Immunology and Cell Biology (1998) 76, 300±317

Review Article
Cytokines: Principles and prospects
ANNE KELSO

The Queensland Institute of Medical Research, Brisbane, Queensland, Australia

Summary Cytokines participate in the induction and e€ector phases of all immune and in¯ammatory responses.
They are therefore obvious tools and targets for strategies designed to promote, inhibit or redirect these
responses. However, the complexity of the cytokine network has hindered the widespread clinical application of
many cytokines and it has become clear that a deeper understanding of the normal operation of this system in
health and disease is needed for the therapeutic potential of cytokines to be fully realized. This review summarizes
some of the principles that are now thought to underlie the diverse functions of the interleukins, interferons,
colony-stimulating factors and tumour necrosis factors in immune and in¯ammatory reactions in vivo. Genetic
and structural relationships between these cytokines, the regulation of their synthesis, and the structures and
functions of their receptors are outlined. Current knowledge of these parameters suggests ways in which multiple
positive and negative regulatory mechanisms are integrated to balance cytokine bene®ts and harm under
physiological conditions and o€ers new prospects for rational exploitation of this system.

Key words: antagonists, colony-stimulating factors, cytokine receptors, cytokines, immunotherapy, interferons,
interleukins, signalling, T lymphocytes, tumour necrosis factors.

Introduction operation of the cytokine network and its exploitation for

The immune system has a communication problem. Unlike
most other mammalian cells which spend their lives or-
ganized into organs and tissues, the cells of the immune
system are peripatetic. The cells that ®rst detect in¯am-
matory stimuli, the cells that present antigen to lympho-
cytes, the lymphocytes themselves and the various e€ector
cells that clear antigen and repair tissue damage sometimes
travel the body in the circulation, sometimes trac through
the organs and tissues, and sometimes form more organized
structures in the lymphoid tissues. This dynamic state pre-
sents a challenge to a cellular system that must raise a rapid,
integrated response to an antigenic insult anywhere in the
body. Cells of the immune system require communication
networks that can, as required, act locally or at a distance,
speci®cally or globally, and transiently or in a sustained
manner. The networks that allow such sophistication in the
mammalian immune response exploit an extraordinary
variety of cell membrane-bound and soluble messengers.
Among the best characterized of these groups of messengers
are the cytokines.
The term `cytokine' de®nes a large group of non-enzymic
protein hormones whose actions are both diverse and
overlapping and which a€ect diverse and overlapping target
cell populations. While the complexity of cytokine actions
and interactions seems to defy a simple understanding of
their physiological function, some broad principles are
emerging that may be useful in considering the normal
Correspondence: Professor A Kelso, The Queensland Institute of
Medical Research, Post Oce Royal Brisbane Hospital, Qld 4029,
Australia. Email: <anneK@qimr.edu.au>
Received 2 March 1998; accepted 30 March 1998.
therapeutic bene®t. This overview attempts to summarize
some of those principles.
Cytokine families
The cytokines to be discussed here are the interleukins (IL)
IL-1 to IL-18 (except the chemokine IL-8), the interferons
(IFN-a, -b and -c), the haemopoietic colony-stimulating
factors (CSF) (granulocyte CSF (G-CSF), macrophage
CSF (M-CSF) and granulocyte-macrophage CSF (GM-
CSF)), and the tumour necrosis factors (TNF). The last
group has three members: the homotrimer TNF-a which
can occur in soluble and membrane-bound form, the sol-
uble homotrimer lymphotoxin-a (or TNF-b), and a mem-
brane-bound heterotrimer of LT-a with LT-b.
The typical cytokine is a glycosylated monomeric pep-
tide of about 150 amino acids.1 Others are homodimers
(e.g. IL-5, M-CSF) or -trimers (TNF-a and LT-a), or he-
terodimers (IL-12) or -trimers (LT-a/b). The cytokines are
not, however, members of a single gene superfamily. Re-
markably few similarities have been noted in their primary
nucleotide or amino acid sequences and their genes are, for
the most part, scattered throughout the genome.
Some important relationships between cytokines can
nevertheless be recognized. For example, several do belong
to gene families (Table 1). IL-1a, IL-1b and the IL-1 re-
ceptor antagonist (IL-1ra, discussed further below) have
about 25% amino acid similarity, interact with the same
receptors, and are encoded by closely linked genes.5 Simi-
larly, the 13 functional members of the human IFN-a gene
family and the IFN-b gene (type I interferons) are closely
linked and encode related proteins which bind a common

Cytokines
Table 1 Cytokine gene families
Cytokine genes Chromosome
hu mu
IL-1a, IL-1b, IL-1ra 2 2
IFN-a, IFN-b 9 4
TNF-a, LT-a, LT-b* 6 17
IL-4, IL-13 5 11
IL-3, IL-5, GM-CSF 5 11
IL-9 , IL-12 p40 5 11
*Members of the immediate TNF family normally exist as trimers. TNF-a is a homotrimer and both this cytokine and the secreted
homotrimeric form of LT-a bind to type I (p55) and type II (p75) TNF receptors. LT-a can also be anchored in the membrane by LT-b as a
heterotrimer; the minor LT-a2b1 form binds TNFRI and II and the dominant LT-a1b2 form binds a distinct receptor, LT-bR.2,3
y
IL-9 is on human chromosome 5 and mouse chromosome 13.4
receptor; in humans this cluster also contains the single
functional gene for another type I interferon, IFN-x, and a
number of IFN-a and IFN-x pseudogenes.6 IFN-c (type II
interferon), on the other hand, is not a member of this
family and only shares their nomenclature for historical
reasons because of its antiviral activity. The three members
of the TNF family also have 25±35% primary sequence
homology, are all encoded in the class III region of the
major histocompatibility complex (MHC) and, in the case
of TNF-a and LT-a, bind the same two receptor types.3,7 A
second type of cytokine family is represented by the
haemopoietin gene cluster on human chromosome 5q23-35
and murine chromosome 11; although IL-4 and IL-13 are
homologous and share receptor components, the other
members of this cluster are not closely related and generally
do not share receptors.8±10
The evolutionary force behind the duplication and di-
vergence of genes in the ®rst type of cytokine family can be
guessed from di€erences in their mechanisms of expression
and the actions of their products. The signi®cance of the
haemopoietin gene cluster on chromosome 5 is less clear
but its maintenance in humans and the mouse suggests
some advantage to the host, perhaps in the higher order
regulation of gene expression. Deletions in one copy of this
region on chromosome 5 are associated with various pro-
liferative and leukaemic myeloid disorders (the 5q- syn-
drome), but these seem not to be linked to loss of a known
cytokine gene.11
A second type of relationship has been revealed at the
protein level by three-dimensional structure studies and
molecular modelling, which have shown or predicted that
many otherwise non-homologous cytokines adopt similar
conformations as bundles of four anti-parallel a-helices.12
These include IL-2 to IL-7, IL-9 to IL-11, IL-12 p35, IL-13,
IL-15, the three interferons and the three CSF. This dis-
covery of a generic cytokine structure complements the
®nding that many cytokine receptors share certain features
in their primary sequences (see below), in fact displaying
greater homology than their ligands. Exceptions are the IL-1
family (b-trefoil structures), the TNF family (b-jellyroll)
and the IL-12 p40 chain (which resembles the extracellular
domain of the IL-6 receptor).12,13 Modelling of the struc-
ture of IL-18 (IFN-c-inducing factor) has led to the sug-
gestion that it is a member of the IL-1 family.14 Sequence
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301
Receptors
IL-1RI, IL-1RII
IFN-aR (two shared receptor chains)
TNFRI, TNFRII (TNF-a, LT-a3, LT-a2b1); LT-bR (LT-a1b2)
Two shared receptor chains (IL-4Ra and IL-13Ra)
One shared receptor chain (bc)
Various
and structural similarities have also shown that TNF-a,
LT-a and LT-b belong to a much larger group of proteins
that includes CD27L, CD30L, CD40L, FasL, TRAIL and
TRANCE, and whose receptors are related to TNF
receptors (R) I and II.7,15
Control of cytokine synthesis
Di€erent immunogens induce the synthesis of di€erent cy-
tokines which in turn activate di€erent immune e€ector
mechanisms. In many circumstances, the nature of this se-
lective cytokine response dictates the outcome of interac-
tion between the host and `parasite' (infectious agent,
tumour, allograft or other antigen source) and is, therefore,
a matter of life or death for both parties. A number of
mechanisms have been identi®ed that enable cytokine-
producing cells to respond to environmental cues by syn-
thesizing appropriate cytokines in the right place and for
the required duration.
Cell specialization
Although every nucleated cell type can produce cyto-
kines, most lineages express only a subset of cytokine
genes. Further specialization can be observed within lin-
eages, for example among T cells (see below), and ac-
cording to di€erentiation stage and activation state.
Whereas some cytokines are expressed by many di€erent
haemopoietic and non-haemopoietic lineages (e.g. IL-1,
IL-6, IFN-a and -b, and TNF-a), others appear highly
restricted (e.g. IL-2, IL-3, IL-4 and IL-5 whose production
is limited to certain leucocytes such as T cells, mast cells
and eosinophils). Specialization therefore contributes to the
anatomical localization of cytokine synthesis, limiting ex-
posure to the wide range of potential target cells in distant
tissues.
Inducing signals
Within a given lineage, there are several critical levels of
control of cytokine synthesis (Fig. 1). One is the inducing
signal. Cytokines are generally not produced constitutively
but the nature of the stimuli that can trigger synthesis varies

302 A Kelso
Figure 1 Multiple levels of regulation of cytokine synthesis.
The types and quantities of cytokines produced by a cell de-
pend ®rst on its lineage, di€erentiation stage and activation
state, and on the nature of the inducing stimulus. The ®gure
shows the main subsequent levels of regulation from stimulus±
receptor interaction to extracellular display or release of the
mature cytokine.
with the cell type and its di€erentiation or activation state,
and determines which cytokines are produced by that cell.
Among the most important are signals recognized either
speci®cally or non-speci®cally as non-self: (i) antigen or
antigen-MHC complexes acting via clonotypic receptors on
B or T cells; (ii) antigen±antibody complexes acting via Fc
and complement receptors on various lymphoid and in-
¯ammatory cell types; (iii) superantigens (such as some
bacterial enterotoxins) acting via non-polymorphic regions
of certain TCR Vb chains; and (iv) other constituents of
micro-organisms (such as LPS, other carbohydrates and
lipids, FMLP and non-methylated CpG-containing DNA)
and viruses (such as double-stranded RNA).
Cytokine synthesis can also be induced or modulated by
self-molecules, including ligands for costimulatory recep-
tors on T cells and cytokines themselves. Cytokine cas-
cades, in which one cytokine stimulates synthesis of the
same or another cytokine, are an important mechanism to
amplify and diversify the initial response.
Intracellular regulation of cytokine synthesis
Just as the ligands and cognate receptors that trigger cy-
tokine synthesis vary between cell lineages, so too do their
associated intracellular signalling pathways. Intense re-
search in this area in recent years has seen many of the steps
that lie between receptor ligation and transcriptional acti-
vation of cytokine genes mapped out and has begun to
provide explanations for certain features of the cytokine
response. For example, the use of similar receptor compo-
nents (e.g. in the TCR and some Fc receptors) and signal
transduction machinery probably contributes to similarities
in cytokine production between some cell types (such as T,
NK and mast cells).16±18 On the other hand, di€erential
involvement of branching downstream pathways in the
activation of di€erent cytokine genes might diversify cyto-
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kine responses in a single cell type.19 Identi®cation of key
signalling intermediates has also revealed the sites of action
of immunosuppressive drugs (such as cyclosporin A and
FK506 in TCR-mediated activation of IL-2 synthesis)20
and has the potential to identify targets for new inhibitors.
Although not yet widely studied, accessibility of cytokine
genes to transcriptional activators is likely to be a primary
determinant of cellular cytokine responses. Changes to
chromatin conformation and demethylation of certain CpG
sites in the promoters of some cytokine genes have been
correlated with their expression in newly activated normal
T cells and in monocytes at various di€erentiation
stages21±24 but the intracellular events that enable these
changes have not been identi®ed.
Once cytokine genes become amenable to transcriptional
activation, there are two major levels at which synthesis is
regulated: transcription rate and mRNA turnover. This has
the practical consequence that cytokine mRNA levels are a
valid guide to protein production levels in many situations.
Stimulation usually increases transcription rate. Some of
the shared and cytokine-speci®c regulatory sequences and
transcription factor complexes that cause either coordinate
or di€erential gene expression have been identi®ed.25±29
Although all of these transcription factors are also involved
in the expression of other genes, members of the NFAT,
NFjB and AP-1 families in particular play central roles in
cytokine gene regulation. Transcript half-life is then limited
by at least two classes of destabilizing sequences found in
the 3¢-untranslated regions of many cytokine mRNA.30±32
Although the half-lives of some cytokine mRNA species
can be prolonged by certain signals, such as CD28 ligation
in T cells,33 and reduced by others, such as thalidomide in
the case of TNF-a,34 most decay within minutes or a few
hours of synthesis. The duration of cytokine production is
thus determined at least in part by the persistence of the
inducing stimulus but can be modulated by other exoge-
nous signals.
Most cytokines are synthesized with a conventional
signal sequence that results in their translocation into the
Golgi apparatus and rapid secretion from the cell. There
are, however, several translational and post-translational
levels at which production and release of some cytokines
are regulated.
(1) Synthesis of IL-1b and TNF-a is translationally
regulated via elements in the 3¢-untranslated region of their
mRNA;35 stimulation can therefore increase both mRNA
levels and translation rates. The class of pyridinyl-imidazole
compounds known as cytokine-suppressive anti-in¯amma-
tory drugs acts by inhibiting cytokine translation at this
level.36
(2) IL-1a, IL-1b, IL-18 and TNF-a are synthesized as
pro-hormones. IL-1a and TNF-a are biologically active in
this form but activity of IL-1b and IL-18 depends on re-
moval of the pro-piece by the IL-1b converting enzyme,
ICE (caspase-1), or other less-speci®c enzymes.5,15,37
(3) Several cytokines are produced as biologically active
membrane-bound proteins. Whereas IL-1b is mainly se-
creted, most IL-1a is found in the cytosol or plasma
membrane.5 LT-a/b heterotrimers are anchored in the cell
membrane by LT-b.2 Pro-TNF-a is also targeted to the cell
membrane where its levels are tightly regulated; cell acti-

Cytokines
vation triggers release of the mature form by matrix
metalloproteinases.38 Indeed, membrane TNF-a may be the
normal physiological form of this molecule, with release
of the soluble form only occurring in extreme conditions.39
Macrophage-CSF also occurs in both membrane-bound
and soluble forms encoded by alternative transcripts.40
(4) A number of cytokines are stored in the secretory
granules of eosinophils and mast cells, enabling their
immediate release in response to stimulation.41,42
(5) T cells can secrete cytokines in a polarized fashion
towards their point of contact with the APC.43,44 Direc-
tional secretion o€ers the potential to maximize cytokine
activity at the target cell membrane while limiting bystander
e€ects.
The observation that some cytokines occur as mem-
brane-anchored proteins has raised the possibility that they
can act as receptors for signal transduction to the producer
cell. This phenomenon of `reverse signalling' has now been
demonstrated for membrane-bound human and mouse
TNF-a following cross-linking with antibody and dimeric
soluble TNFRI respectively45 (A. Watts and G. Chaudhri,
pers. comm., 1998).
Host genetic in¯uences on cytokine synthesis
Marked di€erences have been noted in the magnitude and
pro®le of the cytokine response to a number of immuno-
gens among di€erent strains of experimental animals and
among individuals in human populations.46,47 The under-
lying mechanisms are likely to be diverse but one important
level of variation is seen in the cytokine genes themselves.
Polymorphisms have been identi®ed in coding regions (e.g.
IL-2, LT-a), promoters (IL-1a, IL-1b, IL-1ra, IL-4, IL-10,
TNF-a), introns (IL-1a, IL-1ra, TNF-a, LT-a) and 3¢-
¯anking regions (IL-6, TNF-a). Several of these have been
associated with altered levels of cytokine production or
activity and with susceptibility to various infectious agents,
autoimmune diseases and allergy in humans.48±50 Poly-
morphisms in regulatory regions in particular can be
expected to a€ect the level of expression of that gene, as
recently demonstrated at the transcriptional level for
TNF-a,51 with indirect e€ects on downstream events in the
immune response. Cytokine gene polymorphisms can
Figure 2 Immune regulation by T cell-derived cytokines. T cell populations can produce di€erent combinations of cytokines,
including those classi®ed as type 1, type 2 or shared based on studies with T cell clones. The type 1 and type 2 cytokines activate
di€erent types of immune e€ector response and these in turn play prominent roles in responses to di€erent types of immunogen.
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303
therefore serve both as markers of disease susceptibility or
severity and clues to pathogenesis.
The exemplary case of the T lymphocyte
T cells play a central regulatory role in almost all immune
responses because of their production of cytokines and a
number of the principles outlined above have been estab-
lished best for this cell type. Some aspects of the control of
cytokine synthesis in T cells are therefore worth describing
in more detail.
Mature peripheral T cells do not produce cytokines
until they have been activated as a result of antigen rec-
ognition and costimulation, but they then have the ca-
pacity to synthesize most of the cytokines listed at the
beginning of this article. This can be observed in high-
frequency polyclonal T cell responses, for example to
alloantigens or mitogens in vivo and in vitro, where the
activated T cell population expresses many di€erent cyto-
kine genes.
Specialization can be revealed, however, when T cells are
expanded or cloned from certain types of immune response
in vivo (especially chronic responses) or under certain cul-
ture conditions in vitro.52,53 The best characterized of these
specialized cytokine patterns are those originally labelled
Th1 (for T helper type 1) and Th2 but now better called
type 1 and type 2 to accommodate the ®nding that both
CD4+ and CD8+ T cells can display these patterns. As
illustrated in Fig. 2, the type 1 and type 2 cytokine groups
promote the activation of certain e€ector mechanisms and
are therefore associated with certain types of immune re-
action and responses to certain pathogens. There is also
recent evidence that type 1 and type 2 T cell populations
migrate preferentially into di€erent types of in¯amed tissue
due to their di€erential expression of receptors for P- and
E-selectin, and the chemokine eotaxin, respectively.54,55
Other prominent cytokine patterns have also been de-
scribed, such as those labelled Th3 (high transforming
growth factor-b; no IL-2, IL-4, IL-10 or IFN-c) and Tr1
(high IL-10 and IFN-c, low IL-2, no IL-4), both of which
are proposed to have suppressive activity.56,57
Although T cell populations displaying type 1, type 2 or
other cytokine pro®les are usually described as discrete

304 A Kelso
subsets, this notion is not universally accepted. I have ar-
gued elsewhere that T cell cytokine pro®les form a contin-
uous spectrum in levels and combinations, in which type 1
and type 2 cells may be only two of the possible extreme
phenotypes.58 Support for this alternative view comes from
the growing evidence that expression of each cytokine gene
is independently regulated in T cells, that individual cells
are heterogeneous in their cytokine pro®les, even when
derived from polarized type 1 or type 2 populations, and
that polarized cytokine pro®les are amenable to transient
change by exogenous signals.28,59±62
The `decision' to synthesize a particular set of cytokines
is central to the role of T cells in coordination and mod-
ulation of the immune response. Much has been learned in
the last 5 years about the factors regulating this deci-
sion.53,63 It is now understood that naive peripheral T cells
are multipotential and acquire a restricted cytokine pro®le
by a di€erentiative process that occurs during and after
primary activation.64,65 A variety of stimuli can promote
this process but the best established are IL-12 (and to a
lesser extent IFN-a, IFN-c and IL-18) for type 1 di€er-
entiation, and IL-4 (and IL-1b) for type 2 di€erentia-
tion.63,66±70 Pathogens and certain molecular structures
which induce synthesis of any of these cytokines, for ex-
ample, by cells of the innate immune system or by T cells
themselves, can therefore in¯uence the evolution of the T
cell cytokine response. Whereas a number of non-self sig-
nals have been identi®ed that promote type 1 di€erentia-
tion, especially by inducing IL-12 synthesis,71 the
conditions that lead to preferential type 2 cytokine syn-
thesis are less well understood. In particular, the charac-
teristics of allergens and helminths that promote type 2
cytokine responses have not been de®ned and, while IL-4 is
clearly a potent inducer of type 2 cytokine synthesis, the
signals that trigger its production in the ®rst instance re-
main mysterious.72 Observations that varying the strength
of naive T cell stimulation (for example, by altering TCR
ligand anity or density, or modulating costimulatory
signals) can in¯uence cytokine pro®le development are
provocative but the underlying mechanisms and their
practical importance in normal polyclonal T cell responses
to complex antigens are not yet understood.73±75
Another important but unresolved issue concerns the
stability of T cell cytokine pro®les. Over time in vitro,
murine T cell populations with polarized type 1 or type 2
pro®les progressively lose their ability to change pro®les in
response to type 2 or type 1 polarizing stimuli, respective-
ly.76,77 In both mouse and human, type 2 populations cease
to express an essential component of the IL-12 receptor (IL-
12Rb2) and therefore lose IL-12 responsiveness.78,79 How-
ever, this process appears to be reversible in human T cells
since IL-12Rb2 can be re-induced by IFN-a or IL-12 itself
and some type 2 T cell clones can synthesize IFN-c in re-
sponse to IL-12.62,79
The control of cytokine action
There are several striking features of cytokine action which
are important for understanding the regulation of the cy-
tokine network. The ®rst is that the target cells of cytokines
and their responses are enormously diverse; second, cyto-
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kines can display both speci®city and redundancy in their
actions; and ®nally, cytokines in combination can display
synergy and antagonism. Each of these can now be ex-
plained to some extent by the characteristics of cytokine
receptors.
Cytokine receptors
Cytokines deliver signals to target cells via membrane-
spanning receptors. In general these receptors have disso-
ciation constants (Kd) of around 10)10 to 10)11 mol/L and,
depending on the cytokine and cell type, receptor numbers
may range from 10 to >104 per cell. In at least some cases,
cytokine binding to fewer than 100 membrane receptors is
sucient to induce a biological response,5,80 with the result
that sub-picomolar cytokine concentrations can be biolog-
ically active.
Most cytokine receptors comprise two or more ligand-
binding polypeptide chains and, in many cases, one or more
of these chains is shared with the receptor for another cy-
tokine (Fig. 3). A consequence of this multimeric structure
is that most cytokine receptors can exist in two or more
anity states, depending on the availability of individual
receptor chains to join the complex. One of the best studied
examples is the three-chain IL-2 receptor (IL-2R) in which
IL-2 binds with low anity to the a-chain (CD25)
(Kd ˆ 10)8 mol/L), intermediate anity to the bc dimer
(Kd ˆ 10)9 mol/L in humans; no detectable anity in the
mouse) and high anity to the abc complex
(Kd ˆ 10)11 mol/L).81,82 Because signal transduction is me-
diated principally by the b-chain in cooperation with the c-
chain, only the bc and abc forms of the receptor deliver a
signal to the target cell.
Naturally occurring mutations in the IL-2 gene in man
and inactivation of the IL-2 gene in experimental mice
cause some T cell proliferative defects and ultimately result
in in¯ammatory bowel disease in murine models,83±85 but
these e€ects are modest compared with the consequences of
Figure 3 Multicomponent cytokine receptors. Most cytokine
receptors comprise at least two polypeptide chains which play
distinct roles in cytokine binding and signal transduction. One
or more of these chains may be shared with the receptors for a
di€erent cytokine. Di€erential expression of a cytokine-speci®c
chain and a signal-transducing chain () by various cell types
can account for both the speci®city and redundancy of some
cytokine activities. Thus, the cells on the left and right of the
®gure can only respond to the rectangular and bullet-shaped
cytokines, respectively. The central cell can respond to both
cytokines but cannot distinguish between them because both
receptors use the same signal-transducing chain.
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Cytokines 305

IL-2Rc inactivation. The latter defect is responsible for X-
linked severe combined immunode®ciency in humans in
which mature T and NK cells are absent and B cell function
is impaired.86 IL-2Rc-de®cient mice also lack NK cells and
have reduced T and B cell numbers, but retain T cell pro-
liferative responses.87,88 Inactivation of IL-2Ra or IL-2Rb
in mice creates yet other phenotypes with selective defects in
T cell and NK cell development and regulation.89±91
These striking di€erences in phenotype and severity are
now known to re¯ect the involvement of the c-chain (or cc
for `common') in the receptors for at least four other cy-
tokines (IL-4, IL-7, IL-9 and IL-15) and the b-chain in the
receptor for IL-15 (Table 2). As for IL-2, the receptor for
each of these cytokines includes an a-chain which confers
its cytokine speci®city and is necessary for high-anity
binding. Since cc is insucient for signal transduction, IL-4,
IL-7 and IL-9 each triggers distinct intracellular signalling
pathways. IL-4 and IL-13, on the other hand, share the IL-
4Ra and IL-13Ra chains and have indistinguishable e€ects
on many of their target cells.101 There appear to be two
classes of IL-4 receptor in which IL-4Ra associates either
with cc or with IL-13Ra to form high-anity signal-
transducing receptors. The IL-13R was thought to com-
prise IL-4Ra and IL-13Ra without cc involvement, but the
recent isolation of another IL-13-binding protein points to
additional complexity that is not yet understood.102,103 The
identical biological activities of IL-2 and IL-15 in most
assays are explained by their sharing of both the b-chain
and cc.82 Other overlapping receptor families have been
described for IL-3, IL-5 and GM-CSF which share a
number of activities on their haemopoietic target cells, and
for IL-6, IL-11, leukaemia inhibitory factor, oncostatin M
and ciliary neurotrophic factor, whose activities are linked
through binding to the signal-transducing receptor chain
gp130.92,93,104 From these receptor groups, it can be seen
that the sharing of some but not all receptor components
can account for both the speci®city and the redundancy of
many cytokine activities.
The cytokine receptor components that have now been
cloned and sequenced can be classi®ed into several struc-
tural families based on certain signature sequences and their
use of various combinations of immunoglobulin (Ig) and
®bronectin type III domains (Table 3).1,12 Most of the
a-helical cytokines bind to receptors whose compo-
nents include at least one member of the cytokine receptor
class I (CR1) or haemopoietin receptor superfamily. These
polypeptides are characterized by one or more regions
containing a set of four conserved cysteines and a
tryptophan±serine±X-tryptophan±serine motif (WSXWS;
required for receptor folding and function)109 in their ex-
tracellular domains, and short cytoplasmic regions of ho-
mology associated with signalling elements. Members of the
CR2 or interferon receptor superfamily are distantly related
to the CR1 family but lack the WSXWS motif.94,95 The
IL-1 receptor family of proteins is characterized by three
extracellular Ig domains and other extracellular and intra-
cellular sequence similarities.5,105 High-anity IL-1 binding
and signal transduction depend on association between
IL-1RI and another family member, the accessory protein
IL-1R-accessory protein (AcP); it is not yet clear whether
the IL-18R also requires this or another accessory protein.
The type I and II TNF receptors are part of a large family
of membrane proteins that includes CD27, CD30, CD40,
Fas, RANK and the TRAIL receptor.7,15

Table 2 Sharing of cytokine receptor components and signalling intermediates by the a-helical cytokines

Cytokine Receptor chains JAK STAT

IL-2 IL-2Ra IL-2Rb cc Jak1, Jak3 STAT1, STAT3, STAT5

IL-4 IL-4Ra IL-13Ra cc Jak1, Jak3, Tyk2 STAT6
IL-7 IL-7Ra cc Jak1, Jak3 STAT1, STAT3, STAT5
IL-9 IL-9Ra cc Jak1, Jak3 STAT1, STAT3, STAT5
IL-13 IL-13Ra IL-4Ra Jak1, Jak2, Tyk2 STAT6
IL-15 IL-15Ra IL-2Rb cc Jak1, Jak3 STAT3; STAT5
IL-3 IL-3Ra bc Jak2 STAT1, STAT3, STAT5
IL-5 IL-5Ra bc Jak2 STAT1, STAT3, STAT5
GM-CSF GM-CSFRa bc Jak2 STAT1, STAT3, STAT5
IL-6 IL-6Ra gp130 Jak1, Jak2, Tyk2 STAT1, STAT3, STAT5
IL-10 IL-10R1 IL-10R2 Jak1, Tyk2 STAT1, STAT3
IL-12 IL-12Rb1 IL-12Rb2 Jak2, Tyk2 STAT1, STAT3, STAT4
IFN-a/b IFN-aR1 IFN-aR2 Jak1, Tyk2 STAT1, STAT2, STAT3, STAT4 (hu)
IFN-c IFN-cR1 IFN-cR2 Jak1, Jak2 STAT1, STAT5
G-CSF G-CSFR Jak1, Jak2, Tyk2 STAT1, STAT3, STAT5

Cytokines are grouped into those sharing receptor chains with IL-2, those using bc and others.82,92±95 IL-13Ra and cc appear to be
alternative partners with IL-4Ra in the formation of functional IL-4 receptors. The murine IL-3R also has an alternative b-chain (not shown)
which is not shared with the IL-5 and granulocyte/macrophage colony stimulating factor (GM-CSF) receptors.92 A second obligatory chain of
the IL-10R (IL-10R2) has recently been identi®ed.96,97 Reported Janus-activated kinase (Jak) and signal transducers and activators of
transcription (STAT) usage is shown for each receptor, with the major STATs underlined.98±100 In some cases, di€erent usage has been
reported in di€erent cell types. Not distinguished here are the two isoforms identi®ed for each of STAT1 and STAT5, whose di€erent
functions are poorly understood.

306
Table 3 Cytokine receptor families
Receptor family Members
Cytokine receptor class 1 IL-2Rb, IL-3Ra, IL-4Ra, IL-5Ra,
IL-6Ra, IL-7Ra, IL-9Ra, IL-11a,
IL-12Rb1, IL-12Rb2, IL-13Ra,
IL-13BP, GM-CSFR, G-CSFR,
cc, bc, gp130
Cytokine receptor class 2 IFN-aR1, IFN-aR2, IFN-cR1,
IFN-cR2, IL-10R1, IL-10R2
IL-1 receptor IL-1RI, IL-1RII, IL-1R-AcP,
IL-18R
TNF receptor TNFRI, TNFRII, LT-bR
The IL-18R was ®rst identi®ed as the IL-1R-related protein by
homology with the IL-1 receptors and the IL-1R accessory protein
(AcP).105 Known receptors for the other cytokines discussed here
do not belong to the families shown. The IL-16 receptor is CD4.106
IL-17 and its receptor do not belong to the known cytokine and
cytokine receptor families.107 The macrophage (M)-CSF receptor is
encoded by c-fms.108
An important form of structural variation in cytokine
receptors has been identi®ed with the recent report of allelic
variation in the murine IL-4Ra; the two described allotypes
di€ered in their IL-4-binding properties and may therefore
contribute to mouse strain variation in IL-4-dependent
responses.110
Cytokine receptor signalling
As in all ®elds of cell biology, one of the fastest growing
areas of cytokine research in the 1990s has been the delin-
eation of receptor-linked signalling pathways. The M-CSF
receptor encoded by c-fms is itself a tyrosine kinase and the
only receptor for the cytokines discussed here that has en-
zymic activity.108 In every other case, signalling depends on
association of the cytoplasmic domain(s) with kinases or
phosphatases that link the receptor to downstream path-
ways. Of these, particular attention has been paid to
pathways involving members of the Jak (Janus-activated
kinases) and STAT (signal transducers and activators of
transcription) gene families.
The CR1 and CR2 receptors for a-helical cytokines both
transduce signals at least partly via the Jak-STAT path-
way.98±100 As illustrated in Fig. 4, ligand-induced cross-
linking of cytokine receptor chains causes interaction of
their associated Jaks. It is thought that the Jaks ®rst
phosphorylate each other and then sites in the cytoplasmic
receptor domains; the latter events enable STAT binding
and phosphorylation, as well as triggering other receptor-
linked pathways such as the Ras/MAP kinase and
phosphotidylinositol cascades.81 Activation of the bound
STAT molecule causes homo- or heterodimerization to
another STAT molecule. These STAT dimers then trans-
locate to the nucleus where they bind to the regulatory
regions of the relevant cytokine-responsive genes to initiate
transcription. The recently described family of naturally
occurring cytokine-inducible inhibitors of cytokine signal-
ling appears to be part of a feedback mechanism to limit
Jak/STAT-dependent responses.111±113
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A Kelso
Figure 4 Signal transduction by members of the class 1 cy-
tokine receptor family. Using the case of the IL-4 receptor, the
®gure illustrates how ligand-induced dimerization of two re-
ceptor chains leads to activation of their associated Janus-ac-
tivated kinase (Jak) molecules. Janus-activated kinase-
mediated phosphorylation of relevant sites in the cytoplasmic
tail of the a-chain enables binding and phosphorylation of
signal transducers and activators of transcription (STAT)6 and
recruitment of a second STAT6 molecule. STAT6 dimers
translocate to the nucleus where they bind to speci®c regulatory
sequences in the promoters of IL-4-responsive genes. Jak acti-
vation also triggers the activation of other signalling pathways
that lead to other cellular responses such as proliferation.
Table 2 lists some of the Jaks and STATs known to be
associated with the two major cytokine receptor groups and
highlights the overlap in usage of all four of the known Jaks
and several of the STATs by molecularly and functionally
distinct receptors. On the other hand, di€erences in recep-
tor chain and/or Jak usage between cell lineages and acti-
vation states have been reported for certain receptors, such
as the IL-4R in lymphoid cells and colon carcinoma cells,
the IL-15R in lymphoid cells and mast cells, and the IL-2R
in naive and activated T cells, providing a possible molec-
ular basis for some of the diversity of cytokine responses
among cell types.81,114,115
In general, speci®city in cytokine receptor signalling
appears to be achieved through the association between the
receptor itself and a particular STAT, rather than via the
Jaks. Important examples are IL-4Ra association with
STAT6 (in response to either IL-4 or IL-13 binding), and
IL-12R association with STAT4. In both these cases,
ablation of the cytokine or the corresponding STAT in
gene-targeted mice has yielded a similar phenotype.70,116±118
Jak3, on the other hand, is associated with the cc receptor
chain and is involved in STAT recruitment but does not
otherwise determine the speci®city of the downstream re-
sponse.119 Some of the cc mutations noted above have been
shown to prevent Jak3 activation120 and two cases of au-
tosomal recessive severe combined immunode®ciency have
been traced to mutations in Jak3.121,122 Again, as noted
previously, the severity of these cc and Jak3 defects re¯ects

Cytokines
the impairment of the multiple cytokine signalling path-
ways dependent on the cc receptor chain.
One of the interesting observations to emerge from these
studies of receptor signalling pathways is the ®nding that
distinct regions of a cytokine receptor and hence distinct
downstream events mediate the di€erent functional re-
sponses of a cell to cytokine binding.123,124 IL-4, for ex-
ample, induces proliferation (via the insulin receptor
substrate/phosphotidylinositol 3-kinase pathway) and ex-
pression of MHC class II, CD23 and other genes (via
STAT6); although both responses depend on Jak-1/Jak-3
interaction, they are controlled by di€erent cytoplasmic
regions of the IL-4Ra molecule which activate these di-
vergent signalling cascades.123
Receptor antagonists
Two cytokine-receptor antagonists have now been discov-
ered in nature. The ®rst was IL-1ra, a member of the IL-1
gene family in which presumed mutations in certain resi-
dues have resulted in a protein that binds the type I IL-1R
with high anity but does not trigger signal transduction.
This molecule is readily detectable in biological ¯uids in a
variety of circumstances and appears to function as a
physiological regulator of the IL-1 response.125 The second
was a homodimer of the IL-12 p40 chain which competes
with the biologically active p35±p40 heterodimer for bind-
ing to the b1 chain of the high-anity IL-12 receptor but
does not trigger a response.126 Like IL-1ra, this molecule is
detectable in biological ¯uids and can inhibit IL-12-de-
pendent responses when administered to experimental ani-
mals,127 but evidence that it acts as an agonist for CD8+ T
cells has also been reported.128 Another type of receptor
blocking can occur when two di€erent, biologically active
cytokines compete for access to a shared receptor compo-
nent. This heterologous antagonism can be readily dem-
onstrated in binding studies in vitro but its signi®cance as a
physiological regulatory mechanism is not clear.104
Soluble cytokine receptors
In addition to their membrane-bound forms, many cyto-
kine receptor chains occur in soluble form, produced either
by proteolytic release of the extracellular domain of the
membrane-bound receptor or by translation of a truncated
receptor from an alternative transcript (Fig. 5).129,130 Pro-
duction of soluble receptors by both mechanisms is usually
increased with cellular activation. There are a number of
possible physiological roles, both negative and positive, for
these released or secreted forms, including: (i) desensitiza-
tion of the receptor-bearing cell by receptor shedding; (ii)
inhibition of cytokine action by competition with mem-
brane-bound receptors; (iii) protection of soluble cytokine
from degradation; (iv) cytokine transport; and (v) partici-
pation in functional receptor formation.
The actual consequences of production of a soluble cy-
tokine receptor presumably depend on several parameters,
such as the relative concentrations of the cytokine, soluble
receptor and competing membrane receptor, the relative
anity of the soluble receptor, and its ability to interact
with other molecules.
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307
Figure 5 Cytokine±receptor interactions. Cytokines can exist
in soluble and/or membrane-bound forms. Their receptors are
normally anchored in the cell membrane but some are also
released or secreted as soluble molecules. Signal transduction
to the target cell () can occur when membrane receptors in-
teract with soluble or membrane-bound cytokines, but this
interaction can be competitively inhibited by soluble receptors.
In other circumstances, soluble receptors may protect cyto-
kines from degradation and clearance. It is possible that mul-
timeric receptor interaction with membrane-bound cytokine
induces `reverse signalling' to the producer cell in some cases.
Some soluble receptors have very low anity for their
cytokine in the absence of other receptor components and
must therefore be present in substantial excess to compete
with the membrane receptor complex for cytokine binding.
The best studied example is soluble IL-2Ra, which is pro-
duced by proteolysis and occurs in signi®cant quantities in
the supernatants of activated T cell cultures and in the
circulation in a wide range of conditions in which T cells are
activated, such as infection, malignancy, transplant rejec-
tion and autoimmune disease.130 Since this low-anity
component receptor must be present at 100- to 1000-fold
higher concentrations than the medium- and high-anity
receptor complexes to compete with them for IL-2 binding,
a major physiological role as an IL-2 inhibitor seems un-
likely. Conversely, of course, shedding of all IL-2Ra chains
from a cell would reduce its IL-2 sensitivity by 100-fold. It
therefore seems probable that the primary function of low-
anity receptor release by proteolysis is to limit the cyto-
kine response by desensitizing the target cell.
The generation of soluble receptors from alternative
transcripts (e.g. IL-6Ra, IL-7Ra, GM-CSFRa, G-CSFR)
implies a regulatory role other than desensitization, but
whether that role is normally cytokine inhibition is not yet
clear. Most known soluble cytokine receptors are able to
act as speci®c antagonists in vitro and a number, including
receptors generated by proteolysis (such as IL-1RI and II,
and TNFRI and II), have been shown to function as ef-
fective cytokine inhibitors in vivo in experimental animals
and in clinical trials.5,130 On the other hand, the soluble
form of the IL-1R-AcP appears to be generated by alternate
splicing but does not bind IL-1 on its own.5

308 A Kelso
Some soluble receptors have also been found to function
as agonists in vivo by protecting their bound cytokine from
degradation (e.g. TNF-a and IL-4), thereby increasing cy-
tokine half-life and tissue distribution and serving as a depot
for cytokine release when free ligand concentrations de-
cline.130,131 Soluble IL-6Ra and IL-11Ra also have agonistic
activity, but for a di€erent reason. These receptor chains
bind their respective cytokines with low anity in solution;
remarkably, the complex can then interact with membrane-
anchored gp130 to form a functional receptor and can
therefore render any gp130-bearing cell IL-6-responsive or
IL-11-responsive.132,133 An analogy has been noted between
the IL-6/IL-6Ra complex and IL-12, a disulphide-bonded
heterodimeric cytokine whose p35 and p40 components
show some homology to IL-6 and IL-6Ra and might
therefore have evolved from a ligand±receptor pair.13
One of the most sophisticated examples of interplay
between cytokines and their receptors in the regulation of
cytokine action is provided by IL-1 (Fig. 6).5,130 As noted
above, three isoforms of IL-1 have been identi®ed: (i) IL-1a
occurs mainly in membrane-bound form and is biologically
active in this state; (ii) IL-1b is processed to yield the major
biologically active form of soluble IL-1; and (iii) IL-1ra is
produced as a conventional secreted glycoprotein and binds
to the same receptors as IL-1a and -1b but does not trigger
signal transduction.
Each of these three IL-1 species can bind to either of two
classes of IL-1 receptor: (i) the type I receptor is membrane
bound and delivers a signal on binding of either IL-1a
or -1b in the presence of the IL-1R-AcP; and (ii) the type II
receptor probably does not associate with IL-1R-AcP or
transduce a signal in its membrane form but is proteoly-
tically released to give a soluble IL-1 inhibitor.134
Figure 6 Regulation of IL-1 production and action. IL-1a,
IL-1b and IL-1ra are encoded by distinct but homologous
genes whose expression is independently regulated. IL-1a and
IL-1b are synthesized as pro-hormones. Pro-IL-1b must be
cleaved, for example by the enzyme ICE, for biological activity.
IL-1a is targeted to the cell membrane whereas IL-1b and IL-
1ra are secreted. IL-1RI and II are also encoded by distinct but
related genes. Interaction of IL-1a or IL-1b with IL-1RI results
in signal transduction (). This interaction can be competitively
inhibited either by IL-1ra, which binds to IL-1RI without
triggering signal transduction, or by the soluble decoy receptor,
IL-1RII, which binds preferentially to IL-1a or IL-1b and
limits their access to IL-1RI.
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Whereas the three forms of IL-1 have comparable anities
for IL-1RI and IL-1b binds with similar anity to both
receptors, IL-1a and IL-1ra preferentially bind to type I
receptors. The anity of the IL-1ra for IL-1RII is reported
to be two to three orders of magnitude lower than for IL-
1RI, presumably ensuring that the two naturally occurring
IL-1 antagonists do not normally neutralize each other.
Thus, while IL-1 serves a key positive role as a rapid am-
pli®er of the in¯ammatory response, several mechanisms
exist to limit its action.
Positive and negative regulation of the cytokine network
Why do such elaborate mechanisms exist to control cyto-
kine production and action? One of the early lessons from
experimental and clinical trials of systemically administered
cytokines was that sustained elevation of circulating cyto-
kine concentrations was frequently associated with unac-
ceptable toxicity. In normal health and limited disease,
most cytokines apparently function as paracrine or auto-
crine hormones, produced and consumed at the site of tis-
sue invasion or damage. For example, most of the
interleukins, the interferons, GM-CSF and, of course, the
membrane-bound cytokines (such as membrane TNF-a and
LT-a/b) are produced by and act on APC, lymphocytes and
local in¯ammatory cells within sites of infection and asso-
ciated lymphoid tissues. On the other hand, certain cyto-
kines are frequently found at elevated levels in the
circulation in a wide range of conditions, including infec-
tions, autoimmune disease and host-versus-graft and graft-
versus-host reactions. These commonly include IL-1, IL-6,
TNF-a and, in bacterial infections, G-CSF and are prob-
ably derived from macrophages, endothelial cells and other
widely distributed cell types in liver, lung and the vascular
system itself. In these cases, modest systemic levels pre-
sumably bring bene®t in promoting mild fever, acute phase
protein production and mobilization of haemopoietic pro-
genitors. In severe disease, however, marked elevations of
IL-1, IL-6 and TNF-a can themselves contribute to tissue
wasting and organ failure.5,135
It is therefore not surprising that multiple mechanisms
exist to ensure, on the one hand, that biologically active
cytokine concentrations reach the relevant target cells and,
on the other, that the levels and duration of cytokine syn-
thesis do not lead to inappropriate activation of immune
and in¯ammatory processes (reviewed in reference 136).
Factors that promote local cytokine ecacy operate at
several levels. Cytokine anchoring in the membrane of the
producing cell is the most extreme mechanism to limit
cytokine spread, but directional secretion and binding to
non-signalling cytokine receptors or proteoglycans on cell
surfaces and in the extracellular matrix also serve to
concentrate secreted cytokines at the site of produc-
tion.43,44,137±139 Binding to extracellular matrix and, in
some circumstances to soluble cytokine receptors, auto-
antibodies and other less speci®c binding proteins, might
also protect cytokines from clearance and provide a slow-
release depot.130,138,140,141 The architecture of the tissue can
juxtapose cytokine-producing and responsive cells, for ex-
ample in specialized zones of the lymph nodes where cy-
tokines participate in the activation of naive T cells by

Cytokines
interdigitating dendritic cells and the delivery of T cell help
to B cells.142 The response to a cytokine can then be am-
pli®ed by synergy with other cytokines and signals, by cy-
tokine cascades, and by regulatory pathways that enable
cytokines to stimulate their own production and expression
of their own receptors.
Counteracting forces also operate at several levels to
constrain the cytokine response. Production is usually
transient due to elimination of the inducing stimulus and to
signals that suppress synthesis, such as corticosteroids,
prostaglandins, nitric oxide and other cytokines;143 intra-
cellular feedback mechanisms, such as receptor down-reg-
ulation, also exist to abbreviate the response. Once
cytokines have been released, non-speci®c mechanisms of
di€usion, degradation and clearance normally eliminate
them from the circulation with half-lives of the order of a
few hours. Speci®c receptor-mediated binding and inter-
nalization by target cells also deplete the cytokine at the
same time as it stimulates the cells. Regulation of mem-
brane receptor expression therefore in¯uences both the
cellular response and cytokine concentration. Inhibition of
cytokine action can be achieved by soluble cytokine
receptors, auto-antibodies and other cytokine-binding
molecules.130,131,140,141 Whether these function as negative
or positive regulators depends, as previously noted, on the
relative concentrations and binding anities of the binding
protein, the cytokine and its membrane receptor. The nat-
ural receptor antagonist IL-1ra, is unequivocally inhibitory
provided sucient concentrations are present and appears
to be an important mechanism to limit the IL-1 action
under physiological conditions.125 Once cytokines have in-
teracted with their cellular receptors, feedback mechanisms
exist to curtail the response.111±113 Collectively these diverse
constraints on cytokine levels have the e€ect that responses
are also anatomically limited. The nature of the cytokine
response will therefore depend on the lineages and func-
tional states of the accessible target cells.
The net e€ect of these opposing forces on the cytokine
network can be a tenuous balance between bene®t and
harm for the host. Many of the symptoms caused by the
normal immune challenges of Western life, such as the
fevers, aches and fatigue associated with viral respiratory
tract infections, are caused by endogenous cytokines. When
the challenge is not controlled by the host immune re-
sponse, for example in cerebral malaria and septic
shock,135,144 then cytokines themselves can be life-threat-
ening. This presents its own challenge to the use of cyto-
kines as therapeutic agents.
Therapeutic exploitation of the cytokine network
The potency of many cytokines and their receptors as reg-
ulators of immune and in¯ammatory reactions makes them
an obvious source of, or targets for, new therapeutic agents.
On the other hand, redundancies of cytokine action and the
existence of complex regulatory networks in vivo might
throw doubt on the feasibility of exploiting the cytokine
system in any rational manner for patient bene®t. Indeed
the disappointments of many cytokine-based therapies and
the unexpected outcomes of in vivo administration of cy-
tokines in various experimental and clinical situations (such
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309
as the exacerbation of multiple sclerosis by IFN-c in one
clinical trial)145 probably re¯ect our limited practical un-
derstanding of this complexity. It is encouraging then to
note that individual cytokines can exert remarkably speci®c
and signi®cant e€ects on some processes in vivo. This has
been demonstrated most clearly in two ways.
The ®rst is by elimination of the cytokine, either tran-
siently using neutralizing antibodies or the cognate soluble
receptor, or permanently by gene inactivation as a result of
natural mutation or gene targeting in embryonic stem cells.
Table 4 gives the examples of IL-4 and IL-5 where both
transient neutralization and gene targeting have con®rmed
the key selective roles of these cytokines in IgE synthesis
and eosinophilia respectively, in the immune response to
airway allergens and gut nematodes. In these examples, the
consistency of outcome of the two approaches to cytokine
elimination re¯ects the fact that IgE synthesis and
eosinophilia are induced responses to infectious or aller-
genic challenge. In other circumstances, however, the ab-
sence of a cytokine gene product throughout development
yields a quite di€erent phenotype from neutralization in
adulthood. A striking example is provided by members of
the TNF family. Mice in which the LT-a gene has been
inactivated by targeting fail to develop lymph nodes, Pey-
er's patches and primary and secondary follicles in the
spleen.150 TNF-a-de®cient mice also lack primary and
secondary follicles,151 while LT-b-de®cient mice display a
similar phenotype to LT-a-de®cient mice except that they
usually have mesenteric and cervical lymph nodes.152 In
such instances, the e€ect of transient neutralization is a
more useful guide to therapeutic value.
The second is a remarkable sign from nature that cyto-
kines can be Achilles' heels in the host response to infection.
This is the ®nding that a number of viruses encode homo-
logues of mammalian cytokines, soluble cytokine receptors
or other modulators of cytokine activation or function
(Table 5).153 In many of these cases, the viral gene has been
shown to encode an immunomodulatory product and in-
activation of that gene has been found to reduce virulence.
Presumably these genes have been acquired from the host
genome; subsequent mutation has sometimes then yielded a
protein product with only a subset of the biological activ-
ities of its mammalian counterpart (e.g. the EBV-encoded
homologue of IL-10).160 Apart from their signi®cance for
understanding viral pathogenesis, these viral immuno-
modulators ¯ag the value of targeting individual cytokines
to alter the course of the host response. It is notable that,
despite the importance of acquired immunity in recovery
and protection from viral reinfection, inhibitors of early
Table 4 Cytokine control of murine response to helminths and
airway allergens116,146±149
Treatment IgE Eosinophilia
None +++ +++
Anti-IL-4 antibody + +++
Anti-IL-5 antibody +++ )
IL-4 gene inactivation ) +++
IL-5 gene inactivation +++ )
 14401711, 1998, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1440-1711.1998.00757.x by CAPES, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
310 A Kelso

Table 5 Viral hijacking of the cytokine network153±159 caused fever, hypotension, pleural and peritoneal ¯uid re-
tention, vascular leakage and even mortality, probably due
Virus Viral gene function to the induced production of endogenous TNF-a and other
cytokines. Comparable, though generally modest, bene®t in
Kaposi's IL-6 homologue cancer therapy has since been achieved with lower toxicity
sarcoma-associated using reduced doses, particularly in combination with cy-
herpesvirus
totoxic drugs, and local delivery.161,162 Certain cytokines
Epstein-Barr, orf IL-10 homologue
have nevertheless found a useful place as systemic drugs,
Herpesvirus saimiri IL-17 homologue
including G-CSF, GM-CSF, IFN-a and others not con-
Cowpox, vaccinia Soluble IL-1RII homologue
sidered here, such as erythropoietin.163,164 The best example
Hepatitis B Receptor for cell-bound IL-6
Vaccinia Soluble IFN-a/b-binding protein
is probably G-CSF in the promotion of haemopoietic re-
Myxoma, cowpox, Soluble IFN-cRa homologue covery after myelo-ablative radiotherapy or chemotherapy
smallpox, vaccinia and in myelopoietic disorders such as cyclic neutropenia;163
Myxoma, Shope ®broma Soluble TNFRII (p75) homologue the success of this cytokine perhaps re¯ects its normal
African swine fever IjB homologue (inhibitor of physiological function as a systemic inducer of stem cell
cytokine synthesis) mobilization and neutrophil production. IFN-a has proved
Cowpox ICE inhibitor (crmA) e€ective in the treatment of hairy cell leukaemia, chronic
Adenoviruses, Epstein-Barr, Inhibitors of IFN-a/b and myeloid leukaemia, multiple myeloma and hepatitis B and
vaccinia, Kaposi's TNF-a action C virus infections, as well as having some limited ecacy in
sarcoma-associated the treatment of melanoma and renal-cell carcinoma.164
herpesvirus The lesson from trials with many cytokines, however, is
that maximal ecacy with minimal toxicity is most likely to
be achieved by considering their physiological role as pa-
in¯ammatory cytokines (IL-1, IL-6, TNF-a and IFN-a/b) racrine hormones, for example by administering doses that
have been found most frequently among the cytokine-di- limit their target cell range or by delivering them directly to
rected viral genes identi®ed so far. the tissue site of interest, either in aqueous form or as
There are many ways in which the cytokine network controlled-release depots.161,165
might be exploited therapeutically, whether positively by An alternative approach with enormous potential for
cytokine administration, negatively by inhibition, or by some applications is the delivery of cytokine-encoding nu-
more subtle modulation (Table 6). Actual and potential cleic acids in viral and other vectors, in virally transduced
applications are wide ranging in the therapy of cancers, cells or as naked DNA, to achieve sustained cytokine ex-
autoimmune disease, allergy and chronic infection and in posure at selected sites.165±167 At the moment attention is
prophylactic vaccination. mainly focused on using these techniques to co-deliver cy-
tokines with antigens for vaccination against infectious
agents or tumour antigens. In concept this approach o€ers
Cytokine delivery the advantage of co-localizing the antigen with the cytokine
and enabling them both to be delivered to lymphocyte
Two broad approaches are being attempted to deliver cy-
priming sites by APC that carry the inoculum from the
tokines to experimental animals or human subjects: direct
injection site to draining lymph nodes. Naked non-meth-
administration of the protein, or nucleic acid delivery in an
ylated DNA has the additional adjuvant-like property that
infectious vector or as naked DNA. Systemic delivery of
it induces synthesis of IL-12 and other pro-in¯ammatory
cytokines frequently has toxic e€ects that limit its applica-
cytokines and is therefore useful where type 1 cytokine re-
tion. A good example is IL-2 whose early use at high doses
sponses are desirable.168 Experimental systems in which
cytokines have been expressed in infectious viruses in vivo
have yielded important insights into viral pathogenesis and
Table 6 Therapeutic intervention in the cytokine network immune clearance.166 Promising results have been obtained
in animal and clinical trials to promote anti-tumour
Systemic or local cytokine administration immunity by co-expression of cytokines (most notably
Protein GM-CSF) with tumour antigens in autologous tumour
Nucleic acid cells; this approach may, however, be superseded by
Inhibition of endogenous cytokine production or action delivery of antigen-loaded dendritic cells expanded in vitro
Pharmacologic inhibitors of signal transduction from autologous progenitors using GM-CSF and TNF-a or
Antisense oligonucleotides IL-4.167,169,170
Neutralizing antibodies One of the greatest impediments to the clinical use of
Soluble cytokine receptors cytokines is the diversity of their activities on their many
Natural and synthetic receptor antagonists target cells. Some innovative strategies are being explored
that overcome this limitation by restricting function or
Stimulation or modulation of endogenous cytokine production or
target cell range. One is the mutation of residues in the
action
cytokine that a€ect receptor binding and activation to
Adjuvants
Immune deviation
produce a molecule with only a subset of wild-type activi-
ties.15,171 Another is to target expression of naked DNA to

Cytokines
the desired cell type by linkage of cytokine sequences to a
lineage-speci®c promoter.172 Yet another takes advantage
of the ability of soluble IL-6Ra/IL-6 complexes to stimulate
gp130-bearing cells: linkage of the IL-6Ra to a monoclonal
antibody enables such complexes to be targeted to cells
expressing the corresponding antigen.173
Cytokine inhibition
A powerful way to control immune and in¯ammatory re-
actions in vivo is to inhibit the endogenous cytokine re-
sponse. To date there has been most interest in blocking
cytokines that promote activation of undesirable immune
responses (such as graft rejection and autoimmune reac-
tions) and in suppressing toxicity mediated by in¯amma-
tory cytokines such as IL-1 and TNF-a (for example in
sepsis), but this approach also has potential to redirect
immune responses and to interrupt autocrine growth factor
stimulation of tumour cells.
Several drugs in common use are now known to mediate
their immunosuppressive or anti-in¯ammatory e€ects by
interfering with the intracellular pathways that lead to
cytokine synthesis or cytokine-dependent responses (e.g.
cyclosporin A, FK506, rapamycin, glucocorticoids,
thalidomide).20,34,143,144 Speci®c inhibition of cytokine or
cytokine receptor synthesis can, in principle, be achieved
with antisense oligonucleotides, although there are a num-
ber of obstacles to overcome in their design and use
in vivo.174 Speci®c inhibition of cytokine action can also be
achieved by neutralization with monoclonal anti-cytokine
or anti-receptor antibodies, soluble cytokine receptors, and
natural or synthetic receptor antagonists. Many of this last
group of agents have the advantage that they are naturally
occurring immune modulators whose endogenous equiva-
lents are elevated in the tissues and circulation in a wide
variety of circumstances; they might therefore be better
tolerated as therapeutic agents than cytokines themselves.
They do, however, vary markedly in ligand-binding pa-
rameters and serum half-lives.
Neutralizing anti-cytokine and anti-receptor antibodies
have been especially useful in de®ning the roles of indi-
vidual cytokines in immune activation, regulation and ef-
fector function in animal models (e.g. Table 4). Some
ecacy in clinical disease has also been demonstrated,
particularly when the constant regions of rodent mono-
clonal antibodies have been replaced with the equivalent
regions from human antibodies to reduce immunogenicity.
Human anti-TNF-a antibodies, for example, cause a tem-
porary but signi®cant reduction in the symptoms of rheu-
matoid arthritis.175 Both antibodies and soluble receptors
have the disadvantage that they can promote cytokine ac-
tivity and soluble receptors have the additional limitation of
short half-life in vivo; these reagents must therefore be
present in substantial excess over their ligands to be in-
hibitory.130 One approach to reducing these problems is
dimerization, which improved the inhibitory activity of
soluble TNFRI and II in vitro and in vivo, probably by
increasing avidity for the trimeric TNF-a molecule and
prolonging half-life.176,177 Dimeric human soluble TNFRII
has recently been reported to suppress the symptoms of
rheumatoid arthritis.178
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311
As noted above, two naturally occurring receptor an-
tagonists, IL-1ra and IL-12 p40 homodimer, have been
discovered so far. Of these only IL-1ra has been extensively
tested in experimental models and, to a lesser extent, in
clinical trials, with promising results in the treatment of
rheumatoid arthritis and sepsis.5,179 Arti®cial antagonists
have also been created by site-directed mutagenesis of
critical residues in receptor-binding regions of several
cytokines, including IL-4, IL-5, IL-6 and GM-CSF, and by
designing small peptides that mimic the receptor-binding
sites of cytokines such as IL-1, IL-6 and GM-CSF.171,180±185
Although little information is available about the activities
of these reagents in vivo, this approach is an important step
towards producing a new generation of speci®c inhibitors of
the cytokine response.
Immune regulation
Most of the approaches described above are concerned with
amplifying inadequate responses (as in cancer immuno-
therapy) or inhibiting excessive or inappropriate responses
(as in treatment of rheumatoid arthritis). However, as our
understanding of the pathways that regulate immunity
grows, so too do the possibilities for manipulating switch
points in those pathways to alter the class of an ongoing
immune response. Here the greatest interest is in achieving
`immune deviation'186 by switching T cell cytokine re-
sponses from a type 1 pro®le to a type 2 pro®le, or vice
versa. For example, islet b-cell destruction in autoimmune
diabetes is thought to be exacerbated by IFN-c-producing
T cells and to be either suppressed or una€ected by IL-4-
producing T cells.187±189 Development of vaccination or
other strategies to inhibit the former and promote the latter
class of T cell response might therefore be bene®cial.
Conversely, allergic reactions are mediated by IgE-armed
mast cells and eosinophils; T cells that produce the type 2
cytokines IL-4 and IL-5, as well as IL-3 and GM-CSF,
induce IgE switching in B cells and promote mast cell and
eosinophil production. Immunotherapy to divert the T cell
cytokine response from a type 2 to a type 1 pro®le should
therefore prevent the allergic response to antigen. A num-
ber of studies have found that conventional allergen im-
munotherapy causes a reduction in T cell synthesis of IL-4,
but e€ects on type 1 and other type 2 cytokines are variable
and the underlying mechanisms are not understood.190±192
As previously discussed, the development of type 1 and
type 2 T cell cytokine pro®les is strongly in¯uenced by IL-
12 and IL-4, respectively, as well as by other stimuli. Co-
delivery of antigen with IL-12 or IL-4, or delivery of the
antigen in a manner or form that promotes endogenous
production of IL-12 or IL-4, are accepted strategies to in-
duce primary responses of the desired class. Deviation of an
established response raises additional issues: can the cyto-
kine pro®le of the existing population of cytokine-produc-
ing T cells be changed, or must this existing population be
deleted or suppressed, then replaced with a new population
of the desired phenotype (Fig. 7)? Although some infor-
mation is available about the stability of T cell cytokine
pro®les in vitro (see above), it is not yet known whether
activated and memory T cells in vivo are committed to ex-

312 A Kelso
Figure 7 Possible pathways for re-programming established T
cell cytokine pro®les. Primary T cell activation in the presence
of IL-4 leads to the generation of a T cell population which
preferentially synthesizes type 2 cytokines such as IL-4 and IL-
5. Three pathways can be envisaged that might change this
dominant cytokine pro®le: re-programming of existing type 2
cells (dark shading) to synthesize di€erent cytokines, selective
expansion of existing cells with another cytokine pro®le (e.g.
type 1 cells) (light shading), and selective expansion and de
novo programming of uncommitted cells (no shading). The
second and third of these might require suppression or deletion
of existing type 2 cells.
pression of a single set of cytokine genes. Better under-
standing of the factors controlling the development and
reversibility of T cell cytokine pro®les will assist the rational
design of strategies for immune deviation.
Concluding comments
The cytokine ®eld is now more than 30 years old. Much has
already been learned about cytokine structure, synthesis,
function and regulation and some cytokines have found an
important place in clinical use. However, many others still
hover on the brink of major clinical impact, re¯ecting the
sophistication of the cytokine network and our still limited
understanding of its physiological regulation. The remark-
able advances of the last decades will certainly be translated
into improved human health as we learn simple ways to
stimulate, interrupt and redirect the cascade of cytokines
and other signals that determine the outcome of any im-
munological challenge. Fortunately this need not be an
empirical process: the rules of the game are yielding to
experimentation in the laboratory and clinic and should
serve as guiding principles in developing new therapeutic
applications of the cytokines and their receptors.
Acknowledgements
This article was based on lectures delivered at the Annual
Scienti®c Meeting of the Australasian Society for Immu-
nology (Gold Coast, Australia, December 1995) and the
Joint Scienti®c Meeting of the Colleges of Pathologists
(Singapore, 1997). I am grateful to Dr Keryn Williams for
encouragement to prepare these lectures as an article and to
Dr David Fitzpatrick for valuable comments on the
manuscript. The continuing support of the Queensland
Institute of Medical Research Trust is gratefully acknowl-
edged.
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