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Role of IL-17 in the Pathogenesis of Rheumatoid Arthritis
Sarah L. Gaffen, Ph.D.1
1 Department of Medicine, Division of Rheumatology and Clinical Immunology, University of
Pittsburgh, Pittsburgh PA 15261, USA, sig65@pitt.edu. Ph. 412-383-8903. Fax. 412-383-8864
Abstract
IL-17 (also known as IL-17A) is the signature cytokine of the newly-described “Th17” T helper cell
population, and has been implicated in the pathogenesis of numerous autoimmune diseases including
rheumatoid arthritis. IL-17 is the founding member of a new subclass of cytokines that have highly
pro-inflammatory properties. Studies in rodents, mammalian cell culture systems as well as clinical
settings support a role for IL-17 in promoting rheumatoid arthritis. The history of the discovery of
Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity and perspectives for IL-17-
targeted cytokine therapy are discussed.
Introduction
T helper cells and the new Th17 paradigm
In the last several years, there has been a paradigm-shift in our understanding of the role of T
cells in autoimmunity, particularly with regards to the CD4+ T helper cell subset (Th cells). T
helper cells have long been known as the “masterminds” of the immune system, controlling
the activities of other lymphocytes as well as many aspects of the innate immune response.
Their depletion in the setting of HIV infection highlights the vital role of CD4+ T cells in
coordinating immunity to infectious diseases. T helper cells accomplish their vital tasks
primarily by means of secreting cytokines, protein-based hormones that bind to specific
receptors on target cells. Cytokines have pleiotropic activities, which include triggering
proliferation, cell death, specific gene expression, cellular migration, etc.
In 1986, a seminal model put forth by Coffman and Mossman postulated that different
subpopulations of Th cells could shape immune responses by virtue of differential cytokine
production, and two subsets were initially identified that were termed “Th1 and Th2” (Table
1) (1). This model posits that Th1 cells mediate “cellular immunity,” characterized by
macrophage activation and opsonising antibodies through the actions of the cytokine
interferon-γ (IFNγ). Conversely, Th2 cells mediate “humoral immunity” characterized by
activation of B cells and effector antibodies, which is mediated by interleukin (IL)-4, IL-5 and
IL-13 (Figure 1). Central to this model was the concept that naïve Th cells are not pre-
determined to be either Th1 or Th2, but rather that the environment in which they encounter
antigen dictates their subsequent fate. In accordance with this idea, it was shown that IL-12,
usually derived from antigen-presenting cells (APCs) such as dendritic cells, directs
differentiation of naïve CD4+ T cells into the Th1 lineage, whereas IL-4 promotes development
to the Th2 lineage. Moreover, differentiation of each Th subset is mutually antagonistic and
self-reinforcing by cross-antagonistic signaling pathways mediated by IL-12 and IL-4. For
nearly twenty years the Th1/Th2 model provided a valuable framework in which diseases, both
infectious and autoimmune, were evaluated. Much research effort was devoted to defining the
mechanisms that control Th1/Th2 development, as well as the key cytokines, transcription
factors and microbial/autoimmune stimuli involved in this process (reviewed in (2)).
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Published in final edited form as:
Curr Rheumatol Rep. 2009 October ; 11(5): 365–370.
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However, over time it became apparent that there were glaring discrepancies with this model,
particularly related to Th1 generation and function (2). The generation of various gene deficient
(“knockout”) mouse strains revealed puzzling differences between the Th1 effector cytokine
IFNγ and the Th1 differentiation cytokine IL-12 (Figure 1). IL-12 is a heterodimeric cytokine
composed of two subunits, IL-12p40 and IL-12p35. IL-12p40-deficient mice were developed
to probe the role of this cytokine in vivo, and IL-12p40-/-mice were found to be resistant to
most autoimmune disease models including the rodent model of RA, collagen induced arthritis
(CIA) (3). However, IFNγ-deficient mice and also IFNγ-receptor deficient mice appeared to
be resistant to CIA as well as many other autoimmune disease models; in fact, in some instances
these mice showed enhanced sensitivity to disease (3). The basis for this paradox began to
become clear when IL-12p35-deficient mice were generated, which appeared to have a highly
similar phenotype to the IFNγ-deficient mice and a less severe phenotype than IL-12p40-/-
animals. Thus, it was apparent that IL-12p40 plays an IL-12-independent role in immunity.
Indeed, IL-12p40 is also component of a new cytokine, IL-23, where it partners with a unique
IL-23p19 subunit (Figure 1). Accordingly, IL-12p40-deficient mice are deficient not only in
IL-12, but also in IL-23. Direct comparisons of IL-23p19-deficient mice and IL-12p35-
deficient began to tease apart the biological functions of these two cytokines, and it became
clear that many of the autoimmune functions that had previously been ascribed to IL-12 (e.g.
in CIA, EAE, IBD), were in fact due to the activities of IL-23 (reviewed in (4)).
Based on these findings, the function of IL-23 became a critical question. In other words, if
Th1 cells were not the main effectors of autoimmunity, was there a new, IL-23-dependent T
cell subset that had previously been overlooked? Indeed, IL-23 was shown to stimulate
production of IL-17 (often referred to as IL-17A) in murine CD4+ T cells (5). IL-17A, although
primarily derived from T cells, was not obviously a Th1 or Th2 cytokine, hinting at the
possibility of anew CD4+ T cell lineage involving this cytokine (6). Interestingly, studies in
Lyme disease arthritis models demonstrated that a distinct subset of CD4+ T cells produced
IL-17A (7), although the connection to IL-23 was not made at that time. Putting this together,
two landmark reports showed that an IL-17A-producing CD4+ T cells subset exists that can
be induced to differentiate in vitro (8,9). Moreover, induction of this lineage was found to be
independent on the classic Th1/Th2 STAT factors STAT4 and STAT6, and development of
this so-called “Th17” population could be inhibited by Th1- and Th2-specific cytokines,
IFNγ and IL-4 (Table 1). A veritable avalanche of reports followed over the next few years,
demonstrating that Th17 cells are indeed a separate lineage (reviewed in (4)). Unexpectedly
and in contrast to IL-12, IL-23 was not essential for differentiation of Th17 cells per se, but
rather for their pathogenicity in vivo (10). However, in mice IL-23 is nonetheless essential for
stable development of Th17 cells, and polymorphisms in the IL-23R gene in humans are linked
to susceptibility to Crohn's Disease (11).
Whereas IL-23 is not required for Th17 differentiation, a combination of TGFβ, IL-1, and IL-6
serve in this capacity, and the transcription factor RORγt was found to be key for differentiation
of these cells (reviewed in (4)). Strikingly, Th17 cells arise in opposition to inducible T
regulatory cells (iTregs), in part by virtue of the fact that both lineages depend on TGFβ for
their differentiation (12,13). Thus, in settings of autoimmunity, an altered balance between
immunosuppressive Tregs and inflammatory Th17 cells appears to be a major component in
disease pathogenesis. Related to this issue, an important and often unappreciated feature of Th
cells in vivo are their lineage plasticity. Specifically, differentiation to specific Th1/2/17/Treg
phenotypes is not fixed, but rather there is considerable interconversion among these cell types
observed in vivo and in vitro (14,15). In particular, Treg and Th17 cells have been shown to
interconvert (16), and understanding precisely how and under what circumstances this occurs
has important implications in terms of treating autoimmune disease.
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Although IL-17A is predominantly produced by T cells, it is not only the province of the CD4
+ subset. CD8+ T cells also produce considerable amounts of IL-17A, as do γδ-T cells, NKT
cells and lymphoid tissue inducer (LTi) cells (reviewed in (17)).
IL-17 receptor signaling bridges innate and adaptive immunity
Although IL-17A is eponymous with the Th17 lineage, these cells also produce IL-17F, IL-21,
IL-22, IL-26 (the gene for which is found only in humans), and in some reports TNFα, CCL20,
and G-CSF (Table 1) (17). Although these are very different cytokines, they all function in a
similar manner to promote inflammation, and in some cases can act cooperatively or
synergistically (discussed in more detail below). IL-17A and IL-17F are quite homologous
(∼55%) and can form heterodimers (termed IL-17A/F) that appear to be the major isoform of
the cytokine in human PBMCs (18). All three cytokine forms bind to a common receptor
complex (see below), but exhibit distinct signaling potencies, with IL-17A>IL-17A/F>IL-17F.
IL-17A and IL-17F bind to a multimeric receptor complex composed of at least two subunits,
IL-17RA and IL-17RC. These receptors belong to a specific subclass of cytokine receptors
with distinct molecular features that distinguish this family from other types of receptors
(19). IL-17A and IL-17F signaling through their receptors is unusual compared to typical
adaptive T helper cell cytokines. Rather than activating JAK-STAT pathways, the IL-17-family
cytokines activate pro-inflammatory pathways more typical of innate, pro-inflammatory
cytokines such as IL-1 or TLR agonists. All these cytokines activate NF-κB, and many also
have been shown to induce MAPK signaling and the C/EBP transcription factors. Thus, the
net effect of IL-17A signaling is to induce an innate-type inflammatory effector gene
expression program that mediates potent inflammation and plays a key role in host defense
(reviewed in (20)). Conversely, in conditions of dysregulation, this inflammatory profile can
also promote inflammatory pathology in autoimmunity.
Much of our understanding of IL-17A biology in both infection and autoimmunity comes from
microarray studies of downstream target genes. Receptors for IL-17 are expressed ubiquitously,
but the key responsive cells tend to be non-immune cells such as epithelial cells, mesenchymal
cells (myoblasts, fibroblasts and adipocytes, osteoblasts) and keratinocytes. IL-17 stimulates
expression of inflammatory genes, including cytokines (IL-6, G-CSF, OSM, IL-32),
chemokines (CXCL1, CXCL2, CXCL5, CCL20) and other inflammatory effectors (iNOS,
anti-microbial genes, acute phase response genes) (reviewed in (20)). Accordingly, although
IL-17A is made by T cells, its downstream signals are similar to those induced by typical
“innate” immune receptors such as Toll-like recepor ligands (e.g. LPS) or IL-1β.
As indicated above, IL-17A and IL-17F synergize potently with TNFα, although the
mechanisms underlying this synergy are only partially understood. Thus, IL-17A may act as
a “rheostat” for TNFα signaling. A recent study in human synovial fibroblasts (21) compared
genes induced by IL-17A versus IL-17F, and found that they promoted similar profiles of gene
expression, although IL-17A was quantitatively more active. In the presence of TNFα, the
patterns of induced genes were highly similar. Interestingly, IL-17A and IL-17F upregulate
expression of TNFRII in synoviocytes (21), which may help explain the basis for synergy
between these cytokines. IL-17A also cooperates with IL-1β and IL-22, although the synergy
is generally not as dramatic as that seen with TNFα (22). Therefore, Th17-related cytokines
act cooperatively to amplify inflammatory cascades, which is beneficial in host defense but
deleterious in many autoimmune settings.
IL-17 promotes disease in mouse models of RA
The pathogenic role of IL-17A in murine models of inflammatory arthritis is unequivocal
(23). Elegant work from Erik Lubberts and colleagues has demonstrated a key role for IL-17
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in collage-induced arthritis. This occurs in part due to an altered RANKL:OPG ratio, and is
independent of IL-1 and TNFα (reviewed in (24)). IL-17-deficient mice are resistant to CIA
(25) as well as spontaneous arthritis in IL-1Ra-deficient mice (26). Blocking IL-17 or its
receptor with antibodies reduces disease in mice (reviewed in (24)). Although the mechanisms
are not fully elucidated, IL-17 has both direct and indirect bone destructive properties. Th17
cells express much higher levels of RANKL than Th1 or Th2 cells and thus may be very
efficient at promoting bone turnover (27). IL-17-induced proteins include matrix
metalloproteinases, RANKL and pro-inflammatory effectors such as iNOS that can
cumulatively promote bone loss (23). IL-17 signals directly in osteoblasts and synovial
fibroblasts to promote inflammation (21,28). Accordingly, IL-17 and other Th17 related
cytokines are considered prime targets of anti-cytokine therapy in autoimmune arthritis (24).
The roles of IL-17 and IL-23 on other bone-destructive conditions, however, are complex, and
not necessarily pathogenic. For example, the most common form of bone loss in humans is
actually due to infectious diseases in the oral cavity that lead to periodontal disease and
destruction of the alveolar bone crest of the jaw. Although elevated levels of IL-17 are found
in some instances of human periodontal disease (29), in a mouse model IL-17 receptor signaling
is highly bone protective through its ability to promote neutrophil expansion and recruitment
and hence limit infection (30). IL-23-deficient mice also show abnormalities in maintaining
normal bone mass, suggestive of bone-protective properties unrelated to inflammation (31).
The extent to which these findings in mice will apply to humans is still unknown, but these
observations may raise flags concerning the efficacy of blocking IL-17A or its receptor to treat
bone-destructive diseases.
IL-17 in human RA
There is strong evidence for a role for IL-17 in promoting human RA, although not all studies
agree fully. As much as a decade ago, reports began to indicate that high levels of IL-17 and
its receptor are found in RA synovial fluid and tissue explants, and IL-17 can promote joint
degradation in ex vivo models (32-37). In contrast, there is no convincing data supporting a
role for IL-17 in OA. Moreover, IL-17 together with TNFα was found to be predictive for poor
outcome in RA (38). IL-17 promotes recruitment of both neutrophils and monocytes by means
of inducing various chemokines (37), which can in turn mediate inflammation in RA. However,
studies have been reported suggesting that Th1 cells may be more important than Th17 cells
(39). The impending use of therapeutics that target IL-17A directly will no doubt shed
important light on this issue.
Implications for anti-cytokine therapy
Blocking TNFα has become a mainstay for treating RA in humans, but is not successful in all
situations (reviewed in (40)). TNFα is produced by Th cells but also by macrophages, DCs and
other innate immune cells. However, it is also plausible that anti-TNF therapy directly impacts
generation of Th17 cells and hence production of IL-17. Consistent with this hypothesis, a
recent report examined the consequences of TNF blockade in psoriasis (41). This study of 20
patients reported that 50 mg of etanercept treatment led to improved PASI scores and also to
reduced levels of IL-17A and IL-22 in psoriatic lesions. Antibodies that block IL-12p40
(ustekinumab), which hence block both IL-12 and IL-23, were developed based on the premise
that Th1 cells promote autoimmune disease. Fortuitously, this subunit is shared with IL-23,
and thus this drug presumably limits IL-17A production by blocking Th17 cells as well as Th1
cells. Ustekinumab is quite effective in Crohn's disease and psoriasitic arthritis, although not
for multiple sclerosis (42). Similarly, antibodies to the IL-6 receptor (tocilizumab) have shown
success for treating RA (43), and IL-6 is both upstream of Th17 cells and a major gene target
of IL-17. In contrast, IL-1 appears to be a key driver of Th17 development in human systems,
yet Anakinra (a soluble IL-1R antagonist) failed to be an effective therapy for RA even though
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it is highly successful in diseases involving inflammasome defects (44). Although this could
be due to its short half-life in vivo, a connection to Th17 cells cannot be ruled out. Antibodies
to IL-17A or IL-17RA are presently in Phase I or Phase II clinical trials for a variety of
autoimmune diseases, including psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis and Crohn's Disease (www.clinicaltrials.gov). Early reports of a small psoriasis
study indicate that blocking IL-17A is very efficacious, but clearly larger studies will be needed
to determine its utility in the clinic (D. Patel, unpublished data). It is likely that, even if blocking
IL-17A or its receptor proves efficacious clinically in many patients, it will not be effective in
all who take it.
What are the likely safety issues regarding therapeutic blockade of IL-17A? Blocking TNFα
therapeutically has proved surprisingly safe, although it can promote development of
tuberculosis in patients with latent infections (44,45). Similarly, few major adverse events were
reported with the anti-IL-6R Abs (43). Studies using IL-17A-/- or IL-17RA-/- mice have shown
an important role for this cytokine system in preventing infections to a long list of microbial
pathogens, particularly those that act extracellularly such as gram negative bacteria and the
commensal yeast Candida albicans (46,47). An “experiment of nature” has provided valuable
insight into the possible side effects of blocking Th17 cells in humans. Specifically, humans
with hyper-IgE syndrome (HIES, Job's Syndrome) have recently been shown to have an
inherited, dominant-negative defect in the transcription factor STAT3. STAT3 is required for
development of Th17 cells due to its role in transducing essential signals from IL-23 and IL-6.
Accordingly, HIES patients have a paucity of Th17 cells and IL-17A, but they have normal
levels of Th1 cells and IFNγ (reviewed in (48)). These patients experience a number of recurrent
infectious diseases, including pulmonary infections, staphylococcal abscesses, eczema, and
mucocutaneous Candida albicans infections. There are also bone and connective tissue
disorders related to other functions of STAT3 (reviewed in (49)). Thus, blocking IL-17A may
prove problematic in terms of enhancing susceptibility to common infections.
Conclusions and perspectives
The past few years have been a watershed in our understanding of the T cell-mediated
pathogenesis of autoimmune disease. The impact of the revision of the Th1/Th2 paradigm to
include Th17 cells cannot be overstated. Nonetheless, it is striking that many of the anti-
cytokine therapies that have been developed to target Th1 cells in fact seem to act through the
Th17 lineage instead. It should be noted that, although the Th1 and Th17 cell types are often
considered separately, in fact there is much crosstalk between them (reviewed in {Korn, 2009
#2199; O'Quinn, 2008 #2216}). Understanding how Th17 cells and their downstream cytokines
act at a fundamental level is likely to reveal new strategies for treating RA and other
autoimmune conditions. Conversely, defining the potential side effects of blocking Th17 cells
in animal models as well as rare human populations with genetic defects in these cells is critical
for predicting and being prepared for potential complications associated with this approach.
Acknowledgments
SLG is supported by research grants from the Alliance for Lupus Research, Amgen and the NIH (AR054389,
DE019424). SLG has received travel reimbursement, honoraria and a research grant from Amgen. I thank D. Patel
(Novartis) for sharing unpublished information.
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Figure 1. Old versus new models of Th cell development
In the original paradigm of CD4+ T cell differentiation, most CD4+ T helper cells could be
classified into Th1 cells (typified by production of IFNγ) or Th2 cells (typified by production
of IL-4, IL-5 and IL-13). Th1 cells were considered to promote host defense against most
infectious microbes (both intracellular and extracellular), whereas Th2 cells were thought to
act primarily against large Helminth worms. Th1 cells were also considered to be the major
driver of autoimmune pathology in RA as well as other autoimmune diseases such as psoriasis,
multiple sclerosis and Crohn's Disease. The heterodimeric cytokine IL-12, composed of the
IL-12p40 and IL-12p35 subunits, was shown to be critical for development of Th1 cells, and
hence efforts to block IL-12 with antibodies against the IL-12p40 subunit were pursued. In
2005, the discovery of the Th17 subset revised this model, which was partly revealed based
on a new understanding of the shared role of the IL-12p40 subunit in the cytokine IL-23. Th17
cells are driven to differentiation by a combination of IL-1, IL-6 and TGFβ, and IL-23
(composed of the IL-12p40 and the IL-23p19 subunits) serves to expand and stabilize this
lineage.
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Table 1
T helper subsets and their major functions
Th1 Th2 Th17 iTreg
Major cytokines IFNγIL-4, IL-5, IL-13 IL-17A, IL-17F,
IL-21, IL-22, IL-26
(humans), TNFα,
CCL20
IL-10, TGFβ
Main Antimicrobial activity Intracellular microbes Helminths Extracellular microbes Limit immune-
mediated
damage,
prevent
autoimmunity
Inductive cytokines IL-12 IL-4 IL-1, IL-6, TGFβTGFβ, IL-2
Inductive transcription factors STAT1, Tbet STAT6, GATA3 STAT3, RORγt STAT5, Foxp3
Curr Rheumatol Rep. Author manuscript; available in PMC 2010 April 1.
