REVIEWS

Targeting IL‑17 and TH17 cells

in chronic inflammation
Pierre Miossec1,2 and Jay K. Kolls3
Abstract | The key role of interleukin‑17 (IL‑17) and T helper 17 (TH17) cells in tissue
inflammation, autoimmunity and host defence led to the experimental targeting of
these molecules in mouse models of diseases as well as in clinical settings. Moreover, the
demonstration that IL‑17 and TH17 cells contribute to local and systemic aspects of disease
pathogenesis, as well as the finding that the IL‑17–TH17 cell pathway is regulated by IL‑23,
prompted the identification of inhibitors. These inhibitors include biotechnology products
that target IL‑23 as well as the leading member of the IL‑17 family, IL‑17A, and one
of its receptors, IL‑17 receptor A. Several clinical trials of these inhibitors are underway,
and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing
spondylitis. This Review focuses on the current knowledge of the IL‑17–TH17 cell pathway to
better understand the positive as well as potential negative consequences of targeting them.

T helper 17 cells
(TH17 cells). A lineage of CD4
+
T cells that are defined by the
expression of interleukin‑17A
(IL‑17A) and IL‑17F; the
development of these cells is
controlled by the transcription
factors retinoid-related orphan
receptor-α (RORA) and RORC.
1
Department of Clinical
Immunology and
Rheumatology, University of
Lyon 1, Hôpital Edouard
Herriot, 5 Place d’Arsonval,
69437 Lyon, France.
2
Immunogenomics and
inflammation research unit
EA 4130, University of Lyon 1,
Hôpital Edouard Herriot,
5 Place d’Arsonval, 69437
Lyon, France.
3
Department of Pediatrics,
Children’s Hospital of
Pittsburgh, University
of Pittsburgh School of
Medicine, Pittsburgh,
Pennsylvania PA 15224, USA.
e-mails:
pierre.miossec@univ‑lyon1.fr;
Jay.Kolls@chp.edu
doi:10.1038/nrd3794
Interleukin‑17 (IL‑17) is a pro-inflammatory cytokine1–3
that contributes to the pathogenesis of several inflam‑
matory diseases. A major source of IL‑17 is a lineage of
T cells known as T helper 17 cells (TH17 cells)4–7, which
are distinct from the classical TH1 and TH2 cell subsets
(BOX 1).
Results of studies in mouse models and in humans
have identified a key role of IL‑17 and TH17 cells in the
pathogenesis of inflammation and autoimmunity as well
as in host defence against certain pathogens. Based on
these observations, IL‑17 and TH17 cells are considered
to be potential targets for the treatment of several dis‑
orders. Although the clinical potential of IL‑17 is just
beginning to be realized, results from clinical trials sug‑
gest that IL‑17 inhibition could be beneficial for the treat‑
ment of chronic inflammatory diseases such as psoriasis,
rheumatoid arthritis and ankylosing spondylitis.
In this Review, we describe the key features of the
structure and biology of the IL‑17–TH17 system in order
to better understand the mechanism of action of the new
IL‑17‑targeted therapies. We also highlight how the precise
role of IL‑17 inhibition in the treatment of certain chronic
inflammatory conditions still remains to be defined owing
to the complexity of these inflammatory processes.
Interleukin‑17
Discovery and activity. The Il17 gene and IL‑17 pro‑
tein were first discovered as a product of T cells in
rodents, where they were initially known as cytotoxic
T lymphocyte-associated antigen 8 (CTLA8)3. One of
the earliest documented biological activities of human
IL‑17 involved its effects on synoviocytes from patients
with rheumatoid arthritis and its effects on normal skin
fibroblasts from non-affected individuals, demonstrating
that IL‑17 could induce the production of IL‑6 and IL‑8
(REF. 2) (reviewed in REF. 8). These initial results immedi‑
ately linked IL‑17 activity to inflammation (as reflected
by the production of IL‑6, a major cytokine in inflam‑
mation and host defence) and to neutrophil biology (as
reflected by the production of IL‑8, a chemokine ligand
for CXC chemokine receptor 2 (CXCR2) that mediates
the recruitment of neutrophils into tissues).
Next, it was shown that synovium explants from adult
patients with rheumatoid arthritis produced functional
IL‑17 (REF. 9). When supernatants of cultures of synovium
were incubated with synoviocytes, an IL‑17‑specific
antibody reduced the high levels of IL‑6 production by
two-thirds. This pivotal study, which used the first avail‑
able monoclonal antibody that blocked human IL‑17,
showed that IL‑17 could be targeted to treat chronic
inflammation. Moreover, the study demonstrated that
although IL‑17 alone had a limited effect on the produc‑
tion of IL‑6 by synoviocytes, a combination of IL‑17 with
IL‑1 and tumour necrosis factor (TNF) resulted in an
enhanced production of IL‑6. These early findings sug‑
gested that IL‑17, produced by the synovium in rheuma‑
toid arthritis, interacted with other known stimulating
cytokines to induce IL‑6 production. Such interactions
were later shown to be often the consequence of synergy
between these cytokines10.

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© 2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Box 1 | Subsets of T helper cells
T helper (TH) cells have been divided into three major subsets based on their cytokine
profiles. The TH1 and TH2 subsets were the first to be described; their cytokine signatures
are interferon-γ (IFNγ) and interleukin‑4 (IL‑4), respectively. The TH17 subset was
described more recently and is simply defined by the production of IL‑17. The table
below lists the effector cytokines produced by each TH cell subset. This production is
induced by upstream cytokines, which are mainly produced by dendritic cells as well as
by monocytes and/or macrophages. Each T cell subset and its cytokines are involved in
the response to, and control of, infectious agents. The TH1 subset controls intracellular
bacterial infections, the TH2 subset controls parasitic infections and the TH17 subset
controls fungal and extracellular bacterial infections.
Biotechnology products used for the treatment of chronic inflammatory diseases
can act on these subsets in different ways. Abatacept (also known as cytotoxic
T lymphocyte antigen 4 immunoglobulin (CTLA4‑Ig)) gives a negative signal of
activation to T cells in general and thus acts on all three subsets. Ustekinumab inhibits
the p40 chain that is common to IL‑12 and IL‑23, and acts on both the TH1 and TH17
subsets. An antibody against IL‑23p19 acts specifically on the TH17 subset. Inhibition
of IL‑6 acts upstream on the differentiation of TH17 cells. Inhibitors of IL‑17 act on the
major cytokine of the TH17 subset but do not affect the other cytokines produced by
the TH17 subset, such as IL‑22.
TH1 TH2 TH17
Effector IFNγ and TNF IL‑4, IL‑5 and IL‑17A, IL‑17F, IL‑22, IL‑26, TNF and
molecules IL‑13 GM‑CSF
Proximal IL‑12 and IL‑4, IL‑25 TGFβ, IL‑1β, IL‑6, IL‑21 and IL‑23
regulators IL‑18 and IL‑33
Modulators • Abatacept • Abatacept • Abatacept
• IL-12p40- • IL-12p40-targeted antibodies
targeted • IL‑23p19‑ targeted antibodies
antibodies • IL‑6R‑targeted antibodies
• IL‑17‑targeted antibodies
• IL‑17R‑targeted antibodies
GM-CSF, granulocyte–macrophage colony-stimulating factor; IL‑6R, IL‑6 receptor; TGFβ,
transforming growth factor-β; TNF, tumour necrosis factor.
Structure and function. The IL‑17 molecule is composed
of two monomers that are linked by intramolecular disul‑
phide bonds on cysteine residues to form a homodimer.
IL‑17 is now formally referred to as IL‑17A in the liter­
ature, but generally called IL‑17, and is the founding
member of the IL‑17 family, which is composed of six
members — from IL‑17A to IL‑17F — all of which con‑
tain carboxy-terminal cysteine residues11. The main
IL‑17 family members are IL‑17A and IL‑17F, which
are predominantly produced by TH17 cells. IL‑17 was
discovered in 1993 as a pro-inflammatory cytokine pro‑
duced by TH cells1–3. IL‑17F was the first IL‑17 family
member to be crystallized and the homodimer of this
molecule adopts cystine knots similar to those formed
by the nerve growth factor receptor family 12. IL‑17F has
50% sequence identity with IL‑17A, and IL‑17F homo­
dimers are often co-expressed with IL‑17A; IL‑17F can
also be expressed with IL‑17A as an IL‑17A–IL‑17F het‑
erodimer 13 (FIG. 1). Although IL‑17F alone is usually less
active at inducing inflammation than IL‑17A, its effects
Cystine knots are enhanced when combined with TNF10.
Motifs that were first described However, results from mouse models of inflammation
in nerve growth factor, wherein indicate that some of the pro-inflammatory functions of
two disulphide bridges are
formed from paired cysteine
IL‑17F and IL‑17A are not identical14. For example, in
molecules. This motif conveys an asthma model driven by TH2 cells, genetic deletion of
protein stability. IL‑17F in mice results in a more substantial reduction in
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© 2012 Macmillan Publishers Limited. All rights reserved
neutrophilic lung inflammation than IL‑17A deletion14.
Moreover, genetic deletion of IL‑17F reduces experi‑
mental colitis, whereas deletion of IL‑17A increases dis‑
ease severity 14. However, in synoviocytes, no gene has yet
been identified that is specifically induced by IL‑17F and
not by IL‑17A10. These observations question the utility
of targeting IL‑17F alone or in combination with IL‑17A.
Clearly, more work is needed to better understand the
different responses to IL‑17A and IL‑17F in humans as
well as in experimental models of inflammation.
Research into other IL‑17 family members is still
in its infancy, but it was recently shown that IL‑17C
can amplify the production of IL‑17 from TH17 cells15.
Whether IL‑17C represents an additional therapeutic
target in the IL‑17 pathway remains to be determined.
In contrast to the other members, IL‑17E (also known
as IL‑25) induces allergic responses and activation of the
TH2 pathway 16 but inhibits the function of TH17 cells,
and as such has anti-inflammatory effects in models of
TH17 cell-mediated inflammation17.
Interleukin‑17 receptors
Structure. The first receptor to be identified for IL‑17
was initially referred to as IL‑17 receptor (IL‑17R) but
is now known as IL‑17RA18 following the identification
of additional receptor components that are required in
order to form a functional receptor complex for IL‑17
signalling 19. Indeed, in addition to IL‑17RA, IL‑17RC is
required for cell signalling in response to both IL‑17A
and IL‑17F20,21 (FIG. 1). Four additional receptors have
been identified in the IL‑17R family, based on sequence
homology to IL‑17RA: IL‑17RB, IL‑17RC, IL‑17RD and
IL‑17RE. In addition to IL‑17RC, it has been proposed
that IL‑17RA can form a complex with IL‑17RD and that
IL‑17RD can mediate signalling downstream of IL‑17
(REF. 22). Moreover, IL‑17RA can form a complex with
IL‑17RB, and both receptor chains are required for
IL‑17E‑mediated signalling. It has been recently shown
that IL‑17C signals through a receptor complex con‑
sisting of IL‑17RA and IL‑17RE15,23,24. Thus IL‑17RA
appears to be a common receptor chain for the IL‑17
family of ligands. Targeting IL‑17RA may result in a
broader anti-inflammatory response than targeting
specific IL‑17 ligands or, for example, targeting IL‑17RC,
with the downside of a potentially higher risk of side
effects such as infections.
Signalling. IL‑17RA is unique among interleukin recep‑
tors18 because rather than signalling through a pathway
involving Janus kinase (JAK) and signal transducer and
activator of transcription (STAT), IL‑17RA associates with
an adaptor protein, ACT1 (also known as TRAF3IP2)25,26,
through a conserved motif called a SEFIR domain (named
after SEF (also known as IL‑17RD) and a homologous TIR
(Toll/IL‑1R) domain). The binding of IL‑17A to IL‑17RA
activates nuclear factor-κB (NF-κB) and this activation
requires the presence of both ACT1 and TNF receptor-
associated factor 6 (TRAF6)27. Stimulation of epithelial
cells or fibroblasts with IL‑17A increases the expression
(both at the mRNA and protein level) of growth factors
such as granulocyte colony-stimulating factor (G-CSF)
 REVIEWS

IL-17A–IL-17F TNF was observed that IL‑17A‑producing CD4+ T cells were

IL-17A IL-17F distinct from interferon-γ (IFNγ)-producing effec‑
tor T cells35. In addition, these IL‑17A‑producing cells
expressed TNF and granulocyte–macrophage CSF
(GM-CSF)35. Furthermore, it was shown that IL‑23
(which is produced by dendritic cells) increased the
IL-17RA IL-17RC TNFR1 TNFR2 production of IL‑17 from cultured T cells36,37. IL‑23 is
closely related to IL‑12; it is a heterodimeric cytokine
ACT1 consisting of two subunits — an IL‑23p19 subunit and
TRAF6 an IL‑12p40 subunit. The latter molecule is shared by
IL‑12p70, which is made of the common IL‑12p40 sub­
NF-κB Synergy IL-6, IL-8 unit and the p35 subunit. Of note, as TH17 cells can be
regulated by IL‑23, which shares its p40 subunit with
IL‑12, drugs that were initially developed to target
TH1‑associated diseases (such as antibodies that target the
Increased mRNA p40 subunit of IL‑12) may have much broader effects on
stabilization T cell-mediated immunity by inhibiting both TH1 and
Figure 1 | Structure of IL‑17 and its interaction with IL‑17R.  Interleukin‑17A TH17 responses.
(IL‑17A) and IL‑17F monomers can form homodimers and an IL‑17A–IL‑17F
Nature heterodimer.
Reviews | Drug Discovery Subsequently, in models of autoimmunity such as
These dimeric ligands bind to the IL‑17 receptor (IL‑17R) complex, which is composed experimental autoimmune encephalitis, IL‑23 (but not
of IL‑17RA and IL‑17RC chains. Receptor signalling induces the activation of the IL‑12) was shown to be required for the development
adaptor protein ACT1, nuclear factor-κB (NF-κB) and tumour necrosis factor (TNF) of pathology. Moreover, IL‑23 drove the in vivo dif‑
receptor-associated factor 6 (TRAF6), which leads to increased transcription of the genes ferentiation of a unique subpopulation of CD4+ T cells
encoding IL‑6 and IL‑8. TNF is a homotrimer that acts on TNF receptor 1 (TNFR1) and that produce IL‑17, which were named TH17 cells38–40.
TNFR2. The combination of IL‑17 ligands and TNF often results in synergistic actions, These data suggested that IL‑17 may be produced by a
which can be explained in part by increased mRNA stability and TNFR overexpression.
distinct subset of CD4+ T cells. This was confirmed in
2005, when seminal work showed that IL‑17‑producing
CD4+ T cells were distinct from TH1 and TH2 cells, and
as well as chemokine ligands for CXCR2, including could develop independently of STAT4 and STAT6, which
chemokine CXC motif ligand 1 (CXCL1), CXCL2 and are required for the development of TH1 and TH2 cells,
CXCL8. One major effect of IL‑17 on the subset of genes respectively 4,5.
encoding these proteins is an increase in mRNA stability.
CCAAT/enhancer- This increase in transcript stability has been demonstrated Differentiation of TH17 cells. Based on the crucial role of
binding proteins
for both G-CSF and CXCL1 (REFS 28,29). In addition to this new T cell subset in mediating autoimmune tissue
(C/EBPs). A family of
activating the NF-κB pathway, IL‑17A can activate the inflammation, it was important to understand how these
transcription factors that
regulate gene expression CCAAT/enhancer binding proteins (C/EBPs) C/EBPβ and C/ pathogenic T cells are differentiated from naive T cells,
by interacting with the EBPδ. Because C/EBP binding sites are present in the 5ʹ as this information could reveal additional therapeutic
CCAAT box motif. promoter regions of genes induced by IL‑17, IL‑17 can also targets in the TH17 pathway. It was postulated that, in
increase the transcription of certain target genes, such as addition to IL‑23, other cytokines must be involved in
CCʹ loop region
A region of the cytoplasmic
those encoding IL‑6 or lipocalin 2, though the activation initial TH17 cell differentiation because the IL‑23 receptor
SEFIR domain (named of C/EBPβ and C/EBPδ30. IL‑17RA signalling can be nega‑ is not expressed on naive T cells.
after SEF and a homologous tively regulated by ACT1 degradation mediated by SCF One pathway of initial differentiation of mouse
TIR (Toll/IL‑1R) domain) of (SKP1–CULLIN1–F-box)-type E3 ubiquitin ligase com‑ TH17 cells requires the presence of transforming growth
interleukin‑17 (IL‑17) receptor, plexes31 and by TRAF3 (REF. 32), which can antagonize factor-β (TGFβ) and IL‑6 as well as STAT3 signalling 41–44.
defined by the third strand (C)
IL‑17RA–TRAF6‑mediated NF-κB signalling. ACT1 binds Analogous to the differentiation of TH1 and TH2 cell
and the third helix (Cʹ).
to the CCʹ loop region of the cytoplasmic tail of IL‑17RA, lineages, TH17 cells require additional lineage-specific
Memory CD4+ T cells and peptide mimetics that antagonize this binding can transcription factors. Both retinoid-related orphan
A putative subpopulation of efficiently block IL‑17RA signalling 33. However, it remains receptor-α (RORα) and RORγt (known as RORC in
relatively long-lived CD4+ to be determined whether these proteins or approaches humans) are required for TH17 cell differentiation45,
T cells that have interacted
with their cognate antigen.
could represent therapeutic targets to block or enhance and these transcription factors can be induced by the
IL‑17RA signalling. Last, as signalling occurs following combined presence of TGFβ and IL‑6 in naive T cells.
TH1-associated diseases the oligomerization of extracellular domains of IL‑17RA By activating IL‑1R1 expressed on TH17 cells, IL‑1β can
Diseases attributed to and IL‑17RC, strategies to antagonize this process could augment the proliferation of these cells and induce the
interferon‑γ (IFNγ)-producing
block receptor signalling34. secretion of IL‑17. Indeed, in murine models of inflam‑
CD4+ T cells.
mation, IL‑1β expression and IL‑1R1 signalling are
STAT4 TH17 cells crucial for the production of IL‑17 by TH17 cells as well
Signal transducer and activator When IL‑17A was first cloned, mRNA analysis showed as another subset of T cells that are present at mucosal
of transcription 4; a member of that it was expressed in memory CD4+ T cells2. Following surfaces: γδ T cells46–48. Conversely, IL‑27, a member of the
the STAT protein family that is
required for the development
this observation, several lines of evidence suggested IL‑12 family, reduces inflammation by suppressing
of T helper 1 (TH1) CD4+ that IL‑17 may be produced by a distinct subset of the differentiation of TH17 cells and enhancing the develop­
T cells. CD4+ T cells. Using intracellular cytokine staining, it ment of IL‑10‑producing anti-inflammatory T cells49.

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REVIEWS
STAT6
Signal transducer and activator
of transcription 6; a member of
the STAT protein family that is
required for the development
of T helper 2 (TH2) CD4+
T cells.
Naive T cells
T cells that have not interacted
with their cognate antigen.
RORC
Retinoid-related orphan
receptor-γ. RORC encodes
a transcription factor that is
expressed in interleukin‑17
(IL‑17)-producing cells.
γδ T cells
A subset of T cells that express
a T cell receptor consisting
of a γ- and δ-chain as opposed
to an α- and β-chain. These
cells are enriched at mucosal
surfaces: for example,
in the gastrointestinal tract,
skin and lung.
Invariant NK cells
(iNK cells). A subset of natural
killer (NK) cells that express an
invariant T cell receptor.
Fcε receptor I
A protein that serves as
the high-affinity receptor
for immunoglobulin E.
TH2‑type responses
Immune responses associated
with the T helper 2 (TH2) subset
of CD4+ T cells, such as allergy
or immune responses to
helminth infection.
Acute phase response
An increase in levels of plasma
proteins in response to acute
inflammation.
Matrix metalloproteinases
A family of zinc-dependent
proteases that can degrade
extracellular matrix proteins.
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It has been argued that differentiation of human
TH17 cells could potentially occur independently of
TGFβ, as a combination of IL‑23 and IL‑1β has been
shown to be sufficient to induce TH17 cell differentia‑
tion50. However, murine and human TH17 cells are very
similar; both cell types express IL‑17A, IL‑17F, IL‑21,
IL‑22, GM‑CSF, IL‑23R and IL‑1R1, and require RORα
and RORγt as crucial transcription factors for their dif‑
ferentiation. Moreover, in the murine immune system,
TH17 cells can still arise independently of TGFβ activity 50.
It has been noted that IL‑17A expression can be
induced within hours after infection or immunization with
an adjuvant and before the differentiation of TH17 cells
from native progenitors, which takes several days. This
suggests that cells other than TH17 cells can produce IL‑17.
In addition to the TH cells described above, γδ T cells are a
major source of this early production of IL‑17; γδ T cells
can respond to IL‑23 and IL‑1β46,47,51,52. It has also been
suggested that this pool of γδ T cells can influence the
subsequent TH17 cell response, perhaps through the pro‑
duction of IL‑21 (REF. 46).
Other sources of IL‑17. In addition to T cells, other cellu‑
lar sources of IL‑17 include natural killer (NK) cells, mast
cells and neutrophils. A subset of NK cells — known as
NK1.1 cells — that are found in the lung produce robust
amounts of IL‑17A and are involved in the responses of
airway neutrophils to α‑galactosylceramide (a ligand for
invariant NK cells (iNK cells)) and lipopolysaccharide53.
In another mouse model of ozone-induced airway inflam‑
mation, expression of IL‑17A by iNK cells was required
for airway neutrophil-mediated inflammation and airway
hyperresponsiveness54. iNK cells that produce IL‑17A
have been shown to express neuropilin 1 (REF. 55) and
are recent thymic emigrants, suggesting that they may be
genetically programmed to produce IL‑17A.
Another source of IL‑17A is a subset of immune cells
called innate lymphoid cells, which are morphologi‑
cally similar to lymphocytes but do not express classical
lineage markers (such as T cell receptors or CD45) and
require IL‑7 signalling through the IL‑7R (also known as
CD127)56 for their differentiation. IL‑17 production is also
regulated by RORC in these cells and thus compounds
that are designed to target and block RORC will, in theory,
antagonize IL‑17 production by these cells as well as by
TH17 cells. This could provide a broader therapeutic effect.
Mast cells also produce several members of the IL‑17
family. Following Fcε receptor I‑mediated activation, mast
cells produce substantial amounts of IL‑17E, which can
influence TH2‑type responses57. Mast cells also produce
IL‑17A in response to their activation by Toll-like recep‑
tor 2 (REF. 58); this has been shown in several human
autoimmune and neurodegenerative diseases, including
psoriasis59, rheumatoid arthritis60,61, ankylosing spon‑
dylitis62 and amyotrophic lateral sclerosis63. In some of
these inflammatory conditions, neutrophils have been
shown to express IL‑17 (REF. 61).
The respective contribution of IL‑17 produced by
these different cell types to disease pathology is still
unknown. This will be a crucial question for the selection
of inhibitory compounds according to cell specificity.
© 2012 Macmillan Publishers Limited. All rights reserved
Key functions of IL‑17A and IL‑17F
Below, we review the current knowledge of how IL‑17A-
and IL‑17F‑mediated signalling results in tissue inflam‑
mation and pathology.
Target cells of IL‑17A and IL‑17F. IL‑17RA is expressed
in nearly every cell type of the body, including epithe‑
lial cells, endothelial cells, fibroblasts and myeloid
cells. Although IL‑17RC is also expressed on epithelial
cells and fibroblasts, its expression on myeloid cells is
lower 64. Based on this more restricted expression of
IL‑17RC, it is thought that fibroblasts, epithelial cells
and endothelial cells are a major target of IL‑17A and
IL‑17F. The contribution of IL‑17 to disease is thus
linked to the role of these cells in disease pathology.
For example, IL‑17‑dependent arthritis persists when
myeloid expression of IL‑17RA is ablated in mouse
models65.
Inflammation. Inflammation is composed of several
components, including local (for example, redness and
swelling) and systemic (for example, fever) manifes‑
tations. It is also a dynamic process, with neutrophils
contributing to early stages of inflammation, followed
by the involvement of monocytes and lymphocytes in
later stages. It is well established that IL‑17 activity con‑
tributes to various aspects of acute inflammation. The
IL‑17‑mediated release of IL‑6 and IL‑8 from mesenchy‑
mal cells leads to fever, an acute phase response (caused
by IL‑6) and the accumulation of neutrophils in blood
and tissue (caused by IL‑8)2 (FIG. 2).
IL‑17 activity also contributes to chronic inflamma‑
tion66 (FIG. 2), which is often — but not always — associ‑
ated with matrix destruction. A key function of IL‑17
includes its inhibitory effect on matrix production
in chondrocytes and osteoblasts, which leads to joint
damage and defective tissue repair. IL‑17 activates the
production and function of matrix metalloproteinases, and
a combination of IL‑17 with TNF leads to irreversible
cartilage damage in a murine model67. During inflam‑
mation, local interactions between synoviocytes and
TH17 cells (but not TH1 cells) cause the release of matrix
metalloproteinases from synoviocytes68. Moreover, inter‑
actions between activated naive T cells and local mes‑
enchymal cells lead to the differentiation of TH17 cells
through an IL‑1- and caspase 1‑mediated mechanism69.
Regarding bone destruction, IL‑17 increases the expres‑
sion of receptor activator of NF-κB ligand (RANKL) on
osteoblasts, which leads to increased RANK signalling in
osteoclasts. This links IL‑17 activity to bone destruction,
as seen in rheumatoid arthritis. Conversely, inhibition
of IL‑17 in cultures of bone explants from patients with
rheumatoid arthritis has been shown to reduce bone
destruction70.
B cells accumulate at the site of inflammation, forming
organized lymphoid structures with germinal centres.
Mice that are genetically engineered to have auto­immune
manifestations (BDX2 mice) express more IL‑17 and
show spontaneous development of germinal centres,
leading to the production of pathogenic autoantibodies71.
These features are reduced by inhibiting IL‑17 in these
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Tissue factor, Thrombosis

increased when IL‑17 was combined with other
IL-6 and IL-8 cytokines66. In particular, synergistic interactions occur
Endothelial cells between IL‑17 and TNF or IL‑17 and IL‑1, where IL‑17
IL-6, IL-8, augments the effect of TNF in part by enhancing the
CCL20, G-CSF Inflammation
and GM-CSF expression of TNF receptor 2 (TNFR2)73. In addition, TNF
Epithelial cells enhances the effect of IL‑17 on mRNA stability, lead‑
or fibroblasts ing to increased levels of protein expression. Therefore,
IL-1, TNF and IL-6 because TNF and IL‑17 share effector functions, IL‑17
IL-17 could be targeted in the subsets of patients with inflam‑
MMPs
matory diseases who are not responsive (or insufficiently
• TH17 cells Macrophages or
• Other T cells Cartilage responsive) to TNF inhibitors. The combination of TNF
dendritic cells damage
• Mast cells inhibitors and IL‑17 inhibitors could represent a new
• Neutrophils Nitric approach to control the interactions between the two
oxide cytokines in inflammatory disorders.
Chondrocytes
Granulopoiesis and infections. One of the earliest activi‑
RANKL Osteoclastogenesis Bone erosion
ties attributed to IL‑17A was the differentiation of neu‑
Osteoblasts trophils (known as granulopoiesis) from human bone
Figure 2 | Key functions of IL‑17 and its role in inflammation and matrix marrow progenitor cells2. Overexpression of IL‑17A in
destruction.  Interleukin‑17 (IL‑17) acts on various cellular targets, leading to cell mice results in massive neutrophilia in peripheral blood
Nature
activation. The effect of IL‑17 on endothelial cells leads Reviews | Drug
to inflammation andDiscovery and an increase in neutrophil progenitors in the spleen74.
procoagulant activity. When acting on epithelial cells and fibroblasts, IL‑17 leads to This activity of IL‑17A is dependent on the increased
cytokine and enzyme production. On monocytes and dendritic cells, IL‑17 contributes expression of G-CSF and the transmembrane form of
to inflammation by increasing the production of pro-inflammatory cytokines. In the stem cell factor 75. The granulopoietic response appears
context of joint inflammation, a process that involves osteoblasts and chondrocytes,
to be important in the control of host defences against
IL‑17 activates matrix destruction in cartilage and bone. CCL20, chemokine CC motif
extracellular pathogens.
ligand 20; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–
macrophage CSF; MMP, matrix metalloproteinase; RANKL, receptor activator of IL‑17 is clearly involved in the development of
NF-κB ligand; TH17, T helper 17; TNF, tumour necrosis factor. mucosal immunity to extracellular pathogens, including
bacteria and fungi76. For example, IL‑17A signalling
through IL‑17RA is crucial for both G-CSF production
and neutrophil recruitment during experimental Gram-
mice or in mice deficient in Il17r. This suggests that negative pneumonia induced by Klebsiella pneumoniae77.
B cells are responsive to IL‑17 and could be a target of IL‑17 is also responsible for the elevated granulopoie‑
IL‑17‑specific therapy in autoimmune disease. sis that is observed in leukocyte adhesion deficiency
However, there are limitations to the understanding syndromes and is due to the lack of expression of cell
of the role of IL‑17 in the late stages of chronic inflam‑ adhesion molecules on neutrophils (which are required
Receptor activator
of NF-κB ligand mation as there is a low frequency of IL‑17‑producing for the migration of neutrophils out of the circulation
(RANKL). A member of the cells at this late stage, suggesting that late-stage chronic into tissues)78. This IL‑17‑mediated response requires
tumour necrosis factor inflammation is a dynamic multistep process. It appears the presence of IL‑23, which is regulated by the clear‑
superfamily expressed as though exposure to IL‑17 (which is produced at high ance of apoptotic neutrophils in the lamina propria of
on osteoblasts that can
activate osteoclasts to
levels during the early phase of inflammation) induces the gastrointestinal tract (FIG. 3) — a major site of IL‑17
mediate bone resorption. molecular changes in mesenchymal cells. In vitro studies production by T cells and other cells79. In addition to
using mesenchymal cells such as fibroblasts and synovio‑ regulating granulopoiesis, IL‑17 induces the expression
B cells cytes have indicated that IL‑17 induces the production of several genes that encode antimicrobial factors and
A subpopulation of
of anti-apoptotic molecules such as synoviolin72. This, in chemokines in the epithelium and fibroblasts80.
lymphocytes that develop
in the bone marrow and turn, contributes to the survival of these modified cells Regarding fungal infections, both IL‑17A and its
mediate humoral (that is, and disease chronicity even in the absence of ongoing receptor are important for the control of systemic81
antibody-mediated) immunity. inflammation. A study using a mouse model of arthritis and oropharyngeal candidiasis 82. Moreover, both
indicated that IL‑17 contributes to both early- and late- Il17ra‑knockout mice83 as well as Il17a and Il17f double-
TNF receptor 2
Tumour necrosis factor (TNF)
stage disease activity and synovium inflammation. By knockout mice develop spontaneous Staphylococcus
receptor 2 (TNFR2; also contrast, mice lacking the IL‑17R showed low levels aureus infection in the skin84. IL‑17A alone also has
known as p75 or TNFRSF1B); of arthritis, accompanied by reduced infiltrates, which a crucial role in experimental models of cutaneous
a 75 kDa receptor that can bind occurred as a result of enhanced apoptosis72. This effect S. aureus infection85. In addition to Candida albicans,
to TNF and lymphotoxin-α.
(that is, the reduced infiltrates) may explain the limited studies neutralizing IL-17 with IL-17-targeted antibodies
Neutrophilia efficacy observed with TNF inhibitors in the late chronic have shown that IL‑17 is required for optimal clearance
An increased density of phase of inflammation. These results advocate the use of Pneumocystis murina in mice86 as well as the induc‑
neutrophils in peripheral of IL‑17 inhibitors at an early stage of inflammation to tion of vaccine-induced immunity to North American
blood. induce a longer-lasting remission. endemic mycoses87. The role of IL‑17 in human fungal
Mucosal immunity
In these studies of acute and chronic inflammation, infection has been elucidated recently by the identifi‑
Immune responses that occur it was observed that when IL‑17 was used alone it had cation of patients with dominant-negative IL‑17F or
at mucosal membranes. a modest effect, whereas the effect was substantially recessive IL‑17R mutations; these patients suffer from

NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | O CTOBER 2012 | 767

© 2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
chronic mucocutaneous candidiasis88. Fungi have also
been shown to bind to IL‑17 (REF. 89). Targeting IL‑17
or the differentiation of IL‑17A‑producing cells could
therefore disrupt normal granulopoiesis and increase the
risk of infections with certain extracellular pathogens.
However, the role of IL‑17 in the control of intracell­
ular pathogens appears to be less important than that of
other cytokines. As opposed to TNF or TNFR signalling,
IL‑17R signalling is dispensable for mounting primary
control and TH1-mediated immunity to Mycobacterium
tuberculosis 90,91 and Listeria monocytogenes 90. Thus an
advantage of targeting the TH17 pathway, as opposed to
blocking TNF, may be a reduced risk of infection with
these intracellular pathogens.
In contrast to infection with L. monocytogenes and
M. tuberculosis, in which IL‑17 is dispensable for TH1‑
mediated immunity, IL‑17 is required for TH1‑mediated
immunity against the intracellular pathogen Francisella
tularensis 92. This may be due to a weak induction of
IL‑12p70 expression by this pathogen and a reliance
of the immune system on the pathogen-induced IL‑17
response to induce IL‑12 activity 92. Moreover, vaccine-
induced immunity against fungi76 as well as against intra‑
cellular pathogens such as M. tuberculosis can require
IL‑17 (REF. 93). Thus, the greatest risk of targeting the
TH17 cell pathway may be an increased risk of mucosal
infections by extracellular pathogens and fungi, but it
will also be important to monitor for vaccine-induced
immune responses in patients receiving drugs that target
this pathway.
IL‑17, TH17 cells and diseases
IL‑17 and T H17 cells have been associated with an
increasing number of chronic inflammatory diseases.
Based on these observations, inhibitors — mostly
monoclonal antibodies — have been designed, and the
results of these clinical trials are now being released (as
discussed below).
Inhibition of TNF has substantially advanced the treat­­
ment of inflammatory diseases. Because TNF and IL‑17
have shared functions, the rationale for testing IL‑17
inhibitors in the clinic is often based on the concept that
patients who do not respond to TNF inhibitors may have
an IL‑17‑driven disease. In addition, preclinical stud‑
ies have provided evidence for targeting IL‑17. In this
context, rheumatoid arthritis and multiple sclerosis are
the diseases that have been studied in most detail using
mouse models and preclinical studies in humans.
Rheumatoid arthritis. Rheumatoid arthritis is the most
common form of chronic inflammatory arthritis, in
which infiltration of the joint synovium membrane
leads to bone and cartilage destruction. The presence
of IL‑17‑positive cells in the diseased synovium and the
production of functionally active IL‑17 by this tissue
was first demonstrated in this disorder. Following this,
numerous studies have been conducted using mouse
models of arthritis (FIG. 2). Long-term intra-articular
administration of IL‑17 via gene transfer reproduced the
key features of rheumatoid arthritis, including massive
inflammation, bone erosions and cartilage damage94.
768 | O CTOBER 2012 | VOLUME 11 www.nature.com/reviews/drugdisc
© 2012 Macmillan Publishers Limited. All rights reserved
Conversely, inhibition of IL‑17 with antibodies against
the ligand IL‑17A or its receptor IL‑17RA protected
against the development and consequences of arthritis95.
Furthermore, mice lacking IL‑17RA develop a very mild
form of experimental arthritis96. TNF has been previ‑
ously shown to be a key cytokine in the collagen-induced
arthritis model. Although TNF contributes to the patho‑
genesis of the early stages of the disease, it is not involved
in the pathogenesis of later stages of disease; IL‑17, how‑
ever, has a role throughout all stages of chronic disease97.
This finding is another indication that IL‑17 contributes
to the chronicity of the disease.
Psoriasis and psoriatic arthritis. Psoriasis is an inflam‑
matory skin disease that has been successfully treated
using TNF inhibitors in some but not all patients. Positive
results obtained from early clinical studies using T cell-
targeted treatments such as cyclosporin first indicated the
role of T cells in psoriasis. More recently, positive results
from clinical studies using ustekinumab and briakinumab
(both of which inhibit the p40 subunit of IL‑12) have indi‑
cated that IL‑12 and/or IL‑23 contribute to the pathogen‑
esis of the disease98. Several genetic studies have indicated
that IL23R gene polymorphisms have a role in the patho‑
genesis of psoriasis and psoriatic arthritis99. These results
suggest that IL‑23 contributes to these conditions and
could therefore be targeted for the treatment of psoriasis
and psoriatic arthritis.
Skin biopsy samples taken from patients with psoria­
sis showed high expression of IL‑17 together with high
expression of IL‑23, IL‑22 and IL‑6 (REFS  100–102).
Furthermore, increased numbers of TH1 and TH17 cells
were found in blood and skin lesions of patients, show‑
ing a positive correlation with disease activity 103,104. Local
production of TH17 cytokines within the plaques appears
to contribute to the increased production of chemokine
CC motif ligand 20 (CCL20), a key chemokine that is
necessary for the migration of TH17 cells105. Mast cells
and neutrophils represent additional sources of IL‑17 in
skin that is affected by psoriasis59. Apart from IL‑17, IL‑22
is another TH17 cytokine that mediates IL‑23‑induced
skin inflammation and acanthosis, as seen in skin that
is affected by psoriasis100. By mediating the crosstalk
between the immune system and epithelial cells, IL‑22
represents another target in psoriasis.
Psoriatic arthritis is a form of inflammatory arthritis
that shares numerous patterns that are characteristic of
destructive arthritis with rheumatoid arthritis, but pso‑
riatic arthritis has a different anatomic distribution and
genetic background. For example, psoriatic arthritis
affects distal joints. In both diseases, TNF inhibitors as
well as IL‑12 or IL‑23 inhibitors have been successful in
many — but not all — patients; accordingly, these two
diseases are the subject of clinical trials that aim to test
the efficacy of IL‑17 inhibitors, as discussed below.
Ankylosing spondylitis. Ankylosing spondylitis is
an inflammatory joint disease that affects the spine.
Compared to rheumatoid arthritis, which causes mas‑
sive destruction of bone, ankylosing spondylitis leads
to the formation of ectopic new bone as a result of

Apoe–/– mice
Mice with a homozygous
deletion in the
apolipo­protein E (Apoe)
gene; these mice are a model
of hypercholesterolaemia.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | O CTOBER 2012 | 769
inflammation of tendon insertions, leading to stiffness
of the joint (known as ankylosis). In this disorder, inhibi‑
tion of TNF has been successful in controlling inflam‑
mation but not ankylosis in some patients. Analyses
of bone biopsy samples of the sacro-iliac joints from
patients with ankylosing spondylitis showed staining for
IL‑17. However, it appears that this local IL‑17 secretion
is from cells of the innate immune system rather than
from T cells106. Some of these cells have been character‑
ized as KIT-positive mast cells in biopsy samples from
the synovium62. Much of the rationale for targeting IL‑17
in ankylosing spondylitis was based on the use of TNF
inhibitors in this disorder.
Crohn’s disease. The contribution of TNF is also well
established in Crohn’s disease — an inflammatory bowel
disease (FIG. 3). Several studies have found an association
between polymorphisms in the gene encoding the IL‑23
receptor and the risk of adult and paediatric Crohn’s dis‑
ease107,108. Similarly to the results seen in biopsy samples
taken from patients with psoriasis, samples of lesions
taken from patients with Crohn’s disease showed high
expression of IL‑17 together with high expression of
IL‑23, IL‑22 and IL‑6, which suggests that there are
several therapeutic targets for this disease109. However,
the situation is more complex than psoriasis, as both
pro-inflammatory and potentially protective roles of
IL‑17 have been described in animal models of inflam‑
matory bowel disease. In some models, administration
of IL‑23 was found to exacerbate the disease and its
inhibition had a protective effect 110,111. Conversely,
IL‑17A was found to have a protective effect in another
model of T cell-mediated intestinal inflammation112;
the reasons behind these conflicting results are unclear.
Multiple sclerosis. Multiple sclerosis is a chronic inflam‑
matory disease that leads to brain inflammation and
myelin destruction. However, TNF inhibition does not
have a protective effect in multiple sclerosis; rather, TNF
inhibition was associated with an increase in the number
and activity of brain lesions in patients with multiple
sclerosis. Moreover, TNF inhibition can cause various
central neurological manifestations in patients with other
inflammatory disorders113,114. It remains unclear whether
this is related to the difficulties associated with the pas‑
sage of TNF inhibitors across the blood–brain barrier 115.
Accumulation of cells that secrete IL‑17 (which were
later referred to as TH17 cells) was the first observation
that IL‑17 contributes to the pathogenesis of experi‑
mental autoimmune encephalomyelitis and possibly
multiple sclerosis. As IL‑17 and TH17 cells have been
clearly implicated in mouse models of multiple scle‑
rosis, and an IL‑17A‑targeted auto-vaccine prevents
experimental autoimmune encephalomyelitis, it makes
sense to consider IL‑17 inhibition in this context 38,116.
In addition, the IL17A gene is overexpressed in biopsy
samples taken from the brains of patients with multi‑
ple sclerosis117. However, based on the experience with
TNF inhibition, safety issues related to the use of IL‑17
inhibition in patients with multiple sclerosis have yet
to be clarified.
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Vasculitis and atherosclerosis. There has been a striking
increase in the incidence of cardiovascular disease in
patients with rheumatoid arthritis or systemic lupus erythe­
matosus118,119. This results from the effects of inflamma‑
tion on endothelial cell-mediated functions. Conversely,
the incidence of disease is reduced when inflammation
is controlled using methotrexate and TNF inhibitors120.
To explain the contribution of IL‑17 to this endothelial
dysfunction, recent in vitro studies have indicated that
IL‑17, particularly in combination with TNF, has a pro‑
found procoagulant and prothrombotic effect on human
endothelial cells121. A recent clinical report showed a posi‑
tive correlation between levels of IL‑17 (in the plasma of
patients with rheumatoid arthritis) and endothelial dys‑
function122. In patients with unstable angina, a high peak
in levels of plasma IL‑17 was associated with a subsequent
myocardial infarction123. Most importantly, the presence of
IL‑17- and IFNγ-positive cells has been observed in clini‑
cal specimens of coronary atherosclerosis, suggesting that
IL‑17 and IFNγ have a local effect on vessel dysfunction124.
Results obtained from experiments in mice are in
agreement with these findings. Double-knockout mice
deficient in both the low-density lipoprotein receptor
(LDLR) and IL‑6, which have decreased levels of IL‑17,
have fewer atherosclerotic lesions, suggesting a potential
role for IL‑17 and TH17 cells in the promotion of athero‑
genesis125. In addition, the injection of an IL‑17A‑blocking
antibody into mice lacking apolipoprotein E (Apoe−/−
mice) reduced the development of atherosclerotic lesions
and lowered the risk of plaque rupture, cellular infiltration
and activation into the plaque126. When given a high-fat
diet, Il17a‑knockout mice displayed significantly dimin‑
ished aortic lesion size and macrophage accumulation
compared to wild-type mice127.
Lung disorders, asthma and chronic obstructive pulmo‑
nary disease. Elevated levels of IL‑17A have been found
in the sputum or lung of patients with an exacerbated
form of cystic fibrosis128, as well as in individuals who
are exposed to organic dust129 and in patients with severe
asthma130 (FIG. 3). Transfer of antigen-specific TH17 cells in
a mouse model of asthma results in antigen-induced neu‑
trophilic airway inflammation and bronchial reactivity
that is more steroid-resistant than that caused by the
transfer of TH2 cells131. These data suggest that TH17 cells
may have a role in certain forms of steroid-resistant
asthma in humans. Moreover, complement-dependent
IL‑17 responses mediate more severe forms of airway
obstruction in murine models of asthma132. As mentioned
above, IL‑17A expression can also be induced by ozone,
which can exacerbate pre-existing asthma. In support
of the notion that IL‑17A may be associated with more
severe forms of asthma and airway inflammation, levels
of IL‑17‑producing cells are increased in lung tissues from
patients with severe asthma133 or cystic fibrosis134. Further
work will be needed to define the subset of patients who
may have asthma symptoms that are driven by IL‑17.
Chronic obstructive pulmonary disease. Chronic obstruc‑
tive pulmonary disease (COPD) has been proposed as
a target for TH17‑based therapy. Cigarette smoke, the
REVIEWS
• Activation and release of • Release of CXC
Macrophage antimicrobial peptides chemokines
• Barrier function repair • Release of G-CSF
Dendritic cell Epithelium
IL-22 IL-17A, IL-17F
IL-23, IL-1β
CD3+ CD4+ TH17 cells CD3+ T cells:
TGFβ
IL-21 • γδ T cells
IL-6 • αβ T cells
IL-23 • NK T cells
CD3+ CD4+ TH0 cells
Figure 3 | Key functions of the IL‑17–TH17 pathway and its role in host defence. 
T helper 17 (TH17) cells can be differentiated from naiveNature
precursor T cells
Reviews (TH0 cells)
| Drug Discovery
through antigen presentation, co‑stimulation and TH17 cell-polarizing cytokines,
including transforming growth factor-β (TGFβ) and interleukin‑6 (IL‑6). Both IL‑23 and
IL‑1 can further amplify TH17 cell differentiation. Fully differentiated TH17 cells express
several effector cytokines. These include IL‑17A, IL‑17F, IL‑22, IL‑26 and granulocyte–
macrophage colony-stimulating factor (GM-CSF). IL‑17A and IL‑17F signal through a
complex made of IL‑17 receptor A (IL‑17RA) and IL‑17RC chains. Signalling though
these receptors induces the production of ligands for CXC chemokine receptor 2
(CXCR2) and granulocyte CSF (G-CSF). Activation through this pathway can augment
cell proliferation and the expression of antimicrobial proteins. There are several sources
of IL‑17 that have been described to date, including T cells (γδ T cells and αβ T cells),
innate lymphoid cells and natural killer (NK) cells.
major risk factor for the development of COPD, acts as a
TH17 cell adjuvant by enhancing TH17 cell differentiation
in vitro and in vivo135. The number of IL‑17‑positive cells136
— specifically, the number of IL‑17F‑positive cells137,138 —
is increased in the lung tissue of patients with COPD137,138.
In addition to the effector cytokines IL‑17A or IL‑17F,
expression of RORC2 (the transcription factor that con‑
trols the differentiation of TH17 cells) is increased in the
lungs of patients with COPD139,136.
Studies from transgenic mice provide further evidence
that IL‑17 is involved in the pathogenesis of lung disease.
Il17ra‑knockout mice are resistant to the development
of emphysema after 6 months of exposure to cigarette
smoke135. Conversely, overexpression of IL‑17A in the
airways of transgenic mice accelerates the development
of emphysema when these mice are exposed to cigarette
smoke140, suggesting that IL‑17A is sufficient to mediate
this response.
In addition to asthma and COPD, IL‑17 expression
has been implicated in the development of airway fibro‑
sis in murine models, including fibrosis associated with
hypersensitivity pneumonitis141,142, as well as in the fibrotic
response to challenges with bleomycin143 and silica144.
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© 2012 Macmillan Publishers Limited. All rights reserved
Other conditions. The link between IL‑17 and the patho­
genesis of many diseases is still unclear. Reports have
been published showing high levels of IL‑17 and the over‑
expression of the TH17 cell pathway in several diseases,
including lupus nephritis, Helicobacter pylori-associated
gastritis and gastric cancer as well as autoimmune
myositis145–147. Similar results were obtained in vascu‑
lar diseases such as giant cell arteritis and Wegener’s
granulomatosis148. In this context, arguments for target‑
ing IL‑17 are still unclear, because the demonstration
of increased IL‑17 expression is often based simply on
increased levels of the cytokine in blood or tissue sam‑
ples. It is unclear whether this overexpression indicates
a direct pathogenic role for IL‑17 or whether it is a result
of feedback mechanisms. Although the role of IL‑17 and
TH17 cells in various cancers is becoming established,
this therapeutic field is not discussed here but has been
reviewed in REF. 149.
Targeting of IL‑17 and TH17 cells
There are several ways in which members of the IL‑17
protein and receptor family can be targeted. The first
option to be used was monoclonal antibodies directed
against IL‑17A and IL‑17RA (FIG. 4). More recent plans
include the use of small-molecule inhibitors that target
IL‑17 signalling and TH17 cells.
Tools targeting IL‑17A, IL‑17RA and signalling. Two
monoclonal antibodies directed against IL‑17A have
been tested in clinical trials: ixekizumab (LY2439821), a
humanized IL‑17A‑specific antibody, and secukinumab
(also known as AIN457), a fully human IL‑17A‑specific
monoclonal antibody. Other IL‑17A-targeted antibodies
are in early clinical development, such as SCH‑900117
and RG4934. One monoclonal antibody directed against
IL‑17RA, brodalumab (AMG 827), is in clinical devel‑
opment. The results obtained from the clinical trials of
these antibodies are discussed below.
In addition to these biologics, there are substantial
efforts to target RORγt, RORα and/or RORC using small
molecules to block TH17 cell responses through inhibi‑
tion of the key transcription factors of these lineages150.
Using a RORγt-dependent galectin 4 (GAL4)-driven
insect cell-based reporter system, digoxin was identified
as a specific RORγt inhibitor 151. Moreover, this pathway
has been targeted using synthetic ligands such as SR1001,
which can block RORα and RORγt activity 152. Ursolic acid
has also been shown to antagonize RORγt activity 153.
Other potential modifiers of TH17 cell differentiation
include phosphoinositide 3‑kinase δ-subunit (PI3Kδ)
inhibition154. Further work will be needed to determine
whether any of these small-molecule inhibitors are suit‑
able for use in clinical studies. The use of small molecules
offers easy clinical use but an enhanced risk of off-target
effects, which could possibly be responsible for severe
adverse events.
Other targeting options. At present, clinical trials are
investigating drugs that target only IL‑17A and IL‑17RA.
However, other members of the IL‑17 family will have to
be considered. In addition to IL‑17A, IL‑17F is another

IL-17A–IL-17F
IL-17A-targeted IL-17A IL-17F
antibodies
TH17 cell or
• AIN-457
other cells
• LY2439821 IL-17A–IL-17F-
• SCH-900117 targeted antibody
• RG4934
• RG7624
IL-17RA-targeted IL-17RA IL-17RC
antibody
• AMG 827
Inhibitors of
Target tissue IL-17R signal
Inhibitors of TH17
transduction
cell generation
• RORC
• STAT3
• IL-23p19-targeted
antibody Biological effects
• Inflammation
• Matrix destruction
• Cell migration
Figure 4 | Tools for targeting the IL‑17–TH17 pathway.  Various therapeutic tools are
Nature
available to target the interleukin‑17 (IL‑17)–T helper 17 (TH17)Reviews | Drug Inhibitors
cell pathway. Discovery
of TH17 cell generation target retinoid-related orphan receptor-γ (RORC) as well as
signal transducer and activator of transcription 3 (STAT3). AIN457 and LY2439821 are
two monoclonal antibodies that target IL‑17A, and AMG 837 is a monoclonal antibody
that targets IL‑17 receptor A (IL‑17RA). In addition, there are other inhibitors of
IL‑17R‑mediated signalling that act by blocking various different signalling events.
IL‑17 family member of interest because of its pro-
inflammatory effects, which often involve synergistic
interactions with TNF11. In addition to the IL‑17A–
IL‑17A and IL‑17F–IL‑17F homodimers, there is also an
IL‑17A–IL‑17F heterodimer 13. Secukinumab and ixeki‑
zumab are both specific for IL‑17A–IL‑17A homodimers
and IL‑17A, with no effect on IL‑17F–IL‑17F homodi‑
mers. In a clinical trial, both IL‑17A and IL‑17F were tar‑
geted using the antibody RG7624; results from this trial
have not yet been reported. Thus no clinical information
is available at present regarding the utility of targeting
IL‑17F alone or with IL‑17A and on the respective con‑
tribution of the homo- and heterodimer forms to disease
pathogenesis13. The benefits of targeting both IL‑17A
and IL‑17F would include more effective control of all
or most IL‑17‑driven functions; however, this may be
associated with an increased risk of infections.
To translate the observation that TNF, IL‑17A and
IL‑17F show synergistic interactions in the clinic, vari‑
ous options and tools are under consideration. These
include the combination of a TNF inhibitor with an
IL‑17A inhibitor, administered either as two separate
molecules or as a single molecular construct containing
a TNF binding site and an IL‑17 binding site155. These
binding sites can be two binding sites of an antibody; for
instance, one binding to TNF and the other binding to
IL‑17A (ABT‑122 is one example). Alternatively, it can
be a construct made of smaller parts of an antibody with
a TNF binding site at one end and an IL‑17 binding site
at the other end, which is able to maintain inhibition of
the two ligands in solution. These molecules have not
yet been tested in the clinic. Such combinations would
NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | O CTOBER 2012 | 771
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
provide a better control of two key pathways. Short-term
use of these drug combinations could be a way to limit
the risk of infections.
The other option is the targeting of the IL‑17R
complex 156. Its structure has been clarified as a two-
chain complex made of IL‑17RA and IL‑17RC (rather
than as a single receptor, as it was initially described).
In addition to IL‑17RA, which is the target of broda‑
lumab (AMG 827), IL‑17RC has to be considered as a
potential target 157. For example, inhibition of IL‑17RC
expression using small interfering RNA inhibits the
response of synoviocytes to IL‑17A158, but it remains to
be determined whether antagonism of IL‑17RC alone
will be pursued in the clinic. In addition, IL‑17F uses the
same IL‑17RA–IL‑17RC complex to mediate downstream
signalling. Targeting IL‑17RA — which would simultane‑
ously affect IL‑17A and IL‑17F, as well as IL‑17C, but also
IL‑17E — is thus perhaps the broadest way to inhibit the
IL‑17 pathway. The downside is the inhibition of IL‑17E,
which has anti-inflammatory effects on the consequences
of IL‑17A- and IL‑17F‑mediated inflammation, the net
effect being a reduction in total anti-inflammatory effects.
The role of IL‑6 and IL‑1 on the differentiation and
function of TH17 cells has been discussed above. Part of
the beneficial clinical effects of IL‑6 pathway inhibitors
(such as tocilizumab, an inhibitor of IL‑6R) or IL‑1 path‑
way inhibitors (such as anakinra, an IL‑1R antagonist,
or canakinumab, an inhibitor of IL‑1β) may result from
an effect on the TH17 cell pathway 159. IL‑23 is another
cytokine that contributes to the differentiation of TH17 
cells. Inhibition of IL‑23 is part of the mechanism of
action of ustekinumab and briakinumab, two antibodies
directed against the p40 chain that is common to both
IL‑12 and IL‑23. Furthermore, two IL‑23p19‑specific
antibodies (SCH 900222 (also known as MK‑3222) and
LY2525623) are being or have been tested in psoriasis
(ClinicalTrials.gov identifier: NCT01018810; and see
TABLE 1). These examples illustrate the various options
available to target IL‑17: by acting upstream (for example,
on the differentiation of TH17 cells using an IL‑23 inhibi‑
tor), directly (using an IL‑17 inhibitor) or downstream
(using an inhibitor of receptor signalling).
Clinical results. A summary of clinical trials using anti­
bodies against IL‑17A and IL‑17RA is provided in TABLE 1.
Although inhibition of TNF is a recognized treatment
for several conditions listed in TABLE 1, around 30% of
patients fail to respond to such therapy, indicating the
need for other options. As mentioned above, the inter‑
actions between IL‑17 and TNF suggest that the target‑
ing of IL‑17 could be studied in diseases in which TNF
inhibitors have already been successful, possibly in the
subsets of patients who do not respond (or respond
insufficiently) to TNF inhibitors.
The inhibition of IL‑17A was observed for the first time
in the clinic in a Phase I clinical trial of secukinumab, an
IL‑17A‑specific monoclonal antibody, in patients with
psoriasis160. A single injection of this IL‑17A‑targeted
antibody reduced the surface area covered by skin lesions
as well as the number of IL‑17A‑positive cells in skin
biopsy samples. Subsequently, secukinumab was studied
REVIEWS

Table 1 | Clinical trials using IL‑17 and IL‑17R inhibitors

Drug Target Disease Phase Status Source or publication*
Secukinumab (also IL‑17A Psoriasis II Completed REF. 160
known as AIN457);
43 studies‡ III Ongoing NCT01406938
Rheumatoid arthritis II Completed REF. 160

III Ongoing NCT01377012

Ankylosing II Completed NCT00809159
spondylitis
III Ongoing NCT01358175
Uveitis II Completed REF. 160

II Ongoing NCT00685399
III Terminated NCT01032915;
NCT01095250
Behçet’s uveitis II Terminated NCT01093846
II Completed NCT00995709
Psoriatic arthritis II Recruiting NCT01169844
III Recruiting NCT01392326
Crohn’s disease II Terminated REF. 164

Polymyalgia II Recruiting NCT01364389

rheumatica
Dry eye II Recruiting NCT01250171
Multiple sclerosis II Ongoing NCT01433250
Asthma II Ongoing NCT01478360
Ixekizumab IL‑17A Rheumatoid arthritis II Completed REF. 162
(also known as
LY2439821); Psoriasis II Completed REF. 167
8 studies‡ III Recruiting NCT01597245
Brodalumab IL‑17RA Rheumatoid arthritis II Completed NCT00950989;
(also known as NCT00771030
AMG 827) 11
studies‡ Psoriasis II Completed REF. 163

II Recruiting NCT00975637
Crohn’s disease II Terminated NCT01150890
Asthma II Active, not yet NCT01199289
recruiting
Psoriatic arthritis II Recruiting NCT01516957
ABT‑122 IL‑17A Rheumatoid arthritis I No information See the 2011 Annual Report
and TNF available on the Abbott website
RG4934 IL‑17A Psoriatic arthritis I No information See the Roche website
available
RG7624 IL‑17A Not given I No information See the Roche website
and/or IL‑17F available
SCH‑900117 IL‑17A Rheumatoid arthritis I No information ACTRN12608000555358
available
SCH‑900222(also IL‑23p19 Psoriasis II Active NCT01225731
known as MK‑3222)
IL‑17, interleukin‑17; IL‑17R, IL‑17 receptor; TNF, tumour necrosis factor. *The indications are a summary of trials from the
ClinicalTrials.gov website, publications and other sources where additional details can be obtained (updated 15 August 2012).
‡
Not all clinical trials are listed in this table.

ACR20 response rate

The response rate of patients
in clinical trials for rheumatoid
arthritis who show a 20%
decrease in the clinical
American College of
Rheumatology (ACR) score.
in clinical trials in patients with rheumatoid arthritis and
uveitis160. In rheumatoid arthritis, secukinumab induced
an ACR20 response rate of 46%, compared to 20% with
placebo treatment. The results of this proof-of-concept
study were considered to be encouraging enough to
start a Phase III clinical trial. Preliminary results of a
Phase II study, which were presented as an abstract161,
demonstrated the safety and efficacy of secukinumab for
the treatment of moderate to severe active ankylosing
spondylitis.

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 REVIEWS

A Phase II trial with ixekizumab in patients with
rheumatoid arthritis162 showed that blocking IL‑17A
led to a reduction in clinical parameters as early as
1 week. The results of a Phase II trial with ixekizumab
in 142 patients with rheumatoid arthritis showed that
82% of patients receiving the 150 mg dose showed a 75%
improvement in skin lesions at week 12, compared with
8% in the placebo group. A clinical effect was seen as
early as 1 week after treatment.
Brodalumab (AMG 827) was first administered in
patients with psoriasis. The results of a Phase II trial
have been published163. In 198 patients who were rand‑
omized to receive subcutaneously administered broda‑
lumab, 77% of patients showed a 75% improvement
and 72% showed a 100% improvement in skin lesions
at week 12, whereas no patients responded in the pla‑
cebo group. By contrast, clinical trials of brodalumab
and secukinumab in Crohn’s disease failed to improve
disease symptoms, and even increased disease activity in
some patients, indicating that the role of TH17 cells and
IL‑17A appears to be more complicated than originally
thought 164,165.
As indicated on the ClinicalTrials.gov website, there
are also several ongoing or planned clinical trials to inves‑
tigate the targeting of IL‑17A, IL‑17RA and IL‑23p19
(TABLE 1). These IL-17A- and IL‑17RA‑targeted antibod‑
ies were first administered in humans via intravenous
injection. The initial clinical trials used a single injec‑
tion, and later trials used multiple injections to admin‑
ister increasing doses of the antibody. Subsequent studies
have used, or will use, subcutaneous formulations. One
option for future studies could be the use of intravenous
administration first to give a loading dose, followed
by the subcutaneous administration route to maintain
these levels.
Adverse events. As IL‑8 is a major chemotactic factor for
neutrophils, it could be expected that a lack or inhibition
of IL‑17 would induce defects in the control of infections
linked to extracellular bacteria. As discussed above, this
was indeed seen in animal models that are defective in
IL‑17 or IL‑17R; an increased incidence and severity of
these infections was observed in these animal models166.
A defect in the control of fungal infections could also be
expected. Reactivation of tuberculosis has been clearly
linked to TNF inhibition. The risk of tuberculosis appears
to be reduced when IL‑17 or IL‑23p19 are inhibited, but
patients are tested for tuberculosis reactivity before they
are enrolled into clinical trials of these targets.
At the current stage of drug development, neutro‑
paenia or an increased incidence of infections are not
commonly seen during the early phases of clinical trials.
A few cases of neutropaenia were observed but the
underlying mechanism has not been studied to deter‑
mine the direct contribution of IL‑17 inhibition163,167.
A few cases of local Candida albicans infection have been
observed but the direct role of IL‑17 inhibition has yet
to be clarified160,162.
Conclusion
The story of IL‑17 began more than 10 years ago, and the
clinical potential of targeting this cytokine is now being
realized168. The identification of the TH17 subset of T cells
indicates that these T cells are involved in, and amplify,
the link between chronic inflammation and destruction
of the extracellular matrix. Similar concepts on the role of
TH17 cells in inflammation and matrix destruction apply
to other complex diseases that are associated with inflam‑
mation-induced damage, ranging from local to systemic
manifestations.
Therapeutic tools are now in place to verify whether
these observations are indeed correct. According to
results obtained from clinical trials that have used these
tools, inhibition of IL‑17 activity can be seen as a new
treatment option for patients with chronic inflamma‑
tory diseases, as first observed in psoriasis and rheuma‑
toid arthritis. At this early stage of drug development,
no safety signal was observed. Because IL‑17 acts on
common pathways of inflammation, clinical trials are
underway or being initiated in several disorders, includ‑
ing ankylosing spondylitis, psoriatic arthritis, Crohn’s
disease and multiple sclerosis.
The combination of positive and negative results
obtained from such clinical trials indicates the complex‑
ity in predicting patients’ responses to IL‑17‑targeted
therapy. Despite the conflicting results, it appears that
the actual circulating levels of IL‑17A in normal controls
and patients are very low. But these low levels of IL‑17A
could still contribute to disease pathology, in combina‑
tion with other soluble and membrane-bound cytokines.
A major effort is now underway to better select patients
with inflammatory disease driven by IL‑17 and/or
TH17 cells. Bioassays that measure IL‑17A levels in
serum and other biological fluids could be helpful
in identifying such patient heterogeneity. By excluding
biomarker-negative patients, this personalized approach
will be crucial for improving the response rate and safety
of IL‑17- and/or TH17 cell-targeted therapies.

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Acknowledgements
P.M.’s work is supported by grants from the Institut Mérieux,
the Hospices Civils de Lyon (HCL) and the Institut
Universitaire de France (IUF). J.K.K.’s work was supported by
the National Heart, Lung, and Blood Institute (NHBLI) grant
R37-HL079142.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Abbott 2011 Annual Report (Financial Review: Part 4):
http://www.abbott.com/static/content/microsite/annual_
report/2011/21_review4.php
ClinicalTrials.gov website: http://clinicaltrials.gov
Roche Pharmaceuticals Pipeline:
http://www.roche.com/creating_value/roche_pharma_
pipeline.htm
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