Whereas it has been generally believed that suppressor
cells represent a subset among CD8q cells, recent data
suggest that antigen-specific suppressor activity is associ-
ated with CD4rCD8 double positive clones or leukemic
cell lines w333x. While this information was obtained using
T cell clones, cells of a CD4qrCD8q phenotype have also
been reported to develop among mitogen- or alloantigen-
activated lymphocytes w47,53,54x. Interestingly, it has been
observed that treatment of Con A-activated CD4q T cells
or a CD4q clone of CEM ŽCEM 7. with glucocorticoids
results in the induction of co-expression of CD8. In the
case of CEM 7, induction of the co-expression of CD4 and
CD8 was correlated with development of suppressor activ-
ity indicated by inhibition of PHA-induced proliferation of
PBLs w101x. While this has yet to be directly tested, these
data suggest that a mechanism of glucocorticoid-mediated
immunosuppression could be related to regulation of de-
velopment of CD4qrCD8q cells with suppressor activity.
The effects of adrenal steroids on B lymphocytes are
somewhat more complicated than their effects on T cells
and in several cases there is a divergence in results based
on in vitro versus in vivo administration of hormone. In
general, the early events in B cell activation that precede
DNA synthesis are inhibited by corticosteroids w97x. B cell
proliferation, however, can proceed in the presence of
adrenal steroid hormones under certain conditions, espe-
cially in the presence of soluble growth factors w97x. As for
immunoglobulin production, while in vivo administration
of glucocorticoids suppresses Ig production Žespecially
IgG and IgA., glucocorticoids may suppress, enhance or
have no effect on Ig production in vitro w97,229x. Interest-
ingly, Besedovsky and coworkers found that adrenalec-
tomy significantly enhanced immunological cell mass and
B cell activity following injection of sheep red blood cells,
suggesting that endogenous adrenal steroids may regulate
B cell responses to antigen w109x.
4.2.9. Summary
Adrenal steroids affect many aspects of immune func-
tion and their effects are difficult to categorize. Rather than
being uniformly immunosuppressive, adrenal steroids vari-
ably modulate the immune system and there are important
distinctions between endogenous adrenal steroids and syn-
thetic adrenal steroids in their abilities to gain access to
immune system compartments that will become evident in
the next section. As a result, data from studies with
synthetic adrenal steroids must be interpreted cautiously
when it comes to drawing conclusions about the physio-
logical role of adrenal steroids in immune function.
5. Disease models
The only way to see how effectively the immune sys-
tem works in the living organism is to challenge it with a
104 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
pathogen or tumor or to observe how it operates during
inflammatory or autoimmune states. This is particularly
important for understanding the role of adrenal steroids
and other hormonal and neural modulators of immunity. In
the following section, we will consider glucocorticoid
actions in relation to viral infections, tumors, and inflam-
matory and autoimmune conditions.
5.1. Glucocorticoids and immune responses to Õiral infec-
tions
Viral infections constitute one of the most important
and common of the pathogenic challenges to the immune
system. That psychological andror physical stress in-
creases the susceptibility to a variety of human viral
infections has been appreciated for some time and results
from experimental infections of animals demonstrate that
stressors can modulate viral infections. Glucocorticoids are
part of neuroendocrine responses to stress. Recent studies
indicate that these factors have the potential of modulating
resistance to infections by regulating endogenous immune
responses. Understanding mechanisms for the potential
enhancing and regulatory functions of glucocorticoids dur-
ing immune responses to viral infections is an important
research direction for determining beneficial as well as
negative roles of the endocrine system. Characterizing
these effects as detrimental or beneficial requires an under-
standing of mechanisms of pathology and immunopathol-
ogy that result from different viral infections, role of
glucocorticoids in cytokine production and regulation of
Fig. 13. Phases of the immune response to viral infection.
classes of immune responses and stress induction of gluco-
corticoids during viral infections.
5.1.1. Immune responses to Õiral infections
Although all immune responses share certain character-
istics, there are important differences in the roles played by
soluble and cellular immune components against various
pathogens. Effector components to bacteria, parasitic and
viral infections are elicited through different activation
signals and regulated by qualitatively and quantitatively
different cytokine responses. Protective responses to viral
infections share certain distinguishing characteristics. In
particular, viruses induce expression of the anti-viral cy-
tokines, Type-I interferons ŽIFNs-arb. and activate cyto-
toxic effector cells capable of killing virus-infected host
cells, natural killer ŽNK. cells and cytotoxic T lympho-
cytes ŽCTLs.. These appear to be the major effector mech-
anisms during acute primary viral infections. Virus-specific
antibody production and long term T and B cell memory
are also elicited. These memory responses provide long-
lived immunity to secondary infections and control viruses
establishing latent infections. Based on the composition
and kinetics of induction during acute primary infections
w48,65,465x, the immune responses to acute viral infections
can be divided into early, middle, and late phases Žsee Fig.
13.. The phases have different functions and are associated
with different mechanisms of protection. They are not
absolutely divided in time but occur in waves. Conditions
in earlier waves may influence later phases. The specific
responses in each phase are reviewed below.
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
Innate mechanisms of protection are activated in the
early phase. Circulating levels of IFNs-arb are produced
by virus-infected cells to induce anti-viral states in unin-
fected cells. These factors also activate NK cells to medi-
ated elevated levels of killing and killing of certain virus-
infected cells w48,66,238,421,445,465x. NK cells activated
under these conditions are distinct from T cell populations
and do not express CD3 w50,454x. In addition to eliciting
innate effector mechanisms, early responses may also facil-
itate induction of middle and late phase adaptive immune
responses. During the early phase a variety of other cy-
tokines genes can be expressed, as evaluated at either the
mRNA andror the protein level, including interleukin-1
ŽIL-1 . w72,198 x, tumor necrosis factor ŽTNF .-a
w72,198xŽOrange, Salazar-Mather and Biron, manuscript in
preparation. and IFN-g Žw51x; Salazar-Mather, Ishikawa
and Biron, manuscript in preparation.. Protein products of
these genes, by facilitating antigen processing and pre-
sentation as well as T cell activation, can act to promote
appropriate T cell responses in the middle phase. ŽTNF and
IFN-g may also mediate direct anti-viral effects.. Another
response induced during the early phase is a dramatic
redistribution of lymphocytes from the circulation to re-
gional lymph nodes and splenic white pulp regions
w119,179,218,259,474x. This trafficking results from sys-
temic IFN-arb production. Although the role of cell
redistribution has not yet been definitively established, it
may facilitate the later antigen-specific responses by re-
cruiting large T and B cell repertoires to sites of antigen
presentation.
Middle phase immune responses are associated with
CD4 q and CD8 q T cell activation w48,237–
239,352,405x. A consequence of this activation is produc-
tion of biologically active transforming growth factor-b
ŽTGF-b . w432,433x. Low concentrations of TGF-b can
inhibit early phase NK cell responses and allow andror
enhance expansion of middle phase T cell responses
w433,436x. Activated T cells also produce the potent T cell
growth factor, interleukin-2 ŽIL-2. and the anti-viral and
im m u n e e n h a n c in g c y to k in e , IF N -g
w48,51,157,237,280,405x. Although not completely under-
stood, the conditions at this time are such that there is
expansion of CD8 q T cells and activation of virus-
specific, CD8 q CTLs w8,237,239,271,352,405x. CD8 q
effector T cells play a major role in clearing many viral
infections.
During the late phase, acute effector responses subside
and long term-immunity develops. Activated CD8 q T cell
responses are turned off through mechanisms which may
include the clearance of virus-infected cells, production of
regulatory cytokines w433x, andror apoptosis w359x. Mem-
ory T cells become apparent w267,268x. B cell responses
are elevated and virus-specific antibody production is de-
tectable w65,212x. Because of the high expression of IFN-q
during infection, antibody isotopes are skewed to IgG2a
w212x. There are data demonstrating that interleukin-4 ŽIL-4.
105
and interleukin-10 ŽIL-10. can be first demonstrated at
times coinciding with or overlapping with, IL-2 and IFN-g
expression w337,387,467x. IL-4 and IL-10 are known to
promote antibody responses but inhibit responses produc-
ing IL-2 and IFN-g w142,315x. Our data suggest that,
although IL-4 and IL-10 are first expressed during the
middle phase, they peak at later times post-infection ŽSu,
Kasaian and Biron, unpublished.. Thus, expression of IL-4
and IL-10 during the middle phase may promote late phase
responses. Furthermore, expression of IFN-g during the
middle phase contributes to the selection of antibody iso-
types for expression at later phases.
There are two other distinct immune response phases
after acute responses to viral infections. One of these is the
classic memory response to viral challenge. This response
is apparent after primary responses inducing protective
long term immunity. The other phase is observed during
chronic infections associated with long term immuno-
suppression. This response has been studied after the retro-
viral infections of humans with the human immunodefi-
ciency virus ŽHIV. and of mice with the LP-BM5 virus
mixture. This phase is associated with an inappropriate
shift to elevated IL-4 and IL-10 and reduced IL-2 and
IFNg cytokine production after new stimulation w80,155x.
5.1.2. Pathology during Õiral infections
Although the immune system is activated to fight off
infections and limit pathology directly resulting from in-
fectious organisms, it may also contribute to host damage.
Indeed, during infections with organisms that cause little
or no direct cytopathology, disease may primarily result
from the immune response. A classic example of acute T
cell-mediated immunopathology is mortality resulting from
experimental intracerebral infections of rodents with lym-
phocytic choriomeningitis virus ŽLCMV. w65x. Most strains
of LCMV are relatively non-cytopathic. Intraperitoneal
LCMV infection induces protective acute immune re-
sponses Žsee Fig. 13.. Under these conditions, virus repli-
cation is apparently set up in ‘non-essential’ host cells and
CD8 q CTLs limit infection by targeting infected host
cells. In contrast, if LCMV is introduced into the central
nervous system ŽCNS., infection of ‘essential’ meninges,
chorioid plexus and ependyma results w88x. Under these
conditions, CD8 q CTLs cause a fatal CNS disease by
targeting the infected host cells in the brain. Another
example of T cell-mediated immunopathology, with the
same virus, is the more recently described immunosuppres-
sion resulting from LCMV isolates or infections promoting
infection of macrophages andror CD4 q T cells of the
immune system w483x. Under these conditions, the CD8 q
CTLs appear, through the destruction of infected host
immune cells, to cause disease by precipitating an im-
munosuppressed state. Similar types of T cell-mediated
damage are thought to contribute to a number of diseases
having virus etiologies, including but not limited to dia-
betes and acquired immunodeficiency syndrome ŽAIDS.. If
106 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
a virus infects an ‘essential’ cell, this cell function may be
eliminated by activated virus-specific T cells. Thus, the
immune response can be a bigger problem to the host than
a non-cytopathic virus.
Another form of acute immunopathology can result
from inappropriate overproduction of immune enhancing
cytokines during infections. This mechanism was first
appreciated in septic shock associated with gram-negative
bacterial sepsis w46,74,148,149x. Under these conditions,
the bacterial endotoxin lipopolysaccharide ŽLPS. activates
mononuclear phagocytes to induce extremely high and
systemic cytokine expression. A cytokine cascade of TNF,
IL-1 and interleukin-6 ŽIL-6. is elicited w74,149x. TNF
production contributes to the induction of IL-1 and IL-6
w149x. New data suggest that interleukin-12 ŽIL-12. and
IFN-g may be expressed at very early times in the cy-
tokine cascade w446x. The septic shock syndrome induced
by the endotoxin-induced cytokine cascade response can
be lethal and is characterized by circulatory leakage and
collapse as well as intravascular coagulation. Weight loss
or wasting can result. Detrimental cytokine production also
can be elicited by interactions with T cells. Bacterial
‘super-antigens’ stimulate extremely high frequencies of T
cells in naive hosts and such responses appear to con-
tribute to the toxic shock syndrome associated with certain
gram-positive bacterial infections w199x. Furthermore, ele-
vated cytokine expression by activated T cells may also
contribute to dengue hemorrhagic fever pathology ob-
served during secondary infections with dengue virus w263x
and lung immunopathology during influenza virus infec-
tions w274,278x. These are examples of conditions where
‘too much’ immune response causes disease w279x.
In addition to the aforementioned examples of
cytokine-mediated pathophysiology, immunotoxicity may
also result from high levels of cytokines. We have been
characterizing the effects of administered IL-12 during
experimental viral infections w343,344x. If the factor is
given at high enough concentrations, systemic TNF is
induced. The circulating TNF not only results in a wasting
disease but also inhibits the anti-viral CD8 q T cell re-
sponse w343x. Thus, ‘too much’ of a cytokine can also
inhibit protective immune responses.
5.1.3. Potential glucocorticoid-mediated effects on immune
responses to Õiral infection
Glucocorticoids have the potential to mediate im-
munoregulatory functions at two different levels. The first
is by participating in shaping or directing protective im-
mune responses. The second is by containing the magni-
tude andror kinetics of possibly detrimental immune re-
sponses. The mechanisms by which glucocorticoids could
carry out these functions during viral infections are re-
viewed here.
Endogenously synthesized adrenal steroids have the
potential of mediating a variety of functions that may
contribute to either the different phases of immune re-
sponses andror facilitate the transition between phases
Žsee Fig. 13.. Glucocorticoids have been reported to have
two major effects which may be important during the early
phase. The first of these is the well documented redistribu-
tion of mononuclear cells from peripheral blood to lym-
phoid compartments Žsee subsection 4.1.. Endogenous glu-
cocorticoids may play a role in the IFN-induced redistribu-
tion of lymphocytes from the circulation to regional lymph
nodes and splenic white pulp regions during viral infec-
tions w179,218,259,474x. Corticosteroids have also been
reported to inhibit NK cell activity w329x. Because recent
studies indicate that glucocorticoids can cause increased
detectable TGF-b1 mRNA and protein expression w14x,
they may inhibit NK cells and promote the shift from early
to middle phase immune responses by facilitating TGF-b1
expression.
Many different cytokine genes have steroid response
elements and glucocorticoids have been shown to inhibit
expression of a number of different cytokines w6,247,448x.
During the middle phase, glucocorticoids may shape the
immune response by inhibiting expression of particular
cytokine genes while promoting or permitting expression
of others. Experimental results in vitro and in vivo have
demonstrated that glucocorticoids inhibit IL-2 and IFN-g
but either facilitate w105,106x or inhibit IL-4 expression to
a lesser degree w262x. Such a differential cytokine regula-
tion may have important biological consequences during
infections. IL-2 and IFN-g are associated with T helper
Type 1 ŽTh1. responses important for defense against
infections with intracellular bacteria and parasites. In con-
trast, IL-4 is associated with T helper Type 2 ŽTh2.
responses which are beneficial during nematode infections.
Compared to certain sensitive mouse strains developing
non-protective Th2 responses to the intracellular parasite
Leishmania major, resistant strains develop Th1 responses
during infection and have more modest corticosterone
responses to stress w195x. During viral infections, peak IL-2
and IFN-g induction occurs during the middle phase with
an apparent shift to IL-4 production during the late phase.
Endogenous glucocorticoids may promote such a shift
w371x.
As a consequence of regulating cytokine expression,
glucocorticoids may contribute indirectly to control of T
cell responses and promotion of B cell responses during
late phase immune responses to viral infections. They also
have the potential to directly regulate T cell responses by
contributing to the observed apoptosis w359x. Glucocorti-
coids induce apoptosis w182,232,319,477,480,485x and their
contribution to thymocyte apoptosis in vivo has been
conclusively demonstrated w182,319,477x. A role of gluco-
corticoids for peripheral T cell death, however, is more
controversial w174,221,480,485x. T cell apoptosis can be
induced by an activation-induced pathway as well as a
steroid-induced pathway and these pathways can be mutu-
ally antagonistic w221,480x. Thus, characterization of en-
dogenous steroid effects on peripheral T cells has to
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
distinguish glucocorticoid effects on cell death from ef-
fects on both immune enhancing factors and resulting
activation-induced pathways, i.e., glucocorticoids may di-
rectly induce immune cell death or may indirectly induce
cell death by promoting factors which enhance activation-
induced cell death pathways. Recent studies of peripheral
T cell deletion in response to profound stimulation with
anti-CD3e antibodies or the superantigen Staphlococcus
aureus enterotoxin B suggest that endogenous glucocorti-
coids are required for early peripheral T cell depletion
w174x. These data suggest that glucocorticoids have a po-
tential to regulate the late phase response through both
indirect and direct mechanisms.
5.1.4. Pathways aÕailable for releasing endogenous gluco-
corticoid-mediated effects during immune responses to Õi-
ral infections
Perhaps the first evidence demonstrating the role of
endogenously synthesized steroids in regulating immune
responses to infections was obtained in the cytokine-in-
duced immunopathology associated with bacterial endo-
toxic shock. Long before the pathogenic mechanisms were
understood, it was known that corticosteroids could inhibit
lethal actions of endotoxins w156x. It is now known that
endotoxin-induced systemic TNF and IL-1 and IL-6 ex-
pression w46,74,149,446x activates the HPA axis and in-
d u c e s e le v a te d e n d o g e n o u s c o rtic o s te ro id s
w38,40,44,156,319,464x. As adrenalectomy results in in-
creased sensitivity to the lethal effects of endotoxin, TNF
andror IL-1 w39x, the biological significance of this cas-
cade is proven. Thus, under conditions of endotoxic shock,
systemic cytokine expression apparently induces endoge-
nous steroid production to regulate cytokine expression
and cytokine-mediated immunopathology.
There are clear pathways in place for elevating steroid
levels during early phase responses to viral infections.
Circulating IFNs are present and IFN expression is associ-
ated with corticosterone expression in vivo. The Newcastle
disease virus ŽNDV., although not infectious for mice or
rats, stimulates both IFN expression w179x and cortico-
sterone production in these animals w124,410x and treat-
ments with the chemical IFN-inducer, polyinosinic-
polycytidylic acid Žpoly I:C. w310x induce circulating cor-
ticosterone. In addition to the IFNs, IL-1 and TNF are also
expressed at early times post-infection w72,198x ŽOrange,
Salazar, Mather and Biron, manuscript in preparation.. As
these cytokines can induce a rise in endogenous glucocorti-
coids w38,40,44,319,464x, induction of IFN-g, IL-1 or TNF
during early phase immune responses may induce adrenal
steroids which act to shape the phases of the immune
response.
The mechanisms by which steroids could be induced or
become effective during the middle andror late phases are
less clear. Although it has been suggested that the response
to antigen includes corticosteroid induction
w41,42,124,261,306,424,458x, most of these studies have
107
not distinguished between steroid induction driven by spe-
cific antigen and steroid induction resulting from systemic
cytokine expression. This is particularly important when
NDV, a potent inducer of systemic interferon expression,
is used as the ‘antigen’ w124x. The response to moderate
doses of the antigen, phosphocholine-keyhole limpet
hemocyanin ŽPC-KLH., is associated with undetectable to
minimal changes in the HPA axis w424x. Thus, these data
suggest that if systemic cytokines are not induced, antigens
may not elicit detectable increases in circulating glucocor-
ticoids.
Alternatives to the cytokine pathway for circulating
glucocorticoid induction are pathways activated by physi-
cal stress resulting from infections. Viral infections associ-
ated with extreme virus-induced andror immune-induced
pathology can inhibit normal physiological functions and
cause pain. Examples of these conditions would include
influenza virus and cytomegalovirus ŽCMV. which, during
extensive infections, either directly or indirectly inhibit
lung or liver and lung functions, respectively.
Even if glucocorticoid levels are not elevated during
viral infections, there are pathways by which normal en-
dogenous steroids may become available to regulate im-
mune responses. First, induced decreases in CBG function
may ‘release’ circulating steroids to immune cells Žsee
subsection 4.1.. Alternatively, immune cells responding to
antigen stimulation andror cytokines may be induced to
express higher numbers of steroid receptors w378x. Antigen
activation of these mechanisms has not yet been systemati-
cally evaluated in vivo.
5.1.5. Expression and function of endogenous glucocorti-
coids during infection
A number of experimental murine viral infections are
being used to characterize the induction of steroids andror
steroid functions during infections, including intranasal
infections with influenza virus w123,141,200,201,400x and
intraperitoneal infections with LCMV w49,306x. Although
these models appear to have parallel phases of the immune
responses to infection w48,51,65,198,280,387x, they differ
in the level of pathology and immunopathology associated
with the infection. Intranasal infections with influenza
virus induce profound lung pathology and the immune
response appears to contribute to at least a proportion of
this damage. In contrast, under the intraperitoneal infection
conditions used, LCMV infections are associated with
minimal pathology. Thus, the two models provide impor-
tant information about different pathways of steroid induc-
tion during infections.
Studies with influenza virus A ŽPR8. indicate that circu-
lating corticosterone levels can be elevated at early
w123,201x as well as later times post-infection w141,201x.
Although not directly examined in this work, the kinetics
of the early steroid elevation appears to coincide with
reported early phase cytokine production during influenza
infections w198,421x. Late elevation correlates with the
108 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
induction of T cell responses w5x. However, as there is
extensive lung pathology at these later times, it is impossi-
ble to distinguish between antigen-driven as opposed to
stress-driven induction of steroids.
To evaluate changes in the absence of profound pathol-
ogy, we have recently carried out extensive evaluation of
circulating corticosterone levels in mice infected intraperi-
toneally with a non-immunosuppressive isolate of Arm-
strong strain LCMV w49,306x Žsee Fig. 13.. In these stud-
ies, circulating corticosterone levels have been measured at
both peak and nadir of the diurnal cycle. Modest but
statistically significant changes in steroid levels are found
cresting at earlier times post-infection. The early steroid
response may be associated with early cytokine expression.
The circulating corticosterone levels return to baselines at
times coinciding with middle and late phase immune re-
sponses. To document immune cell responsiveness andror
in vivo exposure to glucocorticoids, steroid receptor Type-
II availability has also been evaluated. Although the mea-
surable changes in steroid levels are modest and early,
there are dramatic drops in available receptor sites for
glucocorticoid binding. These changes are first detected
early and maintained throughout late times post-infections.
Taken together with the measurements of corticosterone,
the receptor studies suggest two exciting possibilities. First,
that through another modification, such as decreases in
CBG, more of the circulating levels of steroid were avail-
able to bind to receptors in responding immune cells. Such
a change would predict that: Ž1. the immune cells receive
endogenous steroid signals; and Ž2. endogenous steroids
shape the in vivo immune response. The alternative possi-
bility is that activated immune cells are modified during
the course of infection to modulate their steroid receptors.
This down modulation might be a consequence of ‘activa-
tion’ through an unknown alternative pathway such as the
recently described heat shock protein pathway w381,399x.
On the other hand, receptor expression may be down
regulated in activated cells to reduce sensitivity to circulat-
ing glucocorticoids. The pathways for reducing available
steroid receptors are not mutually exclusive.
To determine if endogenous adrenal steroids are shap-
ing the immune response to LCMV, early NK cell and late
CTL responses have been evaluated in adrenalectomized
ŽADX. mice or in mice treated with the Type-II receptor
antagonist, RU 486. NK cell responses are not measurably
altered, however, CTL responses are marginally enhanced
when endogenous adrenal steroids are blocked throughout
the course of infection. Given that steroids may mediate
CTL enhancing effects early but inhibiting effects late,
optimizing measurement of steroid-mediated effects will
require the characterization of early vs. late effects.
Taken together, these studies in experimental models
provide compelling evidence that endogenous steroids are
part of normal immune responses to viral infections. A
great deal of work remains to be done to the characterize
the precise effects mediated by endogenous steroid expres-
sion and the molecular mechanisms by which these effects
are driven.
5.1.6. Responses to Õiruses in the context of exogenously
added glucocorticoids or stress
Although the mechanisms are not understood, stress-in-
duced increases in susceptibility to a variety of acute
human virus infections and to reactivation of latent herpes
viruses have been appreciated for some time. Studies
correlating stress with human viral infections have demon-
strated that high-stress examination periods are associated
with increased upper respiratory infections in medical stu-
dents w164x and that psychological stress is associated with
increased rates of infection after deliberate exposure to
rhinoviruses, respiratory syncytial virus or coronovirus
w85,86x. The first studies, to examine the consequences of
applied stress on viral infections in animal models were
surveys evaluating the effects of a variety of psychosocial
and physical stressors on infections with a panel of differ-
ent viral infections. These studies demonstrated that re-
peatedly exposing mice to a shock-avoidance procedures
increased susceptibility to infections with herpes simplex
virus ŽHSV. w362x, poliomyelitis virus w230x, Coxsakie B
virus w231x and polyoma virus w361x and that physical
restraint of mice increased susceptibility to HSV w362x.
More recent studies have focused on the effects of
external stress on viral infections in three detailed and
different experimental murine models with characterized
or partially characterized immune responses; intranasal
infections with influenza virus w141,200,201,400x, footpad
infections with HSV w55–57,265x and intraperitoneal infec-
tions with West Nile virus ŽWNV. w35x. These studies have
used restraint w55–57,141,200,201,400x, electric footshock
w265x and cold or isolation w35x as stressors. The stress
protocols decrease certain parameters of the immune re-
sponse to each of these infections Žsee below.. They also
decrease resistance to infection as evaluated by increased
viral replication during HSV w56,265x or WNV infections
w35x and increased mortality during WNV infection w35x.
Thus, stress can promote conditions which result in in-
creased viral replication. The effects of stress on influenza
viral titers have not been reported. As discussed above,
disease following intranasal infection with influenza virus
is complicated because inflammatory immune responses
contribute to lung pathology. Restraint stress does reduce
the influenza virus-induced inflammatory responses and
lung consolidation w200,400x. In a strain of mice particu-
larly sensitive to influenza virus-induced mortality,
DBAr2, restraint stress also induces an increase in sur-
vival w400x. Thus, in this model with acute immunopathol-
ogy, certain parameters of virus-induced disease are im-
proved by stress.
Stress-induced changes in acute immunological re-
sponses known to mediate anti-viral activity have been
examined during influenza virus and HSV infections. As
most of the cellular immune response parameters have
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
only been examined at one or two time points and limited
cytokine expression data has been obtained, it is difficult
to discuss these stress-induced immune changes in the
context of the different phases of the immune response
ŽFig. 13.. Stress reduces leukocyte numbers in lymphoid
compartments during acute responses to either virus w55–
57,141,200,201,265,400x. As changes in lymph node cell
and spleen cell yields can result from either a redistribu-
tion or a proliferation, it is not clear if the stress-induced
changes in cell yields are a consequence of only one or
both of these mechanisms. It is clear that proliferation
dependent responses are inhibited; stress reduces IL-2
production w200,400x and IL-2 dependent proliferation
driven by antigen stimulation in culture w141,400x as well
as generation of virus-specific CTLs expanded in culture
w56,57,265x. Thus, at least part of the stress-mediated
inhibition is a result of inhibited proliferation, but changes
in cell trafficking may also be induced. Extensive kinetic
studies of virus-specific antibody production have been
done. These indicate that the kinetics and magnitude of
antibody responses are also inhibited by stress w200,265x.
A variety of mediators can contribute to the effects after
stress. Although it is clear that glucocorticoid elevation can
be part of a stress response, the mechanisms by which
stress-induced steroids modulate susceptibility to viral in-
fection have not been clearly delineated and little is known
about the role of stress-induced glucocorticoids. We have
used the synthetic glucocorticoid, dexamethasome ŽDEX.
to evaluate the steroid sensitivity of the various compo-
nents of the immune response to LCMV infections w49,306x
Žsee Fig. 13.. These studies have demonstrated that early
NK cell responses are relatively insensitive to DEX. In
contrast, CTL responses are extremely sensitive to DEX-
mediated inhibition. The results are consistent with the
aforementioned studies examining the consequences of
blocked endogenous adrenal steroids. However, there are
limited studies directly addressing the question of whether
or not stress-induced endogenous glucocorticoids, by
themselves or in concert with other neuroendocrine factors,
actually regulate immune responses during infection. As
stated above, influenza virus infection is known to elevate
circulating corticosterone w123,141,201x. Although restraint
stress inhibits the histopathology associated with influenza
virus infection of all strains of mice tested, it only in-
creases circulating corticosterone to significantly higher
levels in some strains of infected mice w201x. Thus, other
changes may be contributing to the stress-induced modifi-
cations. The issue has been directly addressed by evaluat-
ing stress changes in HSV-infected mice that have been
ADX w57x. These studies demonstrate that adrenal-depen-
dent mechanisms are important for the stress-induced sup-
pression of virus-specific CTLs as measured in culture but
not the reduction in lymphoid cell yields. They also re-
vealed an adrenal-independent mechanism induced by
stress which functioned in synergy with corticosterone to
suppress the lymphadenopathy. Thus, there is some indica-
109
tion that stress-induced glucocorticoids regulate endoge-
nous immune responses, but the characterization of stress-
induced glucocorticoid effects are still very preliminary.
5.1.7. Summary of glucocorticoids and immune responses
to Õiral infections
Although there are data indicating that stress can alter
susceptibility to infection and that glucocorticoids can be
mediators of the stress-induced effects, the mechanisms by
which stress-induced glucocorticoid secretion can modify
defense against infection are only beginning to be appreci-
ated. This appreciation is largely the result of a new and
more thorough understanding of: Ž1. the beneficial as
opposed to the detrimental immune responses to viral
infection; Ž2. the kinetics of the various protective re-
sponses during infection; Ž3. the molecular mechanisms
regulating protective as opposed to susceptible type im-
mune responses to viruses; and Ž4. the sensitivity of
various components of the immune system to steroid sig-
nals. Because of the recent work characterizing glucocorti-
coids effects on various immune cells and cytokine regula-
tors of the immune response, it is possible to propose that
glucocorticoids have the potential to mediate a wide range
of effects during viral infections, and, depending on re-
sponse kinetics and contexts, that the outcome may be
either defense enhancing or suppressing. Given the identi-
fication of precise molecular targets for glucocorticoid
effects on immune responses, it should now be possible to
definitively establish the role of endogenous glucocorti-
coids on immune responses and defense against infection.
5.2. Role of glucocorticoids in tumor establishment and
progression
5.2.1. Background
Numerous studies have suggested that stress can modify
cancer development in animal models and that stress can
either inhibit or promote neoplastic development w335x.
However, it is very important to note that multiple models
of experimental cancer exist and that each model often
emphasizes only a limited aspect of the highly complex
and dynamic process of cancer progression: i.e., initiation,
promotion, progression, angiogenesis, tumor invasion,
metastatic spread and the outgrowth of established metas-
tases w167–169x. Therefore, certain models are more infor-
mative than others in reflecting the pathophysiology of
progressive cancer in humans or in reflecting an appropri-
ate understanding of the role of the immune response in
cancer spread or for being of significance to understanding
the health-modulating effects of stress on disease end-
points, including cancer progression.
5.2.2. Mechanisms of tumor inÕasion and metastatic spread
Progressive steps in malignant neoplastic growth lead to
tumor invasion and cancer metastasis Žsee Fig. 14.. Cancer
metastases are known to be the predominant cause of
110 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
treatment failure, morbidity and death for patients or ani-
mals with solid malignancies w167x. While the treatment
modalities of chemotherapy, radiotherapy and surgical in-
tervention effectively treat approximately 50% of patients
who have developed malignant tumors, the majority of
patients who are refractile to these therapeutic approaches
yield to the direct andror indirect effects of established
tumor metastases or to the adverse sequelae associated
with these therapeutic approaches. It is recognized that at
the time of diagnosis of primary tumors, approximately
50% of patients with solid malignant tumors already have
established micrometastases which often with time expand
and contribute to damage to the host organs. Indeed, a
detected metastatic deposit in an organ may indicate the
presence of additional occult micrometastases. The hetero-
geneity of subpopulations of metastatic tumor cells cou-
pled with their widespread anatomic distribution limits or
prevents effective chemotherapeutic or even surgical thera-
peutic treatments. Moreover, some of these treatment
modalities can lead to immunosuppression and subsequent
mortality arising from infectious disease. It is therefore
quite important to employ tumor models that as much as
possible mimic these critical aspects of the pathophysiol-
ogy of human malignancy including metastatic spread and
the outgrowth of established tumor metastases.
In recent years significant insights into the progressive
stages of malignant neoplastic growth, particularly tumor
invasion and metastatic spread, have arisen from basic
research dealing with the molecular biology, biochemistry,
cell biology, immunology, and the study of selective ex-
perimental therapeutic agents. Insights into the mecha-
nisms of tumor progression to metastasis have emphasized:
biochemical mechanisms of tumor invasion, modes of
Fig. 14. Diagram of cancer invasion and metastasis.
tumor spread and metastasis and the importance of tumor
cell heterogeneity, host vasculature, and the immune re-
sponses. Significant progress has been made in better
understanding the biochemical mechanisms in tumor inva-
sion and metastasis, lymphatic and hematogenous tumor
spread, and sequential stages in tumor invasion.
Recent studies have continued to elucidate the biochem-
ical, cellular, and molecular mechanisms that underlie
tumor invasiveness and cancer metastasis Žreviewed in
w167,170x. During tumor invasiveness, malignant cells pen-
etrate a number of barriers including extracellular matrices
Žsee Fig. 14.. These extracellular matrices include dense,
over-arching lattices of collagen and elastin embedded
within a network of glycoproteins and proteoglycans. One
specialized extracellular matrix that is penetrated as
metastatic tumor cells cross tissue boundaries is the base-
ment membrane. The basement membrane is composed of
proteoglycans. Basement membranes and interstitial stroma
separate tissue compartments from each other.
Subpopulations of tumor cells leave the primary tumor
and interact with extracellular matrices at a number of
stages during the metastatic process including: tumor cell
entry andror exit from the vasculature; the invasion of
muscle and nerve; and during the penetration of epithelial
barriers. During the invasion into or out of blood vessels
Ži.e., intravasation or extravasation., invasive tumor cells
enter through areas that they have degraded in the wall of
a capillary or venule and must cross the perivascular
interstitial stroma prior to the growth of metastatic colonies
in the parenchyma of the organ seeded by the metastatic
tumor cells. Aspects of the homing of metastatic tumor
cells to target organs is dependent upon the interaction of
tumor cell surface molecules with the microvascular en-
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
dothelial cells associated within these organs. Many inves-
tigators have documented that multiple steps are involved
in the sequence of steps that characterizes metastatic spread.
The degradation of extracellular matrices by invasive
tumor cells has been shown to take place in several stages.
The first step is tumor cell attachment to subendothelial
extracellular matrices by cell-surface receptors which bind
to specific matrix components. The second step of matrix
invasion is related to tumor cell protease-mediated degra-
dation of the matrix. The third step is tumor cell locomo-
tion into areas of the matrix locally degraded by tumor cell
proteolysis. Continued invasion of the extracellular matrix
may take place by repetition of these sequential steps.
The process of cancer metastasis is both complex and
selective and dependent on the properties of the tumor,
e.g., tumor invasiveness, as well as the properties of the
host, e.g., the immune response and the vasculature of the
tumor and the host w167x. During the process of metastatic
spread, tumor cells must overcome or evade systemic and
locoregional host immune responses Že.g., lymphoid effec-
tor cells that can infiltrate, accumulate within and exhibit
anti-tumor reactivity within tumor metastases.. Moreover,
following the establishment of tumor metastases in distant
organs, the tumor cells can undergo neovascularization and
colonial outgrowth which is also under complex and dy-
namic regulation dependent upon the host and tumor.
5.2.3. Role of the immune system in preÕenting metastasis
Much evidence exists that the immune response plays
an important role in both the prevention of metastatic
spread and as a potential therapeutic approach for the
control of established tumor metastases w166,172x. While a
detailed survey of the immune response to cancer, includ-
ing tumor metastases, is beyond the scope of this chapter,
it is noteworthy that some components of the immune
response have been shown to play important roles in
protecting against both the onset of tumor metastases as
well as in the therapy of advanced tumors including tumor
metastases. Substantial knowledge exists regarding tumor
associated antigens and the role of antibodies and cellular
immunity in cancer; the characteristics and basic mecha-
nisms of anti-tumor effector cells; the role of immune
effector cells within the tumor microenvironment; tumor-
infiltrating lymphocytes in solid tumors and the localiza-
tion of effector cells of the immune response into tumor
metastases w166x. In recent years, a significant number of
preclinical and clinical studies have shown the therapeutic
potential of immunomodulation for the immunotherapy of
malignancies. The reader is directed towards a recent
summary of immunity and cancer therapy which highlights
major approaches in immune intervention including: tumor
vaccines, immunoaugmenting and immunomodulating
agents, antibodies, cytokines and adoptive cell transfer
w305x. One cell type that has been found to play a particu-
larly important role in the prevention of metastases is the
natural killer ŽNK. cell; it has been found that upon
111
activation with the cytokine IL-2 that such activated natu-
ral killer ŽA-NK. cells accumulate within established
metastases following their adoptive transfer Žreviewed in
w166,172x..
NK cells are a subset of peripheral blood mononuclear
cells which are morphologically large granular lympho-
cytes. Their surface phenotype is distinct from T or B
lymphocytes. Moreover, NK cells can lyse many tumor
cells and virally infected cells in the absence of prior
sensitization. NK cells, which account for 5–15% of circu-
lating blood lymphocytes, can also be found in non-
lymphoid tissue including the intestinal mucosa and the
lung. It is well known that both a number of cytokines and
mononuclear subsets regulate the functions of NK cells.
Moreover, NK cell activation, proliferation and reactivity
can be modulated by events that take place within local
tissue sites. NK cells can therefore quickly respond to local
stimuli in tissues and function as an important regulatory
and defensive effector cell type.
NK cells are recognized as being an important first line
of defense against hematogenous metastases. In animal
models of tumor metastasis, selective depletion of NK
cells leads to the development of a significantly larger
number of tumor metastases in the lungs and other organs;
moreover, selective reconstitution with NK cells restored
resistance to metastasis w20x. It is also well known that
patients with cancer, including those with large tumor
burdens and disseminated tumor metastases, often have
low NK activity in their peripheral blood. While it is not
always clear if this is a result of malignancy rather than a
factor contributing to malignancy, studies of familial can-
cer have indicated that low NK activity can precede the
development of cancer. Indeed, in patients with cancer,
low NK cell activity may have prognostic value in predict-
ing response to treatment or relapse w388x. Moreover, it has
been shown that low levels of NK cell number or activity
in patients with cancer seems to be associated with an
increased chance for tumor progression.
5.2.4. Stress and tumor progression
The role of stress in tumor progression has been exam-
ined using a number of tumor models and an almost
equally varied number of stress paradigms. Stress re-
sponses have been examined using: electric shock, re-
straint, surgery and differential housing. Although there
are numerous studies in each of these catagories, we will
focus on those which correlate stress, tumor progression,
and glucocorticoid levels or immune function. Each of
these paradigms have given a different perspective on the
role of stress on tumor progression. In addition each uses a
different tumor model. However, in evaluating these stud-
ies it is important to keep in mind two points. First, the
most important tumor models are those that deal with the
full array of cancer progression, particularly the establish-
ment and outgrowth of disseminated metastatic cancer.
Second, from an immunologic perspective, the meaningful
112 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
models must take into account the need for employment of
syngeneic tumor models and therefore immunologically
appropriate for particular host animals. In allogeneic tumor
models, immune modulation of tumor progression may
simply be due to host rejection of the allogeneic tumor.
The models described below were conducted in syngeneic
systems.
5.2.4.1. Studies with physical and psychological stressors.
Pioneering studies dealing with the association of stress
with immune competence and cancer included intriguing
studies of the enhancement of tumor growth following
rotation-induced stress on C3H mice w368x. It was assumed
that the stress caused by rotation reduced the immunologi-
cal competence of the mice and permitted rapid growth of
the 6C3HED lymphosarcoma. In contrast, the control ani-
mals retained their capacity for restraining tumor growth.
It was pointed out in this early study that this type of
stress-induced decrease in immunological competence was
consistent with diminution of cellular immunity mediated
by enhanced plasma corticosterone levels. Further studies
indicated that the administration of an exogenous glucocor-
ticoid also enhanced tumor growth. Indeed, it was demon-
strated that stress-associated impairment of immunological
competence may be dependent upon the timing of the
application of stress or of stress simulated by dexametha-
sone administration w368x. It should be noted that dexa-
methasone is especially potent towards the immune system
by reason of its inability to bind to CBG and that its
effects are not representative of endogenous glucocorti-
coids secreted during moderate stress Žsee subsection 4.1..
Thus the mechanism of dexamethasone- and stress-induced
enhancement of tumor growth may not be identical.
The effects of stress have also been investigated on
tumor growth and metastasis in mice bearing the Lewis
lung carcinoma w161x. Stressors examined included antici-
patory anxiety caused by application of spatial disorienta-
tion; early maternal deprivation; behavioral despair; physi-
cal restraint and avoidable vs. unavoidable foot-shock in
conditioned animals. Giraldi and colleagues have claimed
notable results with spatial disorientation with resultant
enhanced levels of metastases. In addition, this group has
reported using various antagonists of neuro-endocrine ef-
fectors that plasma glucocorticoids are not involved
whereas endorphin may be significant. Moreover, the
adrenergic system appears to be involved. These findings
have been interpreted to indicate that psychological stres-
sors may influence tumor metastasis by the host’s antitu-
mor resistance factors via neuroendocrine mechanisms.
Additional studies by Giraldi and colleagues have exam-
ined the effect of stress on antitumor chemotherapy with
the finding that antitumor resistance ‘effectors’ which are
susceptible to neural modulation by stress are possibly
distinct from either CTL or NK cells w162x.
As summarized by Newberry and colleagues w335,336x,
studies on the role of stress in chemically induced tumors
have in many cases involved the DMBA rat mammary
tumor which was induced with 7,12-dimethylbenzanthra-
cene by feeding or i.v. injection. Many of these early
studies suggested that stress, e.g., mild restraint, could
reduce or inhibit tumor growth or weight. A series of
subsequent studies suggested that unpredictable stress failed
to promote DMBA-mediated cancer development. Interest-
ingly, dexamethasone treatment after 5 days of DMBA
administration revealed that glucocorticoid-induced im-
mune suppression might not be a factor in the DMBA rat
mammary tumor model. This study plus a variety of
studies in several carcinogen-induced models with differ-
ent modes of stress modulation have been reviewed w335x.
One view that has emerged is that stress, by alteration
of brain and plasma levels of various neurotransmitters,
hormones and neuropeptides, contributes to immunoregula-
tion w396x. Moreover, the regulation is not always negative
Žsee Section 4, Table 1. and several studies have suggested
that recovery from stress might be protective for tumor
development. Nevertheless, it was not clear, in studies with
female Lewis rats receiving mammary adenocarcinoma
cells subcutaneously, whether stress or recovery from it led
to smaller tumors in restrained rats w425x. In this study,
higher neutrophil and suppressor cell numbers were found
in recovered stressed animals and lower NK cell activity
among controls at the second time of sampling.
5.2.4.2. Escapable and inescapable shock. Another rela-
tively early study investigated tumor rejection in rats fol-
lowing either inescapable or escapable shock w450x. One
day following implantation with a Walker 256 tumor
preparation, rats were subjected to inescapable, escapable
or no electric shock. It was found that 27% of the rats that
received inescapable shock rejected the tumor. In contrast,
63% of the rats receiving escapable shock and 54% of the
rats that did not receive shock rejected the tumors. This
study suggested that the lack of control over stressors
reduces tumor rejection and decreases survival. An addi-
tional study indicated that a form of footshock stress can
lead to suppression of immune functions in rats and de-
crease their resistance to tumor challenge w396x. Interest-
ingly, these effects appeared to be regulated by opioid
peptides released as a consequence of stress. Moreover,
they could be mimicked by systemically administered mor-
phine or by smaller morphine doses delivered intracere-
broventricularly.
Several groups have also examined footshock as a
behavioral stress on tumor development Že.g., w447x.. It
was noted that footshock did not affect the development of
the P815 mastocytoma in DBAr2j mice. Nevertheless,
footshock appeared to block an antitumor effect mediated
by infection with C. parÕum in mice that were group-
housed suggesting the need to carefully assess the relation-
ship of various psychological variables with successful
treatments with immune response modifiers.
A number of studies have examined tailshock, stress
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
hormones and the ability of the host to clear radiolabeled
tumor cells, which is known to be related to NK cell
function w177x. It was reported that 15 min of shock slowed
the rate of elimination of NK cell-sensitive target cells,
e.g., YAC-1 cells but not NK-resistant target cells, e.g.,
P815 cells. It was also observed that opioid antagonists
increased the elimination of NK sensitive target cells in
shocked animals. In contrast, enhancement of the time of
shock to 60 min abolished the elimination of the NK-sensi-
tive tumor cells. Administration of restraint for 3 days
preceding shock increased the elimination of NK-sensitive
tumor cells. Treatment of ACTH during a 2-day period
improved the response of the host to these cells.
5.2.4.3. Housing conditions. A number of studies have
examined the role of differential housing on endocrine
mediation of stressor effects on tumor growth Že.g., w374x..
It has been shown that differential housing alters the
growth rate of the androgen-responsive Shionogi mouse
mammary SC115 carcinoma. Plasma corticosterone levels
were found to be significantly elevated in mice with small
tumors as compared to those of mice with large tumors.
The results of the study suggested that housing conditions
can effect plasma levels of steroid hormones which in turn
may contribute to differential tumor growth rates. Interest-
ingly, the isolation of mice has been employed as a model
of stress for the investigation of NK cell activity and
CIRAS 3 fibrosarcoma pulmonary metastasis formation in
C3H mice w208x. It was found that individually housed
mice, regardless of the conditions of vehicle or tumor
conditions, had higher nk cell responses on day 1 com-
pared to group-housed animals. The data have been inter-
preted to suggest that in response to housing conditions, nk
cell activity differs in tumor-bearing mice and vehicle
controls. Moreover, it has been suggested that plasma
corticosterone does not appear to be a major in vivo
regulator of nk activity in this experimental rodent tumor
paradigm. Lastly, this report is of interest, since it suggests
that housing effects on nk activity and plasma cortico-
sterone levels are dependent upon the specific time win-
dow in which samples are obtained.
5.2.4.4. Surgical stress. Another interesting area exploring
the role of stress in tumor development has been surgical
stress and metastases in several systems including trans-
planted mammary tumors. Evidence for stress-related im-
munodepression was noted in studies with MRMT-1 cells
in young Sprague–Dawley rats where tumor excision was
performed 14 days postinoculation or excision plus laparo-
tomy or identical groups that did not receive tumors w437x.
Tumor formation was enhanced with splenic cells derived
from laparotomized animals versus spleen cells from un-
stressed or tumor-excised animals. Interestingly, among
the tumor-bearing animals followed until death or 80 days
a higher percentage of the laparotomized rats showed
evidence of lung metastases. In comparable studies incor-
113
porating a non-specific immunomodulator, OK-432 as well
as laparotomy, OK-432 administered prior to tumor exci-
sion and laparotomy led to prevention of enhanced lung
metastases compared to laparotomy alone w440x. Of note,
OK-432 did not appear to affect the incidence of metasta-
sis in the absence of laparotomy. Studies with Walker 256
tumor cell-mediated pulmonary metastasis was enhanced
by either surgical stress or stimulation of the midbrain
periaqueductal gray ŽPAG. region w403x. It is noteworthy,
however, that naloxone, given before such PAG stimula-
tion, did not act as an antagonist. An additional study
revealed that laparotomy enhances death from pancreatic
tumors by decreasing latency of primary footpad tumors
and enhances the incidence of tumor metastases w484x. In
this same study, evidence was provided for immunodepres-
sion and following surgery, there were indications of im-
munoenhancement. While C. parÕum had antitumor ef-
fects for even surgically stressed animals, the pattern was
not consistent with the result being linked to blockade of
stress-mediated events.
More recently it has been recognized that surgical stress
can inhibit NK cells effects related to the lysis of tumor
cells in patients with solid tumors including sarcomas
w356x. Moreover, recent studies have indicated that stress
can facilitate the metastatic process by suppression of
aspects of the immune response w355x.
5.2.5. Possible mechanisms
As noted above, the immune response can play a vari-
ety of roles in the destruction of tumors w166,172x. The
totality of immune mechanisms, particularly the function
of NK cells, may likely play key roles in tumor destruc-
tion. However, circulating hormones and neural input to
immune organs play an important modulatory role in
tumor rejection and spread.
Recent studies have examined the role of stress in a
tumor metastasis system in rats with particular attention on
the assessment of natural killer cell activity in rats w33,34x.
The role of stress has been investigated in Fischer 344 rats
using the MADB106 syngeneic mammary tumor metasta-
sis system. Animals exposed to acute stress showed de-
creased NK killing against MADB106 tumor cells in vitro.
When Fischer rats were injected with the MADB106 tu-
mor i.v., they showed a two-fold increase in surface
metastases. Ben-Eliyahu and colleagues noted that the time
period during which stress increases metastases appears to
be the same as that during which the tumor is controlled
by NK cells, thus supporting the view that stress can
facilitate the metastatic process by inhibition of the NK
cell compartment of the immune response w33,34x. This
study has shown that stress, if applied 1 h before but not
24 h after tumor injection, can increase metastases. Simi-
larly, acute stress was found to increase lung metastases
when applied 1 h but not 24 h before tumor injection. The
stress procedure employed in this study used five succes-
sive cycles of placing a 45 grkg weight on the tails of rats
114 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
which were then placed for 3 min in a tank containing
water at 378C w34x. It is noteworthy that enhanced levels of
ACTH and corticosterone were found in stressed animals.
Moreover, preliminary studies had shown that acute isola-
tion stress and intermittent footshock also appeared to
enhance the level of metastases.
As to possible mediators of the effects of stress on
tumor metastasis, the interest in adrenal steroids was cat-
alyzed in part by a well known study suggesting that
chronic stress might induce greater pathophysiological
changes in aged rather than young rats, since aged animals
show a delay in termination of their adrenocortical stress
response and therefore hypersecrete corticosterone in the
poststress period; it was found that stress-induced tumor
growth, associated with the inoculation with fetal rat cells
transformed by a tumor virus, is accelerated in aged rats
w386x. Moreover, simulation of the aged pattern of cortico-
sterone hypersecretion in young rats by steroid administra-
tion was also found to accelerate stress-induced tumor
growth. Whereas this remains an attractive mechanism, it
is premature to conclude that it is the only mechanism, in
light of the parallel and interactive role of other agents
such as sympathetic innervation and opioids Žsee Section 2
above.. Furthermore, as noted above and in Table 1,
adrenal steroids have facilitative as well as inhibitory
effects on aspects of immune function.
Recent studies have examined the effect of adrenalec-
tomy on B16 melanoma pulmonary tumor metastases and
immune functions in C57BLr6 mice to investigate the role
of adrenal corticosteroids w254x. Adrenalectomized mice
were injected with 105 B16 melanoma cells on day 0. On
day 10 the mice were killed and the number of lung
colonies counted. Adrenalectomized animals had a three-
to-four fold increase in the number of metastases as com-
pared with sham operated animals. Steroid replacement
therapy using dexamethasone delivered at 1 mgrh did not
lead to any reduction in tumor metastases in adrenalec-
tomized animals. However, other doses of glucocorticoids,
including the natural glucocorticoid, corticosterone, have
not yet been attempted. It remains to be demonstrated
whether the effects of adrenalectomy are due to the ab-
sence of adrenal steroid or catecholamines or both and
whether normal levels of adrenal steroids may influence
the ability of tumor cells to colonize target organs andror
the ability of the immune system to mount an effective
anti-tumor response. A logical inference is that the com-
bined ability of catecholamines and glucocorticoids to
facilitate immune cell redistribution and to support a de-
layed-type hypersensitivity response may be involved Žsee
subsection 4.2.3..
It has recently been observed that B lymphocytes, ab-
sent from the lung under normal conditions, rapidly in-
crease in the lung within hours after the introduction of
MADB106 tumor cells into Fischer rats w357x. This has led
to the hypothesis that infiltration of B cells may be impor-
tant for the control of metastases. Dr. Jay Weiss and
colleagues have suggested that the identification of changes
that occur in lymphocyte populations in the lung in re-
sponse to the infusion of tumor cells may be quite helpful
to both describe the immunological events by which
metastases are regulated and to describe sequential points
in time at which stress-induced physiological changes in-
tervene to modulate this outcome. Indeed, B-cells are the
most glucocorticoid-sensitive lymphocytes and glucocorti-
coids affect the distribution of lymphocytes in the body
w116x. Therefore, it has been suggested by Jay Weiss and
colleagues that it is possible that B lymphocytes that
contribute to tumor surveillance may be particularly vul-
nerable to stress-induced elevation of glucocorticoids. It is
likely that selective studies with adoptive transfer of puri-
fied populations of effector cells with available methodol-
ogy might be particularly useful in further examining these
issues Že.g., w24,25,166,172x.. Moreover, a detailed investi-
gation of the biochemical mechanisms underlying lympho-
cyte cytotoxicity and migration may also ultimately yield
insights into these processes w171,255,455x.
In addition to the animal research studies described
above, it is also noteworthy that many recent studies
dealing with cancer, stress, neuroendocrinology and psy-
choneuroimmunology relevant to cancer have also been
studied in patients. The reader is directed to a number of
recent reviews that are beyond the scope of this review
w211,277,364,376x.
5.2.6. Summary
Stress has been shown to affect the progression of a
variety of tumors, and, in most cases, the effects of stress
are to exacerbate tumor metastasis. Most studies have
utilized relatively acute or short term stressors, and one
series of studies has uncovered a critical window during
which acute stress can accelerate tumor spread w398x. This
study also utilizes syngeneic tumor cells and circumvents
problems associated with some earlier studies that have
employed tumor allogeneic tumor cells, for which the body
may have additional possibilities for tumor rejection via
immune recognition of differences from self.
This finding is relevant to human studies that have
revealed windows of vulnerability with respect to surgery
for breast cancer w17,90x. In contrast to short term effects
of stress, only a few investigations have begun to address
the long-term consequences of stress and psychosocial
interventions. It has been noted that the timing of surgery
for operable breast cancer in relation to the phase of the
menstrual cycle might affect the outcome in pre-
menopausal women w17,90x. It is also of interest that the
effects of psychosocial treatments have been investigated
on the time of survival for patients with metastatic breast
cancer w418x. Patients with metastatic breast cancer that
had been randomized to weekly group therapy for one year
lived significantly longer, for an average of approximately
eighteen months, than did controls.
As to mediators of the effects of stress and psychosocial
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133 115

influences on the progression of tumors, the influence of

adrenal steroids and other neuroendocrine and neural mod-
ulators of immunity are being given top priority. Recent
evidence suggests that adrenal steroids not only have
long-term negative influence over tumor progression, but
that they may be involved in the short-run in mobilizing
the immune mechanisms that can fight the metastatic
invasion of a solid tumor into other organs or the ability of
an injected tumor to ‘take’. The demonstrated ability of
adrenal steroids to mediate immune cell redistribution and
to enhance delayed-type hypersensitivity responses may be
relevant.
While studies to date have emphasized immune andror
neuroendocrine-based mechanisms of the effects of stress
on tumor growth, other areas where an effect can be
envisioned include possible effects on the tumor itself,
through modulations of its invasiveness, motility, and an-
giogenesis. Indeed, when considering the potential direct
effects of stress and neuroendocrine agents on tumors, i.e.,
not operative through the immune response, it is important
to keep in mind the complexity of tumor invasiveness,
described above and represented in Fig. 14, which con-
tributes to tumor progression and metastatic spread
w167,168x. This is an important direction for future re-
search.

5.3. Glucocorticoids, autoimmune and inflammatory dis-

ease

5.3.1. Background
Pharmacologic doses of adrenal steroids and their syn-
thetic analogs, have been used as potent immunosuppres-
sive and anti-inflammatory agents in the treatment of
autoimmune disease and in a variety of other clinical
situations Žfor a review see w77x.. In addition, it has also
been hypothesized that glucocorticoids might also be re-
sponsible under physiological conditions, for the suppres-
sion of an ongoing immune response so as to prevent it
from reaching levels of reactivity which might cause dam-
age to self w328x. Strong support for this hypothesis comes
from studies which show that adrenalectomized rats die
within 24–48 h after being immunized with horse serum or
Freund’s Complete Adjuvant ŽFCA., but they can be res-
cued by corticosterone replacement therapy w121,122x. A
number of studies involving animal models of inflamma-
tory disorders and autoimmune disease also lend support
for this hypothesis w293x. These studies are based on the
premise that there exists a negative feedback loop between
the immune system and the HPA axis, such that pro-in-
flammatory mediators arising from an ongoing immune
reaction stimulate the HPA axis w40,260,328,385x which in
turn results in the secretion of corticosterone which sup-
presses the immune response and prevents it from poten-
tially damaging the host. Fig. 15.
Current evidence suggests that three contributing factors
result in susceptibility to inflammatory and autoimmune
Fig. 15. Diagram of adrenal steroid containment of inflammatory and
autoimmune responses. Corticosterone is hypothesized to have a primary
suppressive effect on the ongoing inflammatory response. Mediators of
inflammation, such as the cytokines produced by leukocytes at the site of
inflammation, are hypothesized to stimulate the release of CRH from the
hypothalamus and the release of ACTH from the pituitary. This in turn
stimulates corticosterone secretion, which feeds back to inhibit inflamma-
tory responses and keeps them under control.
disorders: first, is the presence of host immune response
genes that carry the potential for contributing to autoimmu-
nity. Second, is exposure to a proinflammatory or anti-
genic challenge which initiates the cascade of immune
reactions that ultimately result in auto-reactivity. Finally,
there is a deficiency in the hypothalamic-pituitary-adrenal
ŽHPA. axis such that it is not capable of mounting an
appropriate immuno-suppressive corticosterone response in
reaction to an immune challenge. Numerous studies have
elegantly investigated the role played by the HPA axis in
protecting the host from autoimmune reactions and some
of these studies are discussed below.
5.3.2. Glucocorticoids and suppression of streptococcal
cell wall-induced arthritis
Sternberg and coworkers have investigated the influ-
ence of the HPA axis on the development of streptococcal
cell wall ŽSCW.-induced arthritis in female rats belonging
116 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
to the genetically related LewisrN ŽLEWrN. and Fischer
344rN ŽF344rN. strains w426–429x. SCW-induced arthri-
tis is induced by a single intraperitoneal injection of group
A streptococcal cell wall fragments. The symptoms include
a severe, rapid onset, acute arthritis which is followed by a
chronic, erosive phase of the disease. It has been shown
that athymic LEW rats develop the acute phase of the
disease, but fail to develop the chronic phase. This indi-
cates that the chronic phase is thymus-dependent, but the
acute phase is not. The HPA axis is thought to play a
major role in the suppression of the acute phase of the
disease and hence to impede its progression into the
chronic phase.
The F344rN strain is resistant to the development of
SCW-induced arthritis whereas the LEWrN strain is sus-
ceptible to this disease. Interestingly, the F344rN strain
mounts a significantly higher corticosterone and adreno-
corticotropin ŽACTH. response than the LEWrN strain
when challenged with a variety of stressors or with inflam-
matory mediators like SCW peptidoglycan polysaccharide
or interleukin-1a ŽIL-1a .. Further, F344rN rats treated
with the glucocorticoid receptor antagonist, RU486, are
rendered susceptible to SCW-induced arthritis indicating
that they do carry the immune response genes with poten-
tial for triggering autoimmunity. Conversely, LEW rats
treated with pharmacologic doses of dexamethasone, be-
come completely resistant to the development of SCW-in-
duced arthritis. Moreover, compared to Fischer 344 ŽF344
rats., adrenal steroid receptors in neural and immune tis-
sues of Lewis ŽLEW. rats show a significantly lower
magnitude of activation in response to stress-induced in-
creases in plasma corticosterone. Thus, strain differences
in plasma corticosterone levels are also manifest as signifi-
cant differences in the extent of activation of cortico-
sterone receptors in target tissues.
In view of the observations described above, it has been
hypothesized that the robust corticosterone response
mounted by the F344rN strain Žin response to inflamma-
tory mediators released by the SCW-induced immune reac-
tion. suppresses the acute inflammatory response and pre-
vents it from becoming self-reactive. In contrast, the weaker
corticosterone response mounted by the LEWrN strain is
thought to be insufficient to suppress the initiation and
progression of an autoimmune response.
5.3.3. Glucocorticoids and suppression of experimental
allergic encephalomyelitis (EAE)
Experimental allergic encephalomyelitis ŽEAE. is an-
other animal model of an autoimmune disease in which the
HPA axis is thought to play a suppressive role Žfor a
review see w293x.. EAE can be induced by immunization of
animals with guinea pig myelin basic protein ŽMBP. ho-
mogenized in Freund’s Complete Adjuvant or by adoptive
transfer of splenocytes from an animal with EAE to a
syngeneic recipient w276,373x. Susceptible strains of rats
Fig. 16. Comparison of susceptibility to EAE of PVG Žsolid square;
ns6. and Lewis Žopen square; ns 5. rats. On day 0 of the experiment,
age- and sex-matched rats of each strain were immunized with guinea pig
myelin basic protein in the hind footpads and were followed for signs of
EAE.
develop a paralytic disease 10–12 days after injection. The
disease phase lasts for 4–5 days after which it remits
spontaneously and animals which recover are refractory to
further attempts to induce the disease.
The LEW strain shows the greatest susceptibility to
EAE, the PVG strain is resistant Žsee Fig. 16.. A large
increase in serum corticosterone levels is observed in LEW
rats during the disease phase and this increase persists until
remission. Adrenalectomy performed before symptoms ap-
pear prevents spontaneous recovery and results in progres-
sion of the disease leading to death. Corticosterone re-
placement in adrenalectomized animals results in recovery
from the disease. Adrenalectomy performed after recovery
has begun, does not hinder further recovery and permits
the development of the refractory phase. The PVG strain is
resistant to the disease. Like the F344 strain, PVG rats
have larger adrenals and mount a greater corticosterone
response to stress than LEW rats. Adrenalectomized PVG
rats are rendered susceptible to EAE, but corticosterone
replacement can rescue adrenalectomized rats from devel-
oping the disease. MacKenzie et al. w286x have suggested
that during the pre-clinical phase of EAE, elevations in
plasma corticosterone may regulate the lymphoprolifera-
tive stage of the disease and that during the clinical phase
of the disease, elevations in plasma corticosterone as well
as splenic norepinephrine may regulate other recovery-ori-
ented immune mechanisms w272x.
Thus, corticosterone is thought to be a major factor in
the suppression of the initial phase of EAE and for the
transition to the refractory phase. Resistance to EAE in the
refractory phase is thought to be dependent on immune
mechanisms independent of regulation by adrenal hor-
mones, since adrenalectomy after recovery from EAE does
not hinder the development of the refractory phase once it
has begun. Moreover, splenocytes from animals in the
refractory phase respond to MPB in vitro and can transfer
EAE to normal recipient animals w36x.
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
5.3.4. EnÕironmental stress-induced suppression of au-
toimmunity
Numerous studies have investigated the effects of envi-
ronmental or psychological stress on autoimmune reac-
tions. Levine et al. w275x have demonstrated that the ad-
ministration of restraint stress to LEW rats before the
induction of EAE resulted in a suppression of the inci-
dence and severity of disease. Administration of restraint
stress after the induction of EAE did not confer protection.
However, prolonged restraint stress Ž7 h per day, 5 days.
administered during the remission period protected stressed
animals from a second episode of EAE which was ob-
served in unstressed controls w275x. The authors hypothe-
sized that increased corticosterone secretion resulting from
the stress of paralysis suppressed the initial attack of EAE.
They further hypothesized that a decrease in plasma cor-
ticosterone resulting from remission of the disease in-
creased susceptibility to a second occurrence of EAE.
Rogers et al. Ž1980. have shown that exposure of LEW
rats to a variety of stressors Žexposure to a predator,
handling and transportation. resulted in a marked suppres-
sion of the clinical and histological manifestations of
Type-II collagen-induced arthritis w308x. As described be-
low, Griffin et al. have also demonstrated suppression of
EAE by prolonged repeated restraint stress w180x.
5.3.5. Glucocorticoid-induced suppression of autoimmune
and inflammatory reactions — possible mechanisms
The inhibitory effects of glucocorticoids on leukocyte
trafficking into a site of inflammation Ždiscussed earlier.
may partially mediate glucocorticoid suppression of au-
toimmune reactions. Furthermore, Mason Ž1991. has hy-
pothesized that stimulation of the HPA axis by inflamma-
tory mediators released during the initiation of the EAE
autoimmune response results in increased plasma cortico-
sterone w293x. Increased corticosterone levels shift the bal-
ance of the ongoing immune reaction from a TH 1-directed
Žcell-mediated. response towards a T H 2-directed Žanti-
body-mediated. response, by promoting the production of
IL-4 and suppressing the production of IL-2 Žas discussed
earlier in this review. w105x. Since the pathology associated
with EAE is thought to be the result of activation of T
cells auto-reactive with peptide fragments of myelin basic
protein w422x, the net result of this shift from cell-mediated
to humoral immunity could be the suppressed EAE.
Griffin and coworkers w180x have shown that repetitive
restraint stress administered to LEW rats before MBP
challenge, resulted in suppression of the clinical and
histopathologic changes associated with EAE. However,
the same stress regimen had no effect on the clinical
course of EAE in rats challenged with MBP peptide
fragment 68–88 ŽMBP 68–88. suggesting that the stress-
induced increase in corticosterone could be affecting
mechanisms involved in processing andror presentation of
the encephalitogen. Importantly, a decrease in frequency of
MBP-reactive cells and a decrease in production of IL-2
117
and IFN-a Ži.e., a condition which would favor a humoral
immune response. was observed in stressed animals rela-
tive to controls.
Antibodies directed against the encephalitogen, MBP,
may be involved in the suppression of EAE, since it has
been reported that anti-MBP antibodies are first detected at
the beginning of the refractory phase after plasma cortico-
sterone levels rise in response to the initial phase of EAE
w287x. Further, it has been observed that symptoms in the
initial phase of the disease are minimal if an animal makes
an anti-peptide antibody response during the early stages
of EAE. Finally, if Lewis rats are immunized with differ-
ent doses of MBP peptide linked to bovine serum albumin
ŽBSA., recipients of low doses make fewer anti-peptide
antibodies and show severe clinical symptoms, the con-
verse being true for recipients of high doses w293x. It is
also possible, that part of the mechanism of suppression
may involve the generation of anti-idiotypic antibodies
directed against variable regions of autoreactive T cell
receptors.
Interestingly, in the case of myasthenia gravis, an au-
toantibody-mediated disease in humans, early investigators
found that intensive treatment of patients with steroids
exacerbated the symptoms. Therefore, the current treat-
ment regimen involves a short initial intensive treatment
followed by alternate-day steroid therapy. Improvement is
observed 10–15 days after the beginning of therapy w79x. It
may be hypothesized that during the initial period of
steroid treatment, the promotion of an antibody-biased
response by steroid treatment might exacerbate the disease
by stimulating autoantibody production. However, later
during steroid treatment, the production of inhibitory anti-
bodies or the activation of other immunosuppressive mech-
anisms might result in suppression of the disease.
Furthermore, recent studies indicate that CD8 q T cells
are involved in the development of the refractory phase of
EAE. Koh and coworkers have shown that CD8 y ry
mice generated from homologous recombination in embry-
onic stem cells, show less mortality but more relapses in
EAE w258x and Jiang et al. Ž1992. have shown that animals
depleted of CD8 q cells by antibody-mediated clearance
show spontaneous recovery from the initial onset of EAE,
but they fail to show resistance to further recurrence of the
disease w227x. It would be interesting to examine whether
the resistance to EAE mediated by CD8 q suppressor cells
could be transferred to naive recipients by adoptive trans-
fer of CD8 q suppressor cells from donor animals in the
refractory phase. Thus, glucocorticoid hormones may play
a role in the development of resistance to EAE by inducing
the formation of anti-encephalitogen antibodies, anti-idio-
typic antibodies and CD8 q suppressor T cells. The mech-
anisms by which glucocorticoids confer this protective
immunosuppression and the immune factors responsible
for effectuating suppression need to be further investi-
gated.
Wilder et al. Ž1986. have demonstrated an increase in
118 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
expression of class II major histocompatibility antigen ŽIa.
in synovial tissues which parallels the development of
SCW-induced arthritis w470x. This increase is observed in
the susceptible LEW strain, but not in the resistant F344
strain w470x. Doeberitz et al. Ž1990. have shown that
long-term treatment with dexamethasone reduces surface
expression, membrane bound protein and mRNA of class I
major histocompatibility antigen on human epithelial cells
w120x. Since strain differences in the ability to mount a
corticosterone response to immune challenge are thought
to be responsible for the strain differences in resistance to
SCW-induced arthritis, it may be hypothesized that gluco-
corticoids may play a role in preventing the immunostimu-
latory upregulation of Ia expression.
Recent evidence suggests that corticotropin-releasing
hormone ŽCRF. produced in peripheral inflammatory sites
might stimulate inflammatory reactions at these sites w236x.
CRF has been shown to stimulate numerous immune func-
tions. Stephanou et al. Ž1990. have demonstrated CRF
mRNA and immunoreactivity in human leukocytes and
CRF binding sites have also been observed on leukocytes
w404x. Importantly, Karalis et al. Ž1991. have shown that
administration of antiserum to CRF significantly sup-
presses inflammatory exudate volume and cell concentra-
tion in a model involving carrageenin-induced aseptic in-
flammation w236x. Further, the same authors have shown
that glucocorticoids ŽDexamethasone, 50 mg. inhibit the
production of immune CRF. Thus, it might be hypothe-
sized that part of the immunosuppressive actions of gluco-
corticoids may involve suppression of CRF production at
sites of inflammation.
Glucocorticoids also have other actions with regard to
inflammation, involving the hydrolysis of phospholipids
and the production of proinflammatory substances. Some
of the anti-inflammatory effects of glucocorticoids may be
due to the inhibition of the production of proinflammatory
metabolites elaborated from the cellular second messenger,
arachidonic acid w147,206x. Adrenal steroids have been
shown to induce the synthesis of a family of phospholipase
inhibitory proteins referred to as lipocortins. Lipocortins
inhibit phopholipases Žespecially phopholipase A 2 . which
are responsible for releasing arachidonic acid from mem-
brane phospholipids w149,206x. Arachidonic acid is the
precursor for a variety of inflammatory compounds known
as eicosanoids including the prostaglandins and leuko-
trienes. These molecules have been demonstrated to influ-
ence vascular permeability, smooth muscle contraction,
vasodilitation, neutrophil chemotaxis, pain thresholds and
pyrogenesis, all important components to the classic symp-
toms of inflammation including redness Žrubor., heat
Žcalor., swelling Žtumor., pain Ždolor. and loss of function
Žfunctio laesa.. Lipocortins also reduce lysozyme release
and superoxide Ž0 2 . production w206,291x. Interestingly,
although adrenal steroids exhibit profound effects on
arachidonic acid metabolism in vitro, several studies have
failed to demonstrate decreases in the production of
eicosanoid metabolites following in vivo administration of
glucocorticoids w334,392x. Moreover, several of the cellular
effects of adrenal steroids on inflammation can not be
reproduced by administration of lipocortins alone w213x.
Taken together, the data indicate that the adrenal steroid
effects on immune and inflammatory responses via
lipocortin remain to be clarified.
5.3.6. Summary
Glucocorticoid effects on autoimmune diseases and in-
flammatory reactions are among the best-studied examples
of the modulatory and beneficial actions of adrenal steroids
on the responses of the immune system to external and
internal challenges. Glucocorticoid containment of the pro-
duction of proinflammatory substances such as arachidonic
acid and CRF constitute mechanisms that are well delin-
eated at the cellular and molecular level. What is less clear
is the mechanism by which genotype influences the effi-
cacy of glucocorticoid containment effects. There is also
need for mechanistic studies to uncover the basis of gender
differences that make females more susceptible to autoim-
mune and inflammatory disturbances.
5.4. Genetic differences in hypothalamo-pituitary-
adrenal-axis responsiÕity — effects on resistance to au-
toimmune disease, infection and cancer
We have emphasized in this review that the real test of
understanding of modulators of immunity is to examine
how stress and other environmental challenges affect the
progression of disease processes, rather than relying on
short-term studies of how a manipulation alters some
isolated measures of immune function. We have also noted
that there are many instances where stressors and glucocor-
ticoids actually protect and reduce symptoms. This sug-
gests that the make up of an individual — e.g., whether
having high or low glucocorticoid or sympathetic reactiv-
ity — may be protective against some diseases while
making the same individuals more vulnerable to other
disorders. Genotype and early developmental influences
are very important, both in directly determining suscepti-
bility to disease and also in determining factors like auto-
nomic and neuroendocrine reactivity which also affect
disease susceptibility w300x. The following examples show
how these multi-dimenional factors interact to ultimately
affect disease outcome.
In the case of autoimmune disease, we have seen above
ŽSection 5. that strains of animals which show a robust
HPA axis response to environmental stress and immune
challenges are relatively resistant to autoimmune diseases
even if they carry potentially autoreactive immune re-
sponse genes and even if they have been exposed to
antigens capable of inducing an autoimmune reaction.
However, one might hypothesize that a robust HPA axis
response which confers protection against an autoimmune
disease via immunosuppression, might result in greater
 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
susceptibility to infectious diseases and cancer which re-
quire a strong and active immune response for their elimi-
nation. The significantly lower corticosterone response to
stress and immune challenge observed in LEW rats com-
pared to F344 rats and the significantly lower activation of
adrenal steroid receptors seen in immune tissues of LEW
rats, may contribute to the increased susceptibility of the
LEW strain to autoimmune diseases. However, these con-
ditions might also serve to protect this strain from diseases
like viral or bacterial infections and cancer which require
an active immune response for their elimination. In con-
trast, the substantially higher levels of corticosterone
Žwhich result in greater activation of adrenal steroid recep-
tors in immune tissues. of F344 rats may protect them
from autoimmune diseases, but may also be responsible for
the reported susceptibility of this strain to diseases like
cancer.
In the case of infectious disease, a similar example is
seen in differences between BALBrc andC57BL6 mice in
their ability to resist infection with Leishmania major. The
BALBrc strain is susceptible to infection whereas the
C57BL6 strain is resistant w195x. Compared to C57BL6
mice, BALBrc mice show a more robust corticosterone
response to stress w293x. It has been hypothesized that the
stronger corticosterone response induced by infection in
BALBrc mice results in a bias towards a T H 2-directed,
humoral immune response which results in susceptibility
to infection. In contrast, the lower corticosterone response
of C57BL6 mice favors a TH 1-directed, cell-mediated
response which confers resistance to the parasite w293x.
Importantly, administration of anti-IL-4 antibody to L.
major-infected BALBrc mice confers resistance to further
infection suggesting that IL-4 may participate in the sup-
pression of cell-mediated immune responses w377x.
Thus, because of the important role of glucocorticoids
in regulating the class of the immune response and the
differential involvement of cellular and humoral immunity
in the resistance to various pathogens, intrinsic differences
in the ability of the HPA axis to respond to stressful
stimuli and immunologic challenge may translate into dif-
ferences in the ability to resist autoimmune or infectious
diseases and cancer. These differences are clearly observed
as species or strain differences, but they may also con-
tribute significantly to individual differences within strains
in relative susceptibility or resistance to disease. Such
individual differences are especially relevant for exten-
sively outbred populations like those of humans. It may be
hypothesized that individuals who show a low HPA axis
responsivity may be relatively susceptible to autoimmune
diseases, but resistant to infectious diseases and cancer.
Similarly, individuals who show a high HPA axis respon-
sivity may be relatively resistant to autoimmune diseases,
but susceptible to infectious diseases and cancer. Thus,
while genetic factors acting at the level of the immune
system may render an individual susceptible to a certain
disease, genetic andror environmental factors acting at the
119
level of the neuroendocrine system may be able to com-
pensate for the immune defect and confer protection upon
susceptible individuals.
6. Conclusions
6.1. A new Õiew of adrenal steroid effects on immune
function
In this article, we have summarized many aspects of
glucocorticoid actions on the immune response; and we
have emphasized the physiological role that adrenal steroids
play as modulators of the immune system, in contrast to
the more traditional view of glucocorticoids as immuno-
suppressors.
First, it is clear that the endogenous glucocorticoids
have far more limited access to adrenal steroid receptors in
immune tissues than synthetic glucocorticoids and that the
actions of synthetic glucocorticoids such as dexamethasone
and prednisone give a distorted picture of the role of these
steroids in immune function. There appear to be protective
mechanisms, such as corticosteroid binding globulin, that
buffer organs such as the spleen and thymus from too
much of the endogenous glucocorticoids. This protective
mechanism does not work in the case of synthetic gluco-
corticoids such as dexamethasone.
Second, two types of receptors for adrenal steroids are
found in immune cells. Although there is yet no clear-cut
role for Type-I receptors, which are present in low levels
and not in all immune cell types, some recent evidence
points to a role for these receptors in the trafficking of
immune cells between blood and various organs. Type-II
receptors show a widespread distribution in the immune
system and are expressed in different levels in different
immune cells, being very high in immature thymus lym-
phocytes, at an intermediate level in mature T and B cells
and at very low level in neutrophils. It also appears likely
that adrenal steroid receptor expression changes as a func-
tion of immune cell activation and maturation and that the
functions that are regulated by the receptors change with
the functional state of the immune cells.
Third, there are many immune processes that are regu-
lated by adrenal steroids. Cytokine production is regulated
in such a way that adrenal steroids can influence the class
of the immune response by enhancing humoral immunity
and suppressing cellular immunity. Yet, the presence of
elevated glucocorticoids very early in an acquired immune
response does have an overall suppressive effect. More-
over, glucocorticoids participate as agents promoting cell
death in immature thymocytes, but they can also block the
apoptosis stimulated by T cell receptor activation. Perhaps
the most under-appreciated aspect of adrenal steroid ac-
tion, however, is the trafficking of immune cells between
the blood and various immune compartments and other
organs of the body. It is very important to adequately test
120 B.S. McEwen et al.r Brain Research ReÕiews 23 (1997) 79–133
the hypothesis that adrenal steroid elevations help cells of
the immune system to go ‘to their battle stations’ during an
infection or spread of cancer cells. Moreover, the mecha-
nism for trafficking, possibly involving the hormonally
regulated expression and activity of cell adhesion molecules
and other factors, requires careful studies not only of
immune cells themselves but also of the blood vessels
through which they must pass to leave the blood stream
and enter tissues and organs. Further studies of the mecha-
nism for glucocorticoid involvement in enhancing the de-
layed-type hypersensitivity response under physiological
conditions of stress should provide an excellent system for
recognizing the role of adrenal steroids in relation to other
modulators.
Fourth, studies of the effects of acute and chronic stress
on immune function and on the disease outcomes influ-
enced by the immune system have not led to any single
conclusion about whether stress is ‘good’ or ‘bad’. Cer-
tainly, this is not surprising given that glucocorticoids are
only one of many modulators of immune function and that
the glucocorticoids themselves have different effects on
immune system function depending upon dose, type of
steroid and where in the immune system the effects are
being measured: e.g., spleen or circulating lymphocyte. In
fact, more studies are required to better characterize the
consequences of long-term stress on the immune system
and to define effects of ‘allostatic load’ w297x Žwear and
tear produced by chronic elevation of adaptive response
systems. on immune function.
6.2. An important role for other immune modulators
In the future it will be essential to study adrenal steroid
modulation of the immune system in relation to other
agents that also modulate immune function, including au-
tonomic innervation, endogenous opioids, and other neu-
ropeptides and circulating protein hormones such as in-
sulin, prolactin, and growth hormone. As indicated in
Table 1, current information indicates that adrenal steroids
have numerous points of interaction with these other im-
mune modulators.
With regard to the autonomic nervous system, we have
noted the evidence that immune function is suppressed by
activation of the sympathetic nervous system. It is impor-
tant to note that the spleen is a relatively privileged site
and relatively inaccessible to endogenous glucocorticoids,
but not to synthetic glucocorticoids. Yet, glucocorticoids
do regulate the b adrenergic receptors on circulating lym-
phocytes ŽTable 1., where it has been shown that they gain
access to glucocorticoid receptors. Moreover, as is the case
for adrenal steroids, the influence of the sympathetic ner-
vous system cannot be interpreted simplistically and the
sympathetic nervous system, like the HPA axis, can have
both positive and negative effects on the immune system.
Another important lesson, equally applicable to sympa-
thetic and glucocorticoid modulation of immunity, is that
the coordinated response to pathogens is not necessarily
well represented by assessment of how the sympathetic
nervous system affects specific elements of the immune
cascade, but rather the entire course of a disease must be
investigated in some detail.
We have noted that glucocorticoids alter the production
and actions of other modulators of immune function such
as corticotrophin releasing factor ŽCRF. and IL-1. These
agents, acting in brain, appear to be involved in stress-in-
duced changes in immune responses, such as suppression
of NK activity. IL-1 effects appear to operate through CRF
and ultimately through the sympathetic nervous system
and HPA axis. Other modulators include a variety of
peptide neuromodulators and hormonesendogenous opoid
peptides and we have noted that these may act directly on
immune cells or indirectly through CNS mechanisms.
Clearly, much more must be done to characterize these
effects and tie them together with the other modulatory
systems.
Acknowledgements
This work was supported by the John D. and Catherine
T. MacArthur Foundation Health Program and the Health
and Behavior Network ŽJudith Rodin, Chair, and Grace
Castellazzo, Administrator..
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