Immunology and Cell Biology (2001) 79, 395399

Special Feature
Hypothalamicpituitaryadrenal axis regulation of inflammation in
rheumatoid arthritis
ERIC F MORAND and MICHELLE LEECH

Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton,
Victoria, Australia

Summary The profound anti-inflammatory effects of glucocorticoids in drug therapy are reflected in the effects
in vivo of endogenous glucocorticoids produced by the adrenals. The production of adrenal glucocorticoids is
driven by the hypothalamus and pituitary, which in turn are responsive to circulating products of the inflammatory
response, especially cytokines. That inflammation can drive the production of anti-inflammatory glucocorticoids
denotes the hypothalamicpituitaryadrenal (HPA)-immune axis as a classic negative feedback control loop.
Defects in HPA axis function are implicated in susceptibility to, and severity of, animal models of rheumatoid
arthritis (RA), and are hypothesized to contribute to the human disease. In this paper, data supporting the concept
of the HPA axis as a regulator of the inflammatory response in animal models of arthritis are reviewed, along with
data from studies in humans. Taken together, these data support the hypothesis that the HPA axis provides one of
the key mechanisms for inhibitory regulation of the inflammatory response. Manipulation of HPA axis-driven
endogenous anti-inflammatory responses may provide new methods for the therapeutic control of inflammatory
diseases.

Key words: adrenal glands, cytokines, glucocorticoids, hypothalamicpituitaryadrenal axis, rheumatoid arthritis.

Introduction glucocorticoids among the range of counter-regulatory

systems built into the immune system.
Rheumatoid arthritis (RA) is one of the most common and
In this review, studies on the role of endogenous gluco-
serious chronic inflammatory diseases in humans. Although
corticoids in regulating inflammation in RA and its models
debate continues as to their place in the treatment of RA,
will be discussed. Prior to reviewing data from studies in
glucocorticoids clearly exert profound and broad-spectrum
humans, studies in animal models, which permit the assess-
inhibition of the immune-inflammatory response and have
ment of glucocorticoid effects on arthritis susceptibility,
been used in the treatment of RA for over 50 years.1 An
severity and mechanisms of action, will be reviewed.
understanding of the interaction between the glucocorticoid
receptor and nuclear factor-B (NF-B) has, in recent years,
provided for the first time a mechanistic basis for under- Studies in animal models
standing the breadth of glucocorticoid effects.2 The concept
Evidence that intrinsic defects in the HPA axis may
that endogenous glucocorticoids produced by the adrenal
contribute to the susceptibility to inflammatory disease is
glands, under the control of the hypothalamus and pituitary,
difficult to acquire from studies in humans, where the onset
have an important role in the control of inflammation has
of inflammation per se leads to difficulty discerning pre-
emerged more recently. It is now clear that the presence of
existing deficits from those that ensue from the inflammatory
inflammation, through the release of cytokines including IL-1,
process itself. The association between susceptibility to
TNF- and IL-6, provides a direct stimulus to the activity of
inflammatory disease and blunted HPA-axis responses has
the hypothalamus and pituitary, resulting in the production of
been examined in animal models. Lewis rats (LEW/N) are
adrenal glucocorticoids under the influence of adrenocorti-
highly susceptible to inflammatory disease, compared with
cotrophic hormone (ACTH).3 As glucocorticoids inhibit
the relatively resistant, histocompatible Fischer strain (F344).
aspects of the immune-inflammatory response including the
This is most apparent in their increased susceptibility to
production of these cytokines, this constitutes a classical
streptococcal cell wall (SCW)-induced arthritis demonstrated
negative feedback control loop. This paradigm represents
by Sternberg et al.4 This inherent susceptibility to arthritis
a framework for understanding the place of endogenous
was subsequently related to a biosynthetic defect in corti-
cotropin-releasing hormone (CRH) in Lewis rats, resulting in
blunted corticosterone responses to challenge with SCW.5
Correspondence: Dr EF Morand, Centre for Inflammatory Accordingly, susceptibility in Lewis rats is reversed by
Diseases, Department of Medicine, Monash University, Monash administration of glucocorticoids in the physiological range
Medical Centre, 246 Clayton Road, Clayton, Vic. 3168, Australia. just as glucocorticoid receptor blockade in Fischer rats over-
Email: eric.morand@med.monash.edu.au comes resistance to SCW arthritis.4 In common with Lewis
Received 18 April 2001; accepted 18 April 2001. rats, inbred dark Agouti rats (DA) are susceptible to a wide
396 EF Morand and M Leech
range of experimental autoimmune diseases including both
collagen and adjuvant-induced arthritis. Pre-existing abnor-
malities in the circadian rhythm of corticosterone with blunt-
ing of the normal diurnal variation are demonstrable in both
strains prior to the onset of experimental arthritis.6 Indeed
knowledge of existing physiological fluctuations in endoge-
nous glucocorticoids levels has been exploited to ascertain
how these hormones may control the immune response. An
extensive study of the diurnal variation in immune cell
subsets and function in rats found a strong inverse correlation
between leucocyte numbers and plasma corticosterone levels,
supporting the importance of glucocorticoids in mediating
this diurnal rhythm.7
Blunted plasma corticosterone responses have been
described in lupus-prone mice prior to the development of
clinical symptoms.8 The recent development of a CRH-
deficient mouse by targeted gene disruption would initially
seem to contradict some of these observations, in that these
rats do not display an increased propensity for the sponta-
neous development of inflammatory disease. It should be
noted, however, that their responses to exogenous inflamma-
tory challenge have not been extensively examined, and
circulating corticosteroid levels in these rats are similar to
wild type, suggesting some ontologic adaptation to the
absence of CRH.9
Animal studies provide abundant evidence that the HPA-
axis response limits inflammation and that interrupting this
adaptive response increases disease severity. In adjuvant
arthritis, there is chronic activation of the HPA axis and loss
of circadian rhythm.10 The disease exacerbation that results
from adrenalectomy in adjuvant arthritis (AA) is accompa-
nied by increased circulating cytokines, including IL-1,11 as
well as increased pituitary IL-6 mRNA and increased splenic
IL-1 expression.12 These findings, particularly the increased
systemic cytokine production, have been postulated to con-
tribute to the increased mortality that is consequent on
adrenalectomy of rats with adjuvant arthritis.13 In adrenalec-
tomised rats with adjuvant arthritis, peripheral blood leuco-
cyte levels of the glucocorticoid-induced anti-inflammatory
protein, annexin I, are reduced compared with sham-operated
rats.14
Endogenous glucocorticoid blockade using RU486 is
associated with enhanced polymorphonuclear neutrophil
(PMN) recruitment in the carrageenan arthritis model in rats.
In this model, endogenous glucocorticoids were demon-
strated to modulate synovial P-selectin expression.15 Evi-
dence that physiological glucocorticoids influence adhesion
molecule expression is found in studies of the spontaneously
hypertensive rat strain (SHR). In these rats, the blunted P-
selectin-mediated rolling response is reversed by administra-
tion of the glucocorticoid receptor antagonist RU486.16 In
both SHR and normotensive Wistar control rats, adrenalec-
tomy resulted in elevated leucocyte adhesion.
In addition to the influence of glucocorticoids on inflam-
matory disease severity and susceptibility, the influence of
glucocorticoids on mechanistic factors relevant to RA patho-
physiology has been examined using animal models. Gluco-
corticoids are known to attenuate adrenal expression of the
putative autoantigen heat-shock protein 70 in rat adjuvant
arthritis, implying that glucocorticoids could impact on
autoreactive responses by decreasing the autoantigen load.17
Removal of endogenous glucocorticoids by adrenalectomy
results in increased T-cell and NK-cell activation as well as
T-cell proliferation in response to both mitogen and
antigen.1820 Unstimulated and LPS-stimulated peritoneal
macrophages collected from adrenalectomy (ADX) rats
release more IL-1 than their sham-operated counterparts.21 A
comparison of serum IL-1 and TNF- responses to endotox-
aemia in Lewis and Wistar rats found that increased produc-
tion of inflammatory cytokines correlated with fewer
circulating corticosteroids in the Lewis rats.22 The effects
on cytokines of exogenous glucocorticoids, mediated via
NF-B, were shown to be operant in the rat adjuvant arthritis
model.23 Mediators of tissue damage including phospholipase
A2 (PLA2), eicosanoids, nitric oxide (NO) and reactive
oxygen species (ROS) are also subject to tonic inhibition by
physiological glucocorticoids. An increase in PLA2 activity
is observed in rats following adrenalectomy, and is negatively
correlated with annexin-1 concentrations.24
Physiological glucocorticoid hormones do, therefore,
modulate a broad range of inflammatory processes relevant
to RA. A deficient physiological glucocorticoid response
could conceivably predispose or perpetuate inflammatory/
immune cell activation. Dysregulation of endogenous gluco-
corticoid control of inflammatory processes is hypothesized
to constitute an additional risk for the development of RA.25
Studies in humans
The hypothesis that the HPA axis can respond to, and in turn
influence, the immune-inflammatory system is clearly more
difficult to test in humans. Existing data do, however, support
the hypothesis that the HPA axis-inflammation negative feed-
back control loop operates in humans. This can be discussed
in terms of the ability of inflammation to stimulate that HPA
axis, and in terms of the ability of the HPA axis to influence
inflammation. Schreiber et al. reported that peripheral
administration of endotoxin induced dramatic increases in the
activity of the HPA axis, accompanied by increases in circu-
lating IL-6.26 In studies where recombinant IL-6 was admin-
istered to humans as part of an anticancer treatment regimen,
Mastorakos et al. reported profound stimulation of peripheral
ACTH and cortisol that exceeded the maximum response
inducible with exogenous ovine CRH.27 In terms of the
ability of endogenous glucocorticoids to modify the activity
of the immune system, Sauer et al. reported effects of
endogenous hyper- and hypo-cortisolaemia on immune cell
function.28 Hypercortisolaemic individuals (with Cushings
disease) exhibited reduced in vitro T-cell IL-2 release and
soluble IL-2 receptor compared to controls. Hypocortiso-
laemic subjects, in contrast, showed increased T-cell IL-2
production and soluble IL-2 receptor levels. In another study,
RU486 induced a skin eruption characterized by a lympho-
cytic infiltrate, despite failing to show effects of RU486 treat-
ment on peripheral blood lymphocyte phenotype or in vitro
proliferative response.29
Given these and other data supporting the existence of a
HPA axis-inflammation feedback control loop in humans,
studies in RA are required in order to determine the relevance
of this loop to this disease. Several studies support the idea
that the HPA axis exerts a direct inhibitory effect on disease
activity in RA. Perhaps the most persuasive evidence was
 HPA axis regulation of inflammation
provided by the observation that clinical signs of inflamma-
tion in RA could be exacerbated by the administration of
metyrapone, an 11-hydroxylase inhibitor that inhibits
adrenal glucocorticoid synthesis.30 Alterations in cortisol
diurnal rhythm have been reported in patients with RA,31
most recently using frequent sampling of salivary cortisol,32
and Arvidson et al. detected a diurnal rhythm of serum IL-6
levels in subjects with RA.33 In an early study, an association
was reported between the well-described diurnal variation of
RA activity, and the diurnal variation of peripheral cortisol
levels.34 The question of whether cytokine patterns induce
diurnal changes in cortisol, or whether altered cortisol
diurnal rhythm in RA might explain the cytokine patterns
observed, has not been resolved.
The question of whether HPA-axis abnormalities exist in
RA, and contribute to disease pathogenesis, has been
addressed in only a small number of studies. Chikanza et al.
have in contrast reported a well-designed study of HPA-axis
function in RA, utilizing neuroendocrine and stress-induced
activation of the pituitaryadrenal axis.35 In this study, cor-
tisol responses to surgical stress were lower in RA subjects
compared to controls without inflammatory disease, and
compared to an inflammatory control group with chronic
bacterial osteomyelitis. This was observed despite higher
levels of cytokines, such as IL-1, in the RA group. In con-
trast, the ACTH and cortisol response of RA subjects to
exogenous CRH was normal. Taken at face value, these data
suggest the presence of an abnormal response to stress
mediated at the hypothalamus. Unfortunately, this study is
also complicated by issues of drug therapy. A majority of the
RA subjects were receiving prostaglandin synthesis
inhibitors at the time of study, and as noted above such
agents clearly interfere with HPA-axis responses to cyto-
kines and other hormones. We reported increased peripheral
ACTH levels, not accompanied by increased cortisol, in
subjects with RA.36 This finding has been confirmed by
other groups,37 most recently by Kanik et al.38 Crofford et al.
have reported the lack of expected cortisol response on
increased circulating IL-6 in RA.39 Subtle abnormalities in
cortisol responses to stress such as hypoglycaemia have been
reported.40 Other researchers have also interpreted a normal
cortisol level as reflecting an under-responsive HPA axis,
given the presence of an inflammatory drive in RA.41 In
general, then, the presence of a lower than expected adrenal
cortisol level is increasingly accepted as a feature of RA.42
The key question that remains unanswered is whether the
HPA-axis abnormalities seen in humans with RA is a
predisposing factor or a consequence of the disease. Most
likely to answer this crucial question are studies such as
those of Masi et al. who have reported (in abstract form) the
predictive value of cortisol levels in a population study.43
Alternatively, the examination of case reports, such as those
of the onset of RA after treatment of Cushings disease, leads
to a strong suspicion of HPA function as a barrier to the
development of RA, which once breached permits this
disease to ensue.44
Conclusions
The review by Munck et al. provided one of the first
descriptions of the HPA axisimmune interaction.45 Much of
397
the evidence accrued since the publication of that work has
supported their contention that activation of the HPA axis
primarily exerts an inhibitory, or limiting, effect on inflam-
mation. As recently reviewed, however, it is becoming clear
that the HPA axis can exert permissive as well as inhibitory
effects on the immune-inflammatory system.46 The normal
human immune response takes place in the presence of low,
but biologically active, levels of glucocorticoids, proposed
to exert a necessary permissive effect on immune function.
The role of the glucocorticoid-induced but pro-inflammatory
cytokine, macrophage migration inhibitory factor, in the
effects of endogenous glucocorticoids has been suggested in
recent studies in rat adjuvant arthritis.47
Notwithstanding these permissive effects, it is clear that
glucocorticoids are critical for the inhibitory regulation of the
immune-inflammatory response. Glucocorticoid deficiency
can profoundly influence the susceptibility to, and severity
of, inflammatory arthritis in animal models. To the extent that
it has been studied in humans, results broadly support the
hypothesis that the HPA axis plays a critical role in the
counter-regulation of the immune-inflammatory response in
RA. Therefore, deficiencies in HPA-axis function are likely
to predispose individuals to the onset, or affect the severity
of, chronic human inflammatory diseases such as RA. It is to
be hoped that a better understanding of this critical regulatory
system will lead to the development of treatments for inflam-
matory diseases.
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