© 2012 Expert Reviews Ltd
Inflammatory bowel disease (IBD) is a chronic
inflammatory disorder of the GI tract that
affects approximately 0.1–0.2% of the general
population, with the highest incidence and prev-
alence rates being described in industrialized
countries, such as northern Europe and North
America, with a so called ‘north–south gradient’
. Disease is usually diagnosed in adolescents
or young adults but it can occur at every age
of life and a clear gender predominance is not
IBD encompasses Crohn’s disease (CD),
ulcerative colitis (UC) and indeterminate colitis
(when overlapping features of CD and UC are
observed). CD can affect any part of the GI tract,
from the mouth to the anus, with discontinuous
transmural inflammation that can lead to the
formation of strictures or fistulas. However, in
UC inflammation only involves the mucosa, the
most superficial layer of the gut wall; it is limited
to the colon and always starts from the rectum,
extending proximally and in continuity. IBD is
characterized by alternating phases of clinical
relapse and remission and both long-standing
UC and CD have been associated with increased
risk of intestinal cancers . Symptoms are
mainly those of diarrhea, abdominal pain and
rectal bleeding. Nevertheless, extra-intestinal
manifestations are also frequent, with possible
involvement of joints (peripheral arthropathy),
skin (erythema nodosum and pyoderma gan-
grenosum) and eyes (uveitis and episleritis) in
up to 10–15% of patients . Patients with IBD
also have an increased risk of developing other
chronic immune disorders, such as psoriasis,
ankylosing spondylitis and primary sclerosing
The etiology of IBD remains unknown.
Nevertheless, recent research has greatly
improved our knowledge of the pathogenesis
of these chronic intestinal disorders, with the
implication of both genetic and environmental
factors. In fact, current evidence supports an
inter-relationship of genetic predisposition and
environmental risk factors that may lead to an
over-active, uncontrolled intestinal immune
response against the commensal microbial flora
with consequent tissue damage .
Many inflammatory molecules have been
implicated in the initiation and/or perpetu-
ation of chronic intestinal inflammation in
IBD. In particular, intestinal inflammation
has primarily been linked with a Th1 type of
immune response, characterized by high levels
of IL-12, IFN-g and TNF-a, in patients with
CD, and to a nonclassical Th2 response, with
increased expression of IL-5 and IL-13, but not
IL-4, in patients with UC [7–11]. In recent years,
therapeutic compounds that antagonize specific
inflammatory mediators have been successfully
introduced into clinical practice. Apart from
the traditional use of aminosalicylates, cortico-
steroids and immunosuppressants, monoclonal
antibodies against TNF-a are now routinely
used and have been proven effective for the treat-
ment of eligible patients with CD and UC .
and Derek P Jewell2
1Translational Gastroenterology Unit,
Nuffield Department of Clinical
Medicine, University of Oxford,
John Radcliffe Hospital, Oxford,
OX3 9DU, UK
2Nuffield Department of Clinical
Medicine, University of Oxford,
John Radcliffe Hospital, Oxford,
OX3 9DU, UK
*Author for correspondence:
Tel.: +44 1865 220663
Fax: +44 1865 275591
The etiology of inflammatory bowel disease is unknown but available evidence suggests that a
deregulated immune response towards the commensal bacterial flora is responsible for intestinal
inflammation in genetically predisposed individuals. IL-23 promotes expansion and maintenance
of Th17 cells, which secrete the proinflammatory cytokine IL-17 and have been implicated in the
pathogenesis of many chronic inflammatory disorders. Recent studies have shown that IL-23
also acts on cells of the innate immune system that can contribute to inflammatory cytokine
production and tissue inflammation. A role for the IL-23/IL-17 pathway in the pathogenesis of
chronic intestinal inflammation in inflammatory bowel disease has emerged from both animal
and human studies. Here we aim to review the recent advances in this rapidly moving field.
Keywords: Crohn’s disease • genes • IBD • IL-17 • IL-23 • inflammation • Th17 • ulcerative colitis
The IL-23/IL-17 pathway in
inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), 223–237 (2012)
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Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
Similarly, antibodies that block the p40 subunit shared by IL-12
and IL-23 have shown some therapeutic efficacy in subsets of
patients with CD in clinical trials [13–15]. In particular, the anti-
p40 antibody ustekinumab has proven to be effective in the treat-
ment of patients with moderate-to-severe CD who had previously
been unresponsive or intolerant to anti-TNF-a treatment .
The IL-23/IL-17 axis has recently been described to play a major
role in the pathogenesis of different tissue-specific immunologi-
cal disorders affecting the brain, joints, skin and gut, such as
multiple sclerosis, rheumatoid arthritis, psoriasis and IBD, respec-
tively [17–27]. Animal studies indicate a pivotal role for this axis in
driving chronic intestinal inflammation and results from human
research also support the involvement of the IL-23/IL-17 pathway
in IBD. These findings not only represent a major advance in our
understanding of mucosal immune responses and immune pathol-
ogy, but also raise the possibility of developing new, effective and
well-tolerated therapeutic strategies for patients with IBD.
A breakthrough: the discovery of IL-23
Until recently, most autoimmune disorders were considered to be
driven by a Th1 type of response, characterized by high secretion
of IFN-g . Th1 cells differentiate from naive T cells in response
to IL-12, which is a heterodimeric Type 1 cytokine mainly pro-
duced by activated macrophages, monocytes and dendritic cells
(DCs) . However, animal studies had shown some inconsis-
tencies with a prototypic model of autoimmune disease, such as
murine experimental autoimmune encephalomyelitis (EAE) being
dependent on IL-12, but showing aggravation in the absence of
IFN-g or after IFN-g inhibition [30–33]. IL-12 comprises a p40
subunit combined with a p35 subunit and acts on the IL-12 recep-
tor, which is composed of IL-12Rb1 and IL-12Rb2 chains and
signals through STAT-4 activation. The recent discovery that p40
can also combine with p19 to form the closely related cytokine
IL-23 has led to reappraisal of the roles of IL-12 and IL-23 in a
variety of inflammatory disorders . In the seminal work by
Cua et al., Il23a-/- mice that specifically lack IL-23, but not IL-12,
did not develop EAE, indicating that it is IL-23 and not IL-12
that drives CNS inflammation in this model . Subsequent stud-
ies have demonstrated that IL-23 is responsible for tissue-specific
inflammation in various other models of immune diseases, such as
rheumatoid arthritis, psoriasis and IBD, and translational research
has confirmed these findings in patients [18–27,35].
Similarly to IL-12, IL-23 is produced by activated monocytes,
macrophages, DCs and endothelial cells in response to pattern
recognition receptor binding (in particular dectin-1, TLR2 and
NOD2), prostaglandin E2 stimulation and CD40/CD40L inter-
action [36–39]. IL-23 acts on the IL-23 receptor, which is composed
of IL-12Rb1 (shared with the IL-12 receptor) and the specific
IL-23R subunit . IL-23R is widely expressed on immune cells
such as memory T-cell, natural killer (NK)-cell, DC, macrophage
and innate lymphoid cell (ILC) populations [17,40–42]. Signaling
through IL-23R involves the JAK/STAT pathway, with pre-
dominant activation of STAT-3, although STAT-1, STAT-4 and
STAT-5 may also be activated . After dimerization the STATs
translocate to the nucleus, where they regulate gene transcription.
IL-23 & Th17 cells
The proinflammatory activity of IL-23 has mostly been linked
to its effects on Th17 cells, a recently described population of T
cells characterized by the production of the inflammatory cyto-
kine IL-17 (also called IL-17A). Th17 cells contribute to physi-
ological immune responses to extracellular bacteria and fungi,
especially at the site of mucosal surfaces, such as in the lung and
intestine, through the induction of inflammatory and chemo-
tactic molecules and antibacterial agents [43–46]. On the other
hand, a number of studies support a major pathogenic role for
Th17 cells in different forms of murine and human immune
pathology [18,47,48]. IL-23 is not strictly required for differentia-
tion of Th17 cells from naive cells, which in fact do not express
IL-23R. However, IL-23 plays a central role in their mainte-
nance, expansion and terminal commitment [49,50], representing
a tissue regulator of Th17 phenotype and function. Studies in
mice have shown that Th17 cells differentiate in the presence
of TGF-b together with inflammatory cytokines, such as IL-6,
but also IL-21, which is induced in activated T cells by IL-6 in
a STAT-3-dependent manner [44,51–55]. IL-1R signaling has also
been reported to promote Th17-cell development, with Il1r1-/-
mice showing decreased Th17 cell differentiation and reduced
incidence of EAE [56,57]. Induction of the transcription factor
RORg-t drives the differentiation of Th17 cells [55,58]. However,
other transcription factors have been involved in murine Th17
differentiation, such as RORa, AHR, IRF4, STAT-3, RUNX
and c-MAF [59–65]. Interestingly, Th17, Th1 and Th2 responses
also appear to be crossregulated. While Th1- and Th2-associated
factors, such as IFN-g and IL-4, can inhibit Th17 differentiation,
IL-17A counteracts Th1 polarization [66,67].
The role of TGF-b in Th17 differentiation has highlighted
the pleiotropic properties of this cytokine, also known to exert
immune regulatory activity through the induction of Treg cells
that are major players in dampening the immune response [68,69].
TGF-b appears to determine Th17- or Treg-cell differentiation
in a dose-dependent manner. Lower concentrations of TGF-b in
the presence of IL-6 or IL-21 induce expression of IL-23R and
promote Th17 differentiation, while higher concentrations inhibit
IL-23R expression and induce the Treg master transcription factor
Foxp3. Interestingly, RORg-t+Foxp3+ cells are found in mice and
Foxp3+ cells that secrete IL-17A have been identified in humans,
highlighting the presence of inter-relation and plasticity between
these two cell subsets. In contrast with previous evidence, recent
work has suggested that TGF-b-independent differentiation of
Th17 cells may also occur. In this study, a combination of IL-23,
IL-6 and IL-1b was sufficient to induce differentiation of Th17
cells that expressed both the T-cell-specific T-box transcription
factor T-bet (the Th1 master regulator) and RORg-t and showed
pathogenic activity in the EAE model . Initial observations
suggested that differentiation of human Th17 cells did not require
the presence of TGF-b [71,72]. However, it is now established that
TGF-b together with a combination of inflammatory cytokines,
such as IL-1b, IL-6, IL-21 and IL-23, is indeed necessary for
human Th17-cell differentiation [73–75]. Human Th17 cells have
been shown to originate from CD161+ precursors and are enriched
Geremia & Jewell
in the CD161+ compartment [76,77]; they also express the chemo-
kine receptor CCR6  and are characterized by the produc-
tion of IL-17A, together with a range of other cytokines, such as
IL-17F, IL-21, IL-22 and IL-26, as well as TNF-a and IFN-g. It
is noteworthy that IL-21 can induce further Th17 differentiation,
creating a positive feedback loop that enhances Th17 responses.
Furthermore, Th17 cells also secrete CCL20, the main ligand for
CCR6, which, in turn, is preferentially expressed on the Th17-cell
surface, representing a paracrine mechanism that can contribute
to Th17-cell accumulation.
IL-23 & innate cells
Recent studies have shown that, besides its activity on Th17 cells,
IL-23 can also act on cells of the innate immune system (Figure 1) .
In particular, unconventional, innate-like T-cell populations
have been found to respond to IL-23 stimulation and secrete
Th17 cytokines. These cells have a distinct developmental origin
from conventional T cells and are characterized by only having
a limited antigen discrimination and specificity. They prefer-
entially home to mucosal sites and take part in early immune
responses against pathogens, suggesting they represent an evo-
lutionarily conserved, ancient innate mechanism of protec-
tion . Unconventional T-cell populations include gdT cells,
invariant NK T (iNKT) cells and the mucosal-associated invari-
ant T (MAIT) cells. A subpopulation of RORg-t-expressing
gdT cells has been shown to produce IL-17A, IL-22 and IL-21
in response to IL-23 in mice and to contribute to inflamma-
tion in EAE and collagen-induced arthritis [81–85]. Similarly,
IL-17 and IL-22-producing gdT cells have been described in
the human peripheral blood, although in low frequencies .
In mice, iNKT cells, which express an invariant T-cell receptor
(TCR) and respond to lipid antigens presented on the MHC-
related molecule CD1d, have also been shown to express IL-23R
and RORg-t and to produce IL-17A after IL-23 stimulation or
antigen recognition . Similarly, human CD56+TCRb+ NKT
cells also secrete IL-17A after stimulation with anti-CD3 and
IL-23 . MAIT cells are characterized by the expression of a
semi-invariant TCR, are CD8+ or CD8-CD4- and CD161high,
and are selected by the MHC-related molecule MR1. MAIT
cells express IL-23R and Dusseaux et al. have recently shown
that they secrete IL-17A after phorbol myristate acetate/iono-
mycin stimulation . This work suggests that MAIT cells
represent the majority of previously described populations of
IL-17A-producing CD161highCD8+ T cells [90,91].
Takatori et al. have shown that IL-23 induces IL-17 and IL-22
production in murine ILCs that share the phenotype of CD3-CD4+
lymphoid tissue inducer (LTi) cells . During fetal develop-
ment, LTi cells are involved in the organogenesis of secondary
lymphoid structures, such as lymph nodes and Peyer’s patches of
the small intestine, through the induction of adhesion molecules
on mesenchymal cells and secretion of chemokines, which lead
to LTi clustering and leukocyte recruitment [93–96]. Beside their
role in development, LTi-like cells have been found in adult tissue
and in particular in the intestine [96,97]. We have recently identi-
fied a population of IL-23-responsive ILCs characterized by a
Sca1+Thy1highcKit- phenotype, which are responsible for intestinal
inflammation in innate models of colitis through secretion of
IL-17A and IFN-g (see discussion below) . IL-23-responsive
ILC populations have also been identified in the human mucosal-
associated lymphoid tissue, such as intestinal Peyer’s patches and
tonsils. Cella et al. described CD3-CD56+NKp44+ cells, which
they termed NK22 cells, which secrete IL-22, but not IL-17A, in
response to IL-23 stimulation . NK22 cells also produce the
Th17 signature cytokine IL-26 and express the Th17 transcrip-
tion factor RORg-t. Although originally described as a subset of
NK cells, current evidence indicates that these cells are develop-
mentally and functionally related to lineage marker (Lin)-CD56-
IL-7R(CD127)+ human LTi cells [99,100]. One recent study has
shown that both CD56+ and CD56-CD127+ human ILCs can also
produce IL-2, IL-5 and IL-13 in accordance with the description
of Th2 cytokine-producing ILCs in mice (so-called nuocytes and
natural helper cells) [101–103]. Furthermore, human ILCs were
found to express different members of the TLR family and are
therefore able to sense and respond to microbial components.
In particular, association of IL-2 or IL-23 together with TLR2
stimulation has been shown to induce proliferation of ILC and
IL-22 production .
Finally, recent studies have reported that mast cells and neutro-
phils may also represent a major source of IL-17A in the synovial
tissue of patients with rheumatoid arthritis and in a model of
ischemia–reperfusion injury [104,105].
Figure 1. Th17 cells and innate lymphoid cells respond to
IL-23 activity. IL-23 induces the expansion and maintenance of
Th17 cells. However, recent studies have shown that innate
lymphocytes, such as gdT, iNKT, MAIT, LTi and other ILC
populations can also respond to IL-23 and secrete Th-17 signature
DC: Dendritic cell; ILC: Innate lymphoid cell; iNKT: Invariant NK T;
LTi: Lymphoid tissue inducer; MAIT: Mucosal-associated
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
Th17 signature cytokines
IL-17A & IL-17F
IL-17A and IL-17F are encoded by genes that lie in adjacent regions
on human chromosome 6 and share the highest sequence homology
(60%) among the members of the IL-17 family of cytokines. They
are normally coexpressed by Th17 cells and their expression appears
to be dependent on the transcription factor STAT-3 . Both
IL-17A and IL-17F production is also impaired in the absence of
RORg, whereas production of IL-17F but not IL-17A is independent
of RORa [58,60]. IL-17A/IL-17F heterodimers have recently been
identified . Interestingly, human Th17 cells seem to produce
mainly IL-17F homodimers and IL-17A/IL-17F heterodimers, with
only very low production of IL-17A homodimers . IL-17A and
IL-17F act on a heteromeric receptor composed of IL-17RA and
IL-17RC subunits [108–110]. IL-17F binds to IL-17RA with lower
affinity compared with IL-17A, while both IL-17F and IL-17A
show high-affinity binding to IL-17RC (to note, murine IL-17A
does not bind IL-17RC) . On target cells, IL-17A induces the
secretion of inflammatory cytokines, such as IL-6, TNF-a and
IL-1b, chemokines (both CXC and CC), granulocyte colony-stim-
ulating factor and granulocyte–macrophage colony-stimulating
factor, which favor local accumulation of neutrophils and other
inflammatory cells. Furthermore, IL-17A stimulates the production
of matrix metalloproteinases (MMPs) that are involved in tissue
remodeling and tissue damage. Besides its inflammatory activity,
IL-17A contributes to the regulation and integrity of mucosal bar-
rier function through the production of antimicrobial peptides such
as b-defensins and S100 proteins . Available evidence suggests
that IL-17F has overlapping biological functions with IL-17A such
as induction of chemokines, granulocyte–macrophage colony-
stimulating factor, MMP and antimicrobial peptides [112–115].
Accordingly, Il17ra-/- mice develop Staphylococcus aureus infections
with a similar phenotype observed in Il17a-/-/Il17f -/-double knock-
out, but not in single knockout mice, and Il17ra-/- mice are more
susceptible to Klebsiella pneumoniae infection than Il17a-/- mice
[116,117]. These data confirm the presence of some redundancy in the
functional activity of IL-17A and IL-17F in conferring protection
against extracellular pathogens. Nevertheless, other studies have
highlighted distinct and even opposite roles for IL-17A and IL-17F
in inflammation [114,116]. IL-17A has been shown to play a dominant
role in the development of arthritis (in IL-1 receptor antagonist-
deficient mice), collagen-induced arthritis, EAE, delayed-type and
contact hypersensitivity; while IL-17F only has minor effects, if
any, in these models . In the ovalbumin-alum-induced model
of asthma, IL-17A contributes to the induction of Th2 responses,
while IL-17F has been shown to have Th2-inhibitory effects.
Moreover, IL-17F appears to be pathogenic in dextran sodium
sulfate-induced colitis, whereas IL-17A plays a protective role in
this model of acute intestinal inflammation (Table 1) . Further
studies are needed in order to elucidate overlapping and unique
effects of IL-17A and IL-17F in different contexts.
IL-21 is mostly produced by activated CD4+ T cells and acts on
a heteromeric receptor composed of a common g-chain and the
IL-21Ra specific subunit, which is widely expressed on both
immune cells (B cells, T cells and NK cells) and nonimmune
cells (epithelial cells and fibroblasts) [118,119]. The IL-21R com-
plex signals via the JAK/STAT pathway, leading primarily to
the activation of STAT-1 and STAT-3 and to weaker activation
of STAT-5 . IL-21 can stimulate proliferation and activa-
tion of CD4+ and CD8+ T cells, inhibit Treg differentiation
and increase resistance of target cells to Treg-mediated inhibi-
tion [118,121–123]. As already discussed, recent studies have shown
that IL-21 together with TGF-b can induce the differentiation
of Th17 cells from naive T cells [53,55,75]. Some studies have
indicated that IL-21 can induce IFN-g production and Th1
responses [124,125]. However, no difference in the production of
IFN-g was observed in Il21r-/- mice, which instead showed higher
delayed hypersensitivity reactions associated with higher levels of
IFN-g, suggesting only partial effects of IL-21 in shaping Th1
and Th2 responses [126,127]. IL-21 can also promote antibody
production, IgG switching and plasma cell differentiation, and
expansion and activation of NK cells [118,126,128,129]. Finally, on
nonimmune cells, such as epithelial cells and fibroblasts, IL-21
has been shown to induce the secretion of chemokines and the
production of MMP [130,131].
A role for IL-21 has been suggested in the pathogenesis of many
immune disorders, such as Type 1 diabetes, atopic dermatitis, sys-
temic sclerosis, systemic lupus erythematosus and IBD [128,132–135].
In particular, IL-21 has been shown to play a pathogenic role in
chemically induced colitis, such as dextran sodium sulfate-colitis
and trinitrobenzene sulfonic acid-colitis, through the induction
of Th17-cell responses (Table 1) . Furthermore, IL-21 expres-
sion has been shown to be increased in the inflamed intestine in
patients with CD . Interestingly, susceptibility variants in
the IL-2/IL-21 genetic region have recently been associated with
celiac disease, UC and primary sclerosing cholangitis [137–139].
IL-22 is a member of the IL-10 cytokine family, together with
IL-26, and acts on the heteromeric receptor that comprises the
IL-10R2 subunit, which is shared with the IL-10R complex
and ubiquitously expressed, and the specific IL-22R1 subunit,
which is only expressed on nonimmune cells, such as epithelial
cells and mesenchymal cells particularly in the skin, kidney,
and digestive and respiratory systems . The highest levels of
expression of IL-22R1 were found in the pancreas and the skin,
where the IL-22R1 is particularly expressed by keratinocytes .
Responsiveness to IL-22 can be further induced during inflam-
mation by exposure to IFN-g and TNF-a [142,143]. The IL-22R
complex signals through the JAK/STAT pathway, leading to
phosphorylation of STAT-3. In humans, the main producers of
IL-22 are activated T cells, not only Th17 cells, but also Th1 and
the recently described Th22 subset, characterized by the produc-
tion of IL-22, but not IL-17A nor IFN-g [144,145]. Furthermore,
innate cells, such as gdT cells and ILC populations have also been
shown to produce IL-22 [82,98].
IL-22 is involved in tissue defence, regeneration and healing,
through the induction of antimicrobial agents (b-defensins and
Geremia & Jewell
S100 proteins) and proteins involved in epithelial cell differen-
tiation and cell mobility, as shown by gene expression arrays in
keratinocytes . IL-22 has been shown to play a major role in
bacterial intestinal and pulmonary infections. Il22-/- mice suc-
cumb to intestinal infection with Citrobacter rodentium due to a
lack of epithelial cell-derived RegIII antibacterial peptides .
Similarly, neutralization of IL-22 has been shown to aggravate
pulmonary infection with K. pneumoniae . Effects of IL-22
on keratinocyte differentiation have been extensively studied
and there is now strong evidence that IL-22 plays a pathogenic
role in different models of psoriasis, where it is responsible for
the induction of acanthosis and hypogranulosis [19,148]. These
data are supported by findings in patients, which show high lev-
els of IL-22 in both skin lesions and peripheral blood [141,142].
Conversely, a protective role for IL-22 has been shown in several
models of liver inflammation, but the molecular mechanisms
remain unclear [149,150]. A protective role for IL-22 has also been
suggested in intestinal inflammation, but data are still contro-
versial. In a model of Th2 colitis, gene delivery of Il22 to the
colonic epithelium led to goblet-cell restitution and amelioration
of colitis [151,152]. Increased IL22 expression has been observed in
the inflamed intestine of patients with both CD and UC [153–155].
In vitro studies have shown that IL-22 can induce secretion of
proinflammatory cytokines by intestinal epithelial cells and sub-
epithelial myofibroblasts, which express the IL-22 receptor com-
plex [153,154]. On the other hand, IL-22 stimulation of intestinal
epithelial cells results in increased cell proliferation and secretion
of antimicrobial agents, suggesting a protective role for IL-22
in promoting mucosal healing and epithelial barrier integrity
. Furthermore, IL-22 has been shown to induce expression
of lipopolysaccharide-binding protein that could contribute to
limiting systemic inflammatory responses to lipopolysaccharide
in patients with CD .
IL-26 was first identified in human T cells transformed with sim-
ian rhadinovirus herpesvirus saimiri as another member of the
IL-10 cytokine family that does not have a homologue in mice
. IL-26 is mainly produced by activated memory T cells with
both Th1 and Th17 phenotypes [72,158]. In addition, activated
NK cells and CD3-CD56+NKp44+ cells have also been shown to
produce IL-26 [98,158]. The IL-26 receptor complex is composed
of the broadly expressed IL-10R2 subunit and IL-20R1, which
is only expressed on limited tissue types. Binding of the receptor
leads to JAK/STAT activation and phosphorylation of STAT-1
and STAT-3 . IL-26 has been shown to target epithelial cells,
such as intestinal cells and keratinocytes, where it induces secre-
tion of IL-10 and IL-8 and overexpression of the adhesion mol-
ecule ICAM-1 . Furthermore, treatment of intestinal cell
lines with IL-26 was shown to inhibit cell proliferation, with an
effect opposite to IL-22, and induce expression of SOCS3 and
proinflammatory cytokines such as TNF-a and IL-8. A role for
IL-26 in intestinal inflammation has been suggested by the obser-
vation of increased gene expression of IL26 in the inflamed versus
the noninflamed intestine of patients with CD  and UC .
The IL-23/IL-17 axis in intestinal inflammation
Results from murine studies have shown that IL-23 is the key cyto-
kine driving intestinal inflammation in both T-cell-independent
and T-cell-dependent models of colitis (Table 1).
In the anti-CD40-induced innate model of acute colitis, T-
and B-cell-deficient Rag-/- mice treated with agonistic anti-CD40
antibodies develop colitis and wasting disease associated with
high serum levels of inflammatory cytokines. Administration
of monoclonal antibodies against the IL-23-specific p19 subunit
completely abrogates colitis in this model, while it does not affect
wasting disease. Consistently, results in Rag-/- Il23a-/- and Il12a-/-
mice that specifically lack IL-23 and IL-12, respectively, show
that intestinal inflammation is completely dependent on IL-23,
while IL-12 is necessary for the development of systemic dis-
ease . These findings have highlighted the presence of tissue
Table 1. The role of the IL-23/IL-17 axis in murine
models of intestinal inflammation.
IFN-g and TNF-a-
IFN-g and IL-17A-
IL-23 restrains Treg
IL-6 and IL-17
DSS-induced IL-17F pathogenic
DSS: Dextran sodium sulfate; ILC: Innate lymphoid cell; TBNS: Trinitrobenzene
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
compartmentalization of IL-23 and its central role in intestinal
In another model of innate colitis, T- and B-cell-deficient
Rag-/- mice are orally infected with the pathogenic bacterium
Helicobacter hepaticus, leading to cecal and colonic inflammation
associated with marked systemic inflammatory responses .
Similarly to what was observed in the anti-CD40 acute model,
administration of anti-IL-23p19 antibodies is sufficient to com-
pletely abrogate colitis in these mice. However, in H. hepaticus-
induced innate colitis, systemic disease is also attenuated by the
anti-IL-23p19 treatment. This observation may reflect the sequen-
tial activation of intestinal and systemic responses by the orally
administered bacteria, compared with the systemic anti-CD40
Both H. hepaticus- and anti-CD40-induced innate colitis
are associated with high intestinal expression of Th17 and Th1
cytokines, such as IL-17A and IFN-g. In the H. hepaticus-driven
model, blockade of IL-17A or IFN-g with specific antibodies is
sufficient to significantly decrease intestinal and systemic inflam-
mation, indicating a functional role for both cytokines in this
disease . However, IL-17A is dispensable for the development
of anti-CD40-induced colitis and wasting disease, which appears
to be dependent on other inflammatory cytokines such as IFN-g
Data from the T-cell-independent models suggested the pres-
ence of an IL-23-dependent innate source of IL-17A in the murine
intestine. Recently, Buonocore et al. were able to identify a novel
population of Sca1+Thy1highcKit- ILCs that is responsible for intes-
tinal inflammation in both the anti-CD40- and H. hepaticus-
induced innate models. Strikingly, ILCs express both RORg-t and
the T-bet and respond to IL-23 with IL-17A, IL-22 and IFN-g
IL-23 was also found to specifically drive intestinal inflamma-
tion in different T-cell-dependent experimental models of colitis
[20,22–24]. In the well-established T-cell transfer model, the adop-
tive transfer of CD45RBhigh naive T cells into immune-deficient
Rag-/- mice induces the development of colitis and systemic disease
[163–165]. Rag-/- Il23a-/- recipients do not develop intestinal inflam-
mation after T-cell transfer, while colitis is not affected by specific
deletion of IL-12 in Rag-/-Il12a-/- recipients. Interestingly, in this
model the presence of either IL-12 or IL-23 is sufficient to induce
systemic signs of disease . Strikingly, the inflammatory activ-
ity of IL-23 is not dependent on its effect on Th17 cells, since
Il17a-/- CD45RBhigh cells can induce colitis in Rag-/- mice .
Conversely, IL-23 exerts its proinflammatory effects restraining
the IL-10- and TGF-b-dependent immune-regulatory activity
of intestinal Tregs in these settings . Furthermore, in the
T-cell-transfer model, IL-23 drives colitis, but not systemic dis-
ease, through direct effects on T cells, inducing intestinal T-cell
proliferation and accumulation and promoting the emergence
of IL-17A+IFN-g+ double-positive T cells . Others have sug-
gested the presence of a redundant role of IL-17A and IL-17F in
T-cell-driven experimental colitis. In this study, reconstitution
of Rag-/- mice with Il17f-/- T cells together with administration
of IL-17A-neutralizing antibodies significantly reduced colitis
severity. However, IL-17A production by non-T-cell sources is
also abrogated in these experimental settings and could contribute
to the observed decrease in intestinal inflammation .
Besides its pathogenic role, the IL-23/IL-17 pathway has also
been shown to mediate protective immunity in the gut. Recent
studies have highlighted the central role of RORg-t+ ILCs and
Th17 responses in controlling enteric bacterial infections. IL-23-
dependent IL-22 production by RORg-t+ ILCs plays a critical role
in limiting infection with the mouse-specific pathogen C. roden-
tium [146,169]. Furthermore, NOD1- and NOD2-dependent induc-
tion of an early innate-like Th17 response is also necessary to
control infection with C. rodentium and Salmonella typhimurium
. Similarly, the IL-23/IL-17 axis plays a protective role in
models of chemically induced intestinal acute inflammation,
where epithelial barrier damage results in exposure of the mucosal
immune system to high bacterial load . In these settings, Th17
cytokines, such as IL-17 or IL-22, may promote the restitution of
epithelial barrier integrity.
Available data from human studies strongly support a role for the
IL-23/IL-17 pathway in IBD.
The strongest evidence comes from results of genome-wide
association studies that have identified IBD susceptibility single
nucleotide polymorphisms (SNPs) in many genes involved in the
IL-23/IL-17 axis [172–176]. SNPs in the IL23R gene that encodes
for the specific subunit of the IL-23 receptor have been identified
and largely replicated in independent cohorts of patients with
IBD . The strongest association was found with the uncom-
mon nonsynonymous coding variant Arg381Gln, which lies in
the cytoplasmic domain of IL-23R and confers increased pro-
tection against IBD. Notably, other SNPs in the intronic and
intergenic regions of the IL23R gene have also been associated
with increased susceptibility. Interestingly, IL23R polymorphisms
have been associated with both CD and UC, suggesting that
the IL-23 axis might represent a shared inflammatory pathway
in chronic intestinal inflammation. To date, the functional role
of the IL23R variants remains largely unknown. However, some
reports indicate that the protective IL23R R381Q variant repre-
sents a loss-of-function mutation and is associated with reduced
STAT-3 phosphorylation [177–179]. Higher serum levels of IL-22
have been found in CD patients carrying risk versus protective
IL23R variants and responsiveness to anti-TNF-a treatment has
been correlated to IL23R genotyping in patients with UC, sug-
gesting the presence of some degree of relation between IL-23
and TNF-a-mediated responses [180,181]. Furthermore, variants in
the IL23R gene have also been linked to other immune disorders
that can be associated with IBD, such as psoriasis and ankylos-
ing spondylitis [182,183]. Other susceptibility genes for both CD
and UC appear to be involved in the IL-23/IL-17 axis, such as
STAT3, JAK2 and TYK2, which take part in IL-23 signal trans-
duction, and IL12B, encoding the common subunit of IL-12 and
IL-23. CD risk variants have also been identified in CCR6, a
chemokine receptor preferentially expressed on IL-17-producing
cells [173–175,184]. As already mentioned, variants in the genetic
Geremia & Jewell
region containing the IL21 gene have also been associated with
UC . Furthermore, mutations in IL17A and IL17F have also
been reported to increase UC susceptibility and phenotype in
Asian populations, but this has not been replicated in Caucasians
(Figure 2) [185–187].
Beside genetic studies, more evidence has come from the
ana lysis of cytokine expression profiles in IBD. Higher levels
of IL-23 have been found in the inflamed intestine of patients
with IBD and particularly in CD compared with UC [35,188–190].
Moreover, Th17 cytokines are increased in both the colon and
serum of patients. Increased mRNA expression of IL17A has been
described in the mucosa of patients with both active UC and CD
[155,190–192]. IL17A expression has been detected in both CD3+ and
CD3- cells, suggesting the presence of both T-cell- and non-T-
cell sources of IL-17A in the inflamed intestine [155,191]. Higher
expression of IL-17A was observed in CD4+ T cells isolated from
the lamina propria compared with the peripheral blood of normal
controls ex vivo and after TCR and IL-23 stimulation . We
have recently found preferential expression of Th17 signature
cytokines not only in CD3+ but also in CD3- cells isolated from
the uninflamed intestine of control individuals compared with
their systemic counterparts . These data confirm the compart-
mentalization of the IL-23/IL-17 axis previously described in mice
and confirm the presence of innate sources of Th17 cytokines in
the human intestine. IL17F is also overexpressed in the inflamed
compared with the uninflamed mucosa of patients with CD and
higher levels of colonic IL17F are observed in UC, even if there
is no difference between inflamed and uninflamed tissue in the
latter . In one study, IL26 was found to be increased in the
inflamed mucosa of patients with CD, but not UC, and RORg-t+
cells expressing IL-26 were visualized by immunofluorescence
ana lysis in active CD . However, we recently found signifi-
cantly higher mRNA expression levels of IL26 in the inflamed
colon of UC patients compared with controls . Interestingly,
the expression of CCL20, a chemokine secreted by Th17 cells,
is increased in the intestine of patients with IBD and may, in
turn, mediate accumulation of IL-17-producing cells, which
preferentially express its receptor CCR6 [78,194,195].
Circulating and intestinal CD161+ Th17 cells with an acti-
vated phenotype have been isolated from patients with CD [76,77].
Interestingly, a high frequency of both IL-17A+ and IL-17A+IFN-g+
double-positive CD161+ Th17 cells has been observed after in vitro
expansion with anti-CD3 and anti-CD28 stimulation . This
observation appears of particular interest in light of our find-
ings in mice, where IL-23 proinflammatory activity promotes
the emergence of intestinal double-positive IL-17A+IFN-g+ cells.
Our recent work shows increased frequency of IL-23-responsive
innate lymphoid sources of Th17 cytokines in the intestine of
patients with CD. In particular, we observed a marked increase
in IL-17A- and IL-17F-producing CD56-CD127+ ILCs in the
inflamed colon and ileum of patients with CD . These cells
share features of human LTi cells and may contribute to intestinal
inflammation through the production of inflammatory cytokines
and the recruitment of other inflammatory cells to the intestine.
This observation resembles the accumulation of IL-17-producing
ILCs, which mediate colitis in the murine innate models, and
opens new insights into IL-23-dependent intestinal immune
Finally, in accordance with a role for IL-23-driven responses
in the pathogenesis of IBD, the administration of monoclonal
antibodies against the p40 subunit, shared by IL-12 and IL-23,
has shown some efficacy in subsets of patients with CD [13–15].
However, anti-IL-12/IL-23 treatment in CD has not achieved
the same levels of response obtained in patients with another
IL-23-associated disease, psoriasis. Interestingly, one study has
showed higher efficacy of ustekimumab in CD patients previously
treated with anti-TNF-a . These observations suggest that IBD
may represent a more heterogeneous disease compared with other
IL-23-linked diseases, such as psoriasis, and that different patho-
genic mechanisms may contribute to intestinal inflammation in
selected subsets of patients.
In this review, we aimed to discuss the available evidence sup-
porting a role for the IL-23/IL-17 pathway in the pathogenesis
of chronic intestinal inflammation. IL-23 and Th17 cells are
involved in the physiological immune response towards extracel-
lular bacteria and fungi, in particular at mucosal surfaces, such
as the skin, lungs and gut. However, different studies have shown
that inappropriate overactivation of IL-23/IL-17 responses can
lead to chronic inflammation and autoimmunity with resulting
tissue damage. Animal studies have shown that IL-23 is the
Figure 2. Multiple single nucleotide polymorphisms in
genes involved in the IL-23/IL-17 pathway have been
associated with inflammatory bowel disease susceptibility.
Mutations in the gene encoding for the IL12B subunit of IL-23, the
IL2/IL21 locus, the IL23R, JAK2, TYK2, STAT3 and CCR6 genes
have been associated with inflammatory bowel disease
susceptibility. Single nucleotide polymorphisms in the IL17A and
IL17F genes have also been associated with ulcerative colitis
susceptibility and phenotype in Asian populations.
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
key cytokine driving intestinal inflammation in both T-cell-
dependent and -independent murine models of colitis. A role
for this axis in the pathogenesis of IBD has been confirmed by
human data emerging from both genome-wide association stud-
ies and translational research studies in patients. Interestingly,
the proinflammatory activity of IL-23 is not exclusively linked
to its effects on Th17 cells. In fact, IL-23-responsive innate cells
have recently been identified in both mice and humans and par-
ticularly at mucosal sites. A pathogenic role for IL-23-responsive
ILCs has recently been identified in innate murine models of coli-
tis and selective accumulation of IL-17A- and IL-17F-producing
ILCs has been found in the intestine of patients, suggesting
that IL-23-dependent innate sources of IL-17 may contribute to
intestinal inflammation in patients with IBD.
IBD is a chronic inflammatory disorder characterized by alter-
nating phases of clinical remission and relapse. Aims of treat-
ment for patients with IBD include rapid induction of remis-
sion of active disease, maintenance of clinical remission once
this is achieved, and the management of complications such as
fistulas, abscesses or strictures. Conventional therapeutic strate-
gies for patients with IBD include the use of aminosalicylates,
corticosteroids and immunosuppressant agents. Recent advances
in our understanding of the pathogenic mechanisms that con-
tribute to inflammation in IBD have led to the development of
novel therapeutic agents that specifically inhibit the inflamma-
tory mediators involved in inflammation, such as anti-TNF-a
compounds for the treatment of selected patients with both CD
and UC. Nevertheless, up to a third of patients do not respond
to anti-TNF-a treatment and at least 50% of initially responsive
patients will lose their response or become intolerant to one or
more anti-TNF-a agents. Furthermore, all treatments currently
available have been associated with the occurrence of worrying
side effects, which mostly derive from the associated nonspecific
systemic immune suppression that may lead to increased risk of
infections and cancer . These observations highlight the need
to develop new therapeutic strategies. In this respect, the recent
identification of a central role for the IL-23/IL-17 pathway in
chronic intestinal inflammation raises exciting new possibilities.
Notably, both murine and human studies have suggested the
presence of compartmentalization of the IL-23/IL-17 axis, with
preferential expression at the intestinal mucosal site. This obser-
vation anticipates that targeted inhibition of this pathway may
lead to fewer side effects compared with conventional immuno-
suppressant treatments because of its tissue specificity. Possible
strategies include inhibition of upstream molecules involved in
Th17 differentiation and expansion (TGF-b, IL-1, IL-6, IL-23
and RORg), direct inhibition of Th17 cytokines (IL-17A and
IL-17F) or their receptors (IL-17RA and IL-17RC) and inhi-
bition of Th17-cell trafficking through chemokine- or CCR-
blocking strategies (CCR6) . Several biologic agents targeting
components of this axis are currently in preclinical or early-phase
clinical trials and efficacy and tolerability outcomes will be acces-
sible in the near future. Results from a double-blind, placebo-
controlled, proof-of-concept study on the use of secukinumab
(a monoclonal anti-IL-17A antibody, AIN457) for treatment of
moderate-to-severe CD were presented at the ECCO Congress
2011 and clearly showed no efficacy of treatment versus placebo
. In fact, administration of secukinumab appeared to exac-
erbate disease in a subset of patients with increased inflamma-
tory markers . However, this outcome was anticipated by
results in mice, where Il17a-/- T cells can still induce colitis in
the T-cell transfer model [166,168,200]. Similarly, IL-17A inhibi-
tion was shown to only partially ameliorate colitis in the Il10-/-
model of colitis . From the evidence reviewed here it appears
clear that IL-23/IL-17 responses are characterized by a much
higher grade of complexity than initially proposed. We have
discussed how Th17 cells are characterized by the secretion of
a great variety of factors with both proinflammatory and anti-
inflammatory properties and how some studies have indicated
redundant effects of Th17 cytokines, such as IL-17A and IL-17F.
Furthermore, plasticity and crossregulation between T-helper-
cell populations add another degree of complexity, and inhibi-
tion of Th17 responses may in fact result in expansion of Th1
or Th2 cells, leading to counteracting proinflammatory effects.
Furthermore, besides its activity on Th17 cells, we have described
the presence of a variety of IL-23-responsive innate immune cells,
which appear to also be characterized by high response versatility
and can contribute not only to secretion of Th17, but also Th1
• IL-23 induces expansion and maintenance of Th17 cells, which are characterized by expression of the transcription factor RORg-t and
secretion of the proinflammatory cytokine IL-17A.
• Human Th17 cells secrete IL-17A, IL-17F, IL-22, IL-21 and IL-26, together with TNF-a and IFN-g.
• Innate lymphocytes, such as gdT, invariant NK T, mucosal-associated invariant T, lymphoid tissue inducer and innate lymphoid cell
populations, have been shown to respond to IL-23 and secrete Th17 signature cytokines.
• The IL-23/IL-17 axis plays a major role in many immune disorders, such as multiple sclerosis, rheumatoid arthritis, psoriasis and
inflammatory bowel disease.
• IL-23 is the key cytokine driving intestinal inflammation in both T-cell-dependent and -independent murine models of colitis.
• Results of genome-wide association studies have strongly supported a role for the IL-23/IL-17 axis in inflammatory bowel disease with
the identification of multiple susceptibility single nucleotide polymorphisms in different genes involved in this pathway.
• Results of translational studies indicate that the IL-23/IL-17 axis contributes to both ulcerative colitis and Crohn’s disease, and may
represent a promising target for the treatment of patients.
Geremia & Jewell
Papers of special note have been highlighted as:
• of interest
Loftus EV Jr. Clinical epidemiology of
inflammatory bowel disease: incidence,
prevalence, and environmental influences.
Gastroenterology 126(6), 1504–1517
Loftus EV Jr, Sandborn WJ.
Epidemiology of inflammatory bowel
disease. Gastroenterol. Clin. N. Am.
31(1), 1–20 (2002).
Triantafillidis JK, Nasioulas G, Kosmidis
PA. Colorectal cancer and inflammatory
bowel disease: epidemiology, risk factors,
mechanisms of carcinogenesis and
prevention strategies. Anticancer Res. 29(7),
Bernstein CN, Blanchard JF, Rawsthorne
P, Yu N. The prevalence of extraintestinal
diseases in inflammatory bowel disease:
a population-based study. Am. J.
Gastroenterol. 96(4), 1116–1122 (2001).
Bernstein CN, Wajda A, Blanchard JF.
The clustering of other chronic
inflammatory diseases in inflammatory
bowel disease: apopulation-based study.
Gastroenterology 129(3), 827–836 (2005).
Abraham C, Cho JH. Inflammatory bowel
disease. N. Engl. J. Med. 361(21),
Fuss IJ, Neurath M, Boirivant M et al.
Disparate CD4+ lamina propria (LP)
lymphokine secretion profiles in
inflammatory bowel disease. Crohn’s
disease LP cells manifest increased
secretion of IFN-g, whereas ulcerative
colitis LP cells manifest increased secretion
of IL-5. J. Immunol. 157(3), 1261–1270
Monteleone G, Biancone L, Marasco R
et al. Interleukin 12 is expressed and
actively released by Crohn’s disease
intestinal lamina propria mononuclear
cells. Gastroenterology 112(4), 1169–1178
Parronchi P, Romagnani P, Annunziato F
et al. Type 1 T-helper cell predominance
and interleukin-12 expression in the gut of
patients with Crohn’s disease. Am. J. Pathol.
150(3), 823–832 (1997).
10 Heller F, Florian P, Bojarski C et al.
Interleukin-13 is the key effector Th2
cytokine in ulcerative colitis that affects
epithelial tight junctions, apoptosis, and
cell restitution. Gastroenterology 129(2),
11 Niessner M, Volk BA. Altered Th1/Th2
cytokine profiles in the intestinal mucosa of
patients with inflammatory bowel disease as
assessed by quantitative reversed transcribed
polymerase chain reaction (RT-PCR). Clin.
Exp. Immunol. 101(3), 428–435 (1995).
12 Lee TW, Fedorak RN. Tumor necrosis
factor-a monoclonal antibodies in the
treatment of inflammatory bowel disease:
clinical practice pharmacology.
Gastroenterol. Clin. N. Am. 39(3), 543–557
13 Mannon PJ, Fuss IJ, Mayer L et al.
Anti-interleukin-12 antibody for active
Crohn’s disease. N. Engl. J. Med. 351(20),
14 Sandborn WJ, Feagan BG, Fedorak RN
et al. A randomized trial of Ustekinumab,
a human interleukin-12/23 monoclonal
antibody, in patients with moderate-to-
severe Crohn’s disease. Gastroenterology
135(4), 1130–1141 (2008).
15 Toedter GP, Blank M, Lang Y, Chen D,
Sandborn WJ, de Villiers WJ. Relationship
of C-reactive protein with clinical response
after therapy with ustekinumab in Crohn’s
disease. Am. J. Gastroenterol. 104(11),
16 Sandborn WJ, Gasink C, Gao L et al.
A multicenter, randomized, double-blind,
placebo-controlled, Phase 2b study of
ustekinumab, a human monoclonal
antibody to IL-12/23p40, in patients with
moderately to severely active Crohn’s
disease: results through week 22 from the
Certifi trial. Gastroenterology
140(5 Suppl. 1), S109 (2012).
17 Cua DJ, Sherlock J, Chen Y et al.
Interleukin-23 rather than interleukin-12 is
the critical cytokine for autoimmune
inflammation of the brain. Nature
421(6924), 744–748 (2003).
18 Murphy CA, Langrish CL, Chen Y et al.
Divergent pro- and antiinflammatory roles
for IL-23 and IL-12 in joint autoimmune
inflammation. J. Exp. Med. 198(12),
19 Zheng Y, Danilenko DM, Valdez P et al.
Interleukin-22, a T(h)17 cytokine,
mediates IL-23-induced dermal
inflammation and acanthosis. Nature
445(7128), 648–651 (2007).
20 Yen D, Cheung J, Scheerens H et al. IL-23
is essential for T cell-mediated colitis and
promotes inflammation via IL-17 and
IL-6. J. Clin. Invest. 116(5), 1310–1316
21 Uhlig HH, McKenzie BS, Hue S et al.
Differential activity of IL-12 and IL-23 in
mucosal and systemic innate immune
pathology. Immunity 25(2), 309–318
22 Hue S, Ahern P, Buonocore S et al.
Interleukin-23 drives innate and T cell-
mediated intestinal inflammation. J. Exp.
Med. 203(11), 2473–2483 (2006).
23 Kullberg MC, Jankovic D, Feng CG et al.
IL-23 plays a key role in Helicobacter
hepaticus-induced T cell-dependent colitis.
J. Exp. Med. 203(11), 2485–2494 (2006).
24 Elson CO, Cong Y, Weaver CT et al.
Monoclonal anti-interleukin 23 reverses
active colitis in a T cell-mediated model in
mice. Gastroenterology 132(7), 2359–2370
and Th2 signature cytokines, recruitment of inflammatory cells
and organization of secondary and tertiary lymphoid structures.
Future work should focus on dissecting the role and function
of IL-23-responsive adaptive and innate cells in the intestine in
homeostasis and disease. We envisage that a better understanding
of this novel, composite and inter-regulated immune response
will lead to the development of specific and effective treatments
for patients with IBD.
Financial & competing interests disclosure
This work was supported by the Wellcome Trust and the Lee Placito Medical
Fund. The authors have no other relevant affiliations or financial involve-
ment with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
25 Li Y, Chu N, Hu A, Gran B, Rostami A,
Zhang GX. Increased IL-23p19 expression
in multiple sclerosis lesions and its
induction in microglia. Brain 130(Pt 2),
26 Lee E, Trepicchio WL, Oestreicher JL et al.
Increased expression of interleukin 23 p19
and p40 in lesional skin of patients with
psoriasis vulgaris. J. Exp. Med. 199(1),
27 Kim HR, Cho ML, Kim KW et al.
Up-regulation of IL-23p19 expression in
rheumatoid arthritis synovial fibroblasts by
IL-17 through PI3-kinase-, NF-kB- and
p38 MAPK-dependent signalling pathways.
Rheumatology (Oxford) 46(1), 57–64
28 Langrish CL, McKenzie BS, Wilson NJ,
de Waal Malefyt R, Kastelein RA, Cua DJ.
IL-12 and IL-23: master regulators of
innate and adaptive immunity. Immunol.
Rev. 202, 96–105 (2004).
29 Trinchieri G. Interleukin-12 and the
regulation of innate resistance and adaptive
immunity. Nat. Rev. Immunol. 3(2),
30 Willenborg DO, Fordham S, Bernard CC,
Cowden WB, Ramshaw IA. IFN-g plays a
critical down-regulatory role in the
induction and effector phase of myelin
J. Immunol. 157(8), 3223–3227 (1996).
31 Krakowski M, Owens T. Interferon-g
confers resistance to experimental allergic
encephalomyelitis. Eur. J. Immunol. 26(7),
32 Duong TT, St Louis J, Gilbert JJ,
Finkelman FD, Strejan GH. Effect of
anti-interferon-g and anti-interleukin-2
monoclonal antibody treatment on the
development of actively and passively
induced experimental allergic
encephalomyelitis in the SJL/J mouse.
J. Neuroimmunol. 36(2–3), 105–115
33 Billiau A, Heremans H, Vandekerckhove F
et al. Enhancement of experimental allergic
encephalomyelitis in mice by antibodies
against IFN-g. J. Immunol. 140(5),
34 Oppmann B, Lesley R, Blom B et al. Novel
p19 protein engages IL-12p40 to form a
cytokine, IL-23, with biological activities
similar as well as distinct from IL-12.
Immunity 13(5), 715–725 (2000).
35 Stallmach A, Giese T, Schmidt C, Ludwig
B, Mueller-Molaian I, Meuer SC.
Cytokine/chemokine transcript profiles
reflect mucosal inflammation in Crohn’s
disease. Int. J. Colorectal. Dis. 19(4),
36 LeibundGut-Landmann S, Gross O,
Robinson MJ et al. Syk- and CARD9-
dependent coupling of innate immunity to
the induction of T helper cells that
produce interleukin 17. Nat. Immunol.
8(6), 630–638 (2007).
37 Re F, Strominger JL. Toll-like receptor 2
(TLR2) and TLR4 differentially activate
human dendritic cells. J. Biol. Chem.
276(40), 37692–37699 (2001).
38 van Beelen AJ, Zelinkova Z, Taanman-
Kueter EW et al. Stimulation of the
intracellular bacterial sensor NOD2
programs dendritic cells to promote
interleukin-17 production in human
memory T cells. Immunity 27(4),
39 Sheibanie AF, Tadmori I, Jing H,
Vassiliou E, Ganea D. Prostaglandin E2
induces IL-23 production in bone
marrow-derived dendritic cells. FASEB J.
18(11), 1318–1320 (2004).
40 Parham C, Chirica M, Timans J et al.
A receptor for the heterodimeric cytokine
IL-23 is composed of IL-12Rb1 and a
novel cytokine receptor subunit, IL-23R.
J. Immunol. 168(11), 5699–5708 (2002).
41 Awasthi A, Riol-Blanco L, Jager A et al.
Cutting edge: IL-23 receptor gfp reporter
mice reveal distinct populations of
IL-17-producing cells. J. Immunol.
182(10), 5904–5908 (2009).
42 Buonocore S, Ahern PP, Uhlig HH et al.
Innate lymphoid cells drive interleukin-
23-dependent innate intestinal pathology.
Nature 464(7293), 1371–1375 (2010).
43 Huang W, Na L, Fidel PL,
Schwarzenberger P. Requirement of
interleukin-17A for systemic anti-Candida
albicans host defense in mice. J. Infect.
Dis. 190(3), 624–631 (2004).
44 Mangan PR, Harrington LE, O’Quinn
DB et al. Transforming growth factor-b
induces development of the T(h)17
lineage. Nature 441(7090), 231–234
45 Ye P, Garvey PB, Zhang P et al.
Interleukin-17 and lung host defense
against Klebsiella pneumoniae infection.
Am. J. Respir. Cell. Mol. Biol. 25(3),
46 Khader SA, Bell GK, Pearl JE et al. IL-23
and IL-17 in the establishment of
protective pulmonary CD4+ T cell
responses after vaccination and during
Mycobacterium tuberculosis challenge. Nat.
Immunol. 8(4), 369–377 (2007).
47 Langrish CL, Chen Y, Blumenschein WM
et al. IL-23 drives a pathogenic T cell
population that induces autoimmune
inflammation. J. Exp. Med. 201(2),
48 Korn T, Bettelli E, Oukka M, Kuchroo
VK. IL-17 and Th17 cells. Annu. Rev.
Immunol. 27, 485–517 (2009).
49 Stritesky GL, Yeh N, Kaplan MH. IL-23
promotes maintenance but not
commitment to the Th17 lineage.
J. Immunol. 181(9), 5948–5955 (2008).
50 McGeachy MJ, Chen Y, Tato CM et al.
The interleukin 23 receptor is essential for
the terminal differentiation of interleukin
17-producing effector T helper cells in vivo.
Nat. Immunol. 10(3), 314–324 (2009).
51 Veldhoen M, Hocking RJ, Atkins CJ,
Locksley RM, Stockinger B. TGFb in the
context of an inflammatory cytokine milieu
supports de novo differentiation of
IL-17-producing T cells. Immunity 24(2),
52 Bettelli E, Carrier Y, Gao W et al.
Reciprocal developmental pathways for the
generation of pathogenic effector Th17 and
regulatory T cells. Nature 441(7090),
53 Zhou L, Ivanov II, Spolski R et al. IL-6
programs T(h)-17 cell differentiation by
promoting sequential engagement of the
IL-21 and IL-23 pathways. Nat. Immunol.
8(9), 967–974 (2007).
54 Nurieva R, Yang XO, Martinez G et al.
Essential autocrine regulation by IL-21 in
the generation of inflammatory T cells.
Nature 448(7152), 480–483 (2007).
55 Korn T, Bettelli E, Gao W et al. IL-21
initiates an alternative pathway to induce
proinflammatory T(h)17 cells. Nature
448(7152), 484–487 (2007).
56 Chung Y, Chang SH, Martinez GJ et al.
Critical regulation of early Th17 cell
differentiation by interleukin-1 signaling.
Immunity 30(4), 576–587 (2009).
57 Sutton C, Brereton C, Keogh B, Mills KH,
Lavelle EC. A crucial role for interleukin
(IL)-1 in the induction of IL-17-producing
T cells that mediate autoimmune
encephalomyelitis. J. Exp. Med. 203(7),
58 Ivanov II, McKenzie BS, Zhou L et al.
The orphan nuclear receptor RORgt directs
Geremia & Jewell
the differentiation program of
proinflammatory IL-17+ T helper cells. Cell
126(6), 1121–1133 (2006).
59 Zhang F, Meng G, Strober W. Interactions
among the transcription factors Runx1,
RORgt and Foxp3 regulate the
differentiation of interleukin 17-producing
T cells. Nat. Immunol. 9(11), 1297–1306
60 Yang XO, Pappu BP, Nurieva R et al.
T helper 17 lineage differentiation is
programmed by orphan nuclear receptors
ROR a and ROR g. Immunity 28(1),
61 Kimura A, Naka T, Nohara K, Fujii-
Kuriyama Y, Kishimoto T. Aryl
hydrocarbon receptor regulates Stat1
activation and participates in the
development of Th17 cells. Proc. Natl Acad.
Sci. USA 105(28), 9721–9726 (2008).
62 Veldhoen M, Hirota K, Westendorf AM
et al. The aryl hydrocarbon receptor links
Th17-cell-mediated autoimmunity to
environmental toxins. Nature 453(7191),
63 Huber M, Brustle A, Reinhard K et al.
IRF4 is essential for IL-21-mediated
induction, amplification, and stabilization
of the Th17 phenotype. Proc. Natl Acad.
Sci. USA 105(52), 20846–20851 (2008).
64 Harris TJ, Grosso JF, Yen HR et al.
Cutting edge: an in vivo requirement for
STAT3 signaling in Th17 development and
J. Immunol. 179(7), 4313–4317 (2007).
65 Bauquet AT, Jin H, Paterson AM et al.
The costimulatory molecule ICOS
regulates the expression of c-Maf and IL-21
in the development of follicular T helper
cells and Th-17 cells. Nat. Immunol. 10(2),
66 Park H, Li Z, Yang XO et al. A distinct
lineage of CD4 T cells regulates tissue
inflammation by producing interleukin 17.
Nat. Immunol. 6(11), 1133–1141 (2005).
67 Nakae S, Iwakura Y, Suto H, Galli SJ.
Phenotypic differences between Th1 and
Th17 cells and negative regulation of Th1
cell differentiation by IL-17. J. Leukoc. Biol.
81(5), 1258–1268 (2007).
68 Zheng SG, Gray JD, Ohtsuka K, Yamagiwa
S, Horwitz DA. Generation ex vivo of
TGF-b-producing regulatory T cells from
CD4+CD25- precursors. J. Immunol.
169(8), 4183–4189 (2002).
69 Chen W, Jin W, Hardegen N et al.
Conversion of peripheral CD4+CD25-
naive T cells to CD4+CD25+ regulatory
T cells by TGF-b induction of
transcription factor Foxp3. J. Exp. Med.
198(12), 1875–1886 (2003).
70 Ghoreschi K, Laurence A, Yang XP et al.
Generation of pathogenic T(h)17 cells in
the absence of TGF-b signalling. Nature
467(7318), 967–971 (2010).
71 Acosta-Rodriguez EV, Napolitani G,
Lanzavecchia A, Sallusto F. Interleukins 1b
and 6 but not transforming growth
factor-b are essential for the differentiation
of interleukin 17-producing human T
helper cells. Nat. Immunol. 8(9), 942–949
72 Wilson NJ, Boniface K, Chan JR et al.
Development, cytokine profile and
function of human interleukin
17-producing helper T cells. Nat. Immunol.
8(9), 950–957 (2007).
73 Manel N, Unutmaz D, Littman DR. The
differentiation of human T(h)-17 cells
requires transforming growth factor-b and
induction of the nuclear receptor RORgt.
Nat. Immunol. 9(6), 641–649 (2008).
74 Volpe E, Servant N, Zollinger R et al.
A critical function for transforming growth
factor-b, interleukin 23 and
proinflammatory cytokines in driving and
modulating human T(h)-17 responses.
Nat. Immunol. 9(6), 650–657 (2008).
75 Yang L, Anderson DE, Baecher-Allan C
et al. IL-21 and TGF-b are required for
differentiation of human T(h)17 cells.
Nature 454(7202), 350–352 (2008).
76 Cosmi L, De Palma R, Santarlasci V et al.
Human interleukin 17-producing cells
originate from a CD161+CD4+ T cell
precursor. J. Exp. Med. 205(8), 1903–1916
77 Kleinschek MA, Boniface K, Sadekova S
et al. Circulating and gut-resident human
Th17 cells express CD161 and promote
intestinal inflammation. J. Exp. Med.
206(3), 525–534 (2009).
78 Acosta-Rodriguez EV, Rivino L, Geginat J
et al. Surface phenotype and antigenic
specificity of human interleukin
17-producing T helper memory cells. Nat.
Immunol. 8(6), 639–646 (2007).
79 Cua DJ, Tato CM. Innate IL-17-producing
cells: the sentinels of the immune system.
Nat. Rev. Immunol. 10(7), 479–489
80 Chua WJ, Hansen TH. Bacteria,
mucosal-associated invariant T cells and
MR1. Immunol. Cell Biol. 88(8), 767–769
81 Lochner M, Peduto L, Cherrier M et al.
In vivo equilibrium of proinflammatory
IL-17+ and regulatory IL-10+ Foxp3+
RORg t+ T cells. J. Exp. Med. 205(6),
82 Martin B, Hirota K, Cua DJ, Stockinger B,
Veldhoen M. Interleukin-17-producing gd
T cells selectively expand in response to
pathogen products and environmental
signals. Immunity 31(2), 321–330 (2009).
83 Roark CL, French JD, Taylor MA, Bendele
AM, Born WK, O’Brien RL. Exacerbation
of collagen-induced arthritis by oligoclonal,
IL-17-producing gd T cells. J. Immunol.
179(8), 5576–5583 (2007).
84 Sutton CE, Lalor SJ, Sweeney CM,
Brereton CF, Lavelle EC, Mills KH.
Interleukin-1 and IL-23 induce innate
IL-17 production from gd T cells,
amplifying Th17 responses and
autoimmunity. Immunity 31(2), 331–341
85 Ito Y, Usui T, Kobayashi S et al. gd T cells
are the predominant source of
interleukin-17 in affected joints in
collagen-induced arthritis, but not in
rheumatoid arthritis. Arthritis Rheum.
60(8), 2294–2303 (2009).
86 Ness-Schwickerath KJ, Jin C, Morita CT.
Cytokine requirements for the
differentiation and expansion of IL-17A-
and IL-22-producing human Vg2Vd2 T
cells. J. Immunol. 184(12), 7268–7280
87 Michel ML, Keller AC, Paget C et al.
Identification of an IL-17-producing
NK1.1(neg) iNKT cell population involved
in airway neutrophilia. J. Exp. Med.
204(5), 995–1001 (2007).
88 Rachitskaya AV, Hansen AM, Horai R
et al. Cutting edge: NKT cells
constitutively express IL-23 receptor and
RORgt and rapidly produce IL-17 upon
receptor ligation in an IL-6-independent
fashion. J. Immunol. 180(8), 5167–5171
89 Dusseaux M, Martin E, Serriari N et al.
Human MAIT cells are xenobiotic-
resistant, tissue-targeted, CD161hi
IL-17-secreting T cells. Blood 117(4),
90 Northfield JW, Kasprowicz V, Lucas M
et al. CD161 expression on hepatitis C
virus-specific CD8+ T cells suggests a
distinct pathway of T cell differentiation.
Hepatology 47(2), 396–406 (2008).
91 Billerbeck E, Kang YH, Walker L et al.
Analysis of CD161 expression on human
CD8+ T cells defines a distinct functional
subset with tissue-homing properties. Proc.
Natl Acad. Sci. USA 107(7), 3006–3011
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
92 Takatori H, Kanno Y, Watford WT et al.
Lymphoid tissue inducer-like cells are an
innate source of IL-17 and IL-22. J. Exp.
Med. 206(1), 35–41 (2009).
93 Vondenhoff MF, Kraal G, Mebius RE.
Lymphoid organogenesis in brief. Eur. J.
Immunol. 37(Suppl. 1), S46–S52 (2007).
94 Mebius RE, Rennert P, Weissman IL.
Developing lymph nodes collect
CD4+CD3- LTb+ cells that can differentiate
to APC, NK cells, and follicular cells but
not T or B cells. Immunity 7(4), 493–504
95 Randall TD, Carragher DM, Rangel-
Moreno J. Development of secondary
lymphoid organs. Annu. Rev. Immunol. 26,
96 Cupedo T, Crellin NK, Papazian N et al.
Human fetal lymphoid tissue-inducer cells
are interleukin 17-producing precursors to
RORC+ CD127+ natural killer-like cells.
Nat. Immunol. 10(1), 66–74 (2009).
97 Schmutz S, Bosco N, Chappaz S et al.
Cutting edge: IL-7 regulates the peripheral
pool of adult RORg+ lymphoid tissue
inducer cells. J. Immunol. 183(4),
98 Cella M, Fuchs A, Vermi W et al. A human
natural killer cell subset provides an innate
source of IL-22 for mucosal immunity.
Nature 457(7230), 722–725 (2009).
99 Crellin NK, Trifari S, Kaplan CD, Cupedo
T, Spits H. Human NKp44+IL-22+ cells
and LTi-like cells constitute a stable
RORC+ lineage distinct from conventional
natural killer cells. J. Exp. Med. 207(2),
100 Satoh-Takayama N, Lesjean-Pottier S,
Vieira P et al. IL-7 and IL-15 independently
program the differentiation of intestinal
CD3-NKp46+ cell subsets from Id2-
dependent precursors. J. Exp. Med. 207(2),
101 Crellin NK, Trifari S, Kaplan CD,
Satoh-Takayama N, Di Santo JP, Spits H.
Regulation of cytokine secretion in human
CD127(+) LTi-like innate lymphoid cells by
Toll-like receptor 2. Immunity 33(5),
102 Moro K, Yamada T, Tanabe M et al. Innate
production of T(h)2 cytokines by adipose
tissue-associated c-Kit(+)Sca-1(+) lymphoid
cells. Nature 463(7280), 540–544 (2009).
103 Neill DR, Wong SH, Bellosi A et al.
Nuocytes represent a new innate effector
leukocyte that mediates Type 2 immunity.
Nature 464(7293), 1367–1370 (2010).
104 Hueber AJ, Asquith DL, Miller AM et al.
Mast cells express IL-17A in rheumatoid
arthritis synovium. J. Immunol. 184(7),
105 Li L, Huang L, Vergis AL et al. IL-17
produced by neutrophils regulates
IFN-g-mediated neutrophil migration in
mouse kidney ischemia–reperfusion injury.
J. Clin. Invest. 120(1), 331–342 (2010).
106 Yang XO, Panopoulos AD, Nurieva R et al.
STAT3 regulates cytokine-mediated
generation of inflammatory helper T cells.
J. Biol. Chem. 282(13), 9358–9363 (2007).
107 Wright JF, Guo Y, Quazi A et al.
Identification of an interleukin 17F/17A
heterodimer in activated human CD4+
T cells. J. Biol. Chem. 282(18),
108 Yao Z, Spriggs MK, Derry JM et al.
Molecular characterization of the human
interleukin (IL)-17 receptor. Cytokine
9(11), 794–800 (1997).
109 Toy D, Kugler D, Wolfson M et al. Cutting
edge: interleukin 17 signals through a
heteromeric receptor complex. J. Immunol.
177(1), 36–39 (2006).
110 Kuestner RE, Taft DW, Haran A et al.
Identification of the IL-17 receptor related
molecule IL-17RC as the receptor for
IL-17F. J. Immunol. 179(8), 5462–5473
111 Xu S, Cao X. Interleukin-17 and its
expanding biological functions. Cell. Mol.
Immunol. 7(3), 164–174 (2010).
112 Kawaguchi M, Onuchic LF, Li XD et al.
Identification of a novel cytokine, ML-1,
and its expression in subjects with asthma.
J. Immunol. 167(8), 4430–4435 (2001).
113 Kawaguchi M, Kokubu F, Odaka M et al.
Induction of granulocyte-macrophage
colony-stimulating factor by a new
cytokine, ML-1 (IL-17F), via
Raf I–MEK–ERK pathway. J. Allergy Clin.
Immunol. 114(2), 444–450 (2004).
114 Yang XO, Chang SH, Park H et al.
Regulation of inflammatory responses by
IL-17F. J. Exp. Med. 205(5), 1063–1075
115 Liang SC, Tan XY, Luxenberg DP et al.
Interleukin (IL)-22 and IL-17 are
coexpressed by Th17 cells and cooperatively
enhance expression of antimicrobial
peptides. J. Exp. Med. 203(10), 2271–2279
116 Ishigame H, Kakuta S, Nagai T et al.
Differential roles of interleukin-17A and
-17F in host defense against mucoepithelial
bacterial infection and allergic responses.
Immunity 30(1), 108–119 (2009).
117 Schwarzenberger P, Kolls JK. Interleukin 17:
an example for gene therapy as a tool to
study cytokine mediated regulation of
hematopoiesis. J. Cell Biochem. Suppl. 38,
118 Parrish-Novak J, Foster DC, Holly RD,
Clegg CH. Interleukin-21 and the IL-21
receptor: novel effectors of NK and T cell
responses. J. Leukoc. Biol. 72(5), 856–863
119 Ozaki K, Kikly K, Michalovich D, Young
PR, Leonard WJ. Cloning of a Type 1
cytokine receptor most related to the IL-2
receptor b chain. Proc. Natl Acad. Sci. USA
97(21), 11439–11444 (2000).
120 Spolski R, Leonard WJ. Interleukin-21:
basic biology and implications for cancer
and autoimmunity. Annu. Rev. Immunol.
26, 57–79 (2008).
121 Zeng R, Spolski R, Finkelstein SE et al.
Synergy of IL-21 and IL-15 in regulating
CD8+ T cell expansion and function. J. Exp.
Med. 201(1), 139–148 (2005).
122 Fantini MC, Rizzo A, Fina D et al. IL-21
regulates experimental colitis by modulating
the balance between Treg and Th17 cells.
Eur. J. Immunol. 37(11), 3155–3163 (2007).
123 Peluso I, Fantini MC, Fina D et al. IL-21
counteracts the regulatory T cell-mediated
suppression of human CD4+ T lymphocytes.
J. Immunol. 178(2), 732–739 (2007).
124 Strengell M, Matikainen S, Siren J et al.
IL-21 in synergy with IL-15 or IL-18
enhances IFN-g production in human NK
and T cells. J. Immunol. 170(11),
125 Monteleone G, Monteleone I, Fina D et al.
Interleukin-21 enhances T-helper cell Type 1
signaling and interferon-g production in
Crohn’s disease. Gastroenterology 128(3),
126 Ozaki K, Spolski R, Feng CG et al.
A critical role for IL-21 in regulating
immunoglobulin production. Science
298(5598), 1630–1634 (2002).
127 Wurster AL, Rodgers VL, Satoskar AR et al.
Interleukin 21 is a T helper (Th) cell 2
cytokine that specifically inhibits the
differentiation of naive Th cells into
interferon g-producing Th1 cells. J. Exp.
Med. 196(7), 969–977 (2002).
Geremia & Jewell
128 Ozaki K, Spolski R, Ettinger R et al.
Regulation of B cell differentiation and
plasma cell generation by IL-21, a novel
inducer of Blimp-1 and Bcl-6. J. Immunol.
173(9), 5361–5371 (2004).
129 Pene J, Gauchat JF, Lecart S et al. Cutting
edge: IL-21 is a switch factor for the
production of IgG1 and IgG3 by human B
cells. J. Immunol. 172(9), 5154–5157
130 Monteleone G, Caruso R, Fina D et al.
Control of matrix metalloproteinase
production in human intestinal fibroblasts
by interleukin 21. Gut 55(12), 1774–1780
131 Caruso R, Fina D, Peluso I et al.
A functional role for interleukin-21 in
promoting the synthesis of the T-cell
chemoattractant, MIP-3a, by gut epithelial
cells. Gastroenterology 132(1), 166–175
132 King C, Ilic A, Koelsch K, Sarvetnick N.
Homeostatic expansion of T cells during
immune insufficiency generates
autoimmunity. Cell 117(2), 265–277
133 Jin H, Oyoshi MK, Le Y et al. IL-21R is
essential for epicutaneous sensitization and
allergic skin inflammation in humans and
mice. J. Clin. Invest. 119(1), 47–60 (2009).
134 Distler JH, Jungel A, Kowal-Bielecka O
et al. Expression of interleukin-21 receptor
in epidermis from patients with systemic
sclerosis. Arthritis Rheum. 52(3), 856–864
135 Sawalha AH, Kaufman KM, Kelly JA et al.
Genetic association of interleukin-21
polymorphisms with systemic lupus
erythematosus. Ann. Rheum. Dis. 67(4),
136 Fina D, Sarra M, Fantini MC et al.
Regulation of gut inflammation and Th17
cell response by interleukin-21.
Gastroenterology 134(4), 1038–1048
137 van Heel DA, Franke L, Hunt KA et al.
A genome-wide association study for celiac
disease identifies risk variants in the region
harboring IL2 and IL21. Nat. Genet. 39(7),
138 Glas J, Stallhofer J, Ripke S et al. Novel
genetic risk markers for ulcerative colitis in
the IL2/IL21 region are in epistasis with
IL23R and suggest a common genetic
background for ulcerative colitis and celiac
disease. Am. J. Gastroenterol. 104(7),
139 Stallhofer J, Denk GU, Glas J et al.
Analysis of IL2/IL21 gene variants in
cholestatic liver diseases reveals an
association with primary sclerosing
cholangitis. Digestion 84(1), 29–35 (2011).
140 Xie MH, Aggarwal S, Ho WH et al.
Interleukin (IL)-22, a novel human
cytokine that signals through the interferon
receptor-related proteins CRF2-4 and
IL-22R. J. Biol. Chem. 275(40),
141 Wolk K, Kunz S, Witte E, Friedrich M,
Asadullah K, Sabat R. IL-22 increases the
innate immunity of tissues. Immunity
21(2), 241–254 (2004).
142 Wolk K, Witte E, Wallace E et al. IL-22
regulates the expression of genes responsible
for antimicrobial defense, cellular
differentiation, and mobility in
keratinocytes: a potential role in psoriasis.
Eur. J. Immunol. 36(5), 1309–1323 (2006).
143 Wolk K, Haugen HS, Xu W et al. IL-22
and IL-20 are key mediators of the
epidermal alterations in psoriasis while
IL-17 and IFN-g are not. J. Mol. Med.
87(5), 523–536 (2009).
144 Duhen T, Geiger R, Jarrossay D,
Lanzavecchia A, Sallusto F. Production of
interleukin 22 but not interleukin 17 by a
subset of human skin-homing memory
T cells. Nat. Immunol. 10(8), 857–863
145 Trifari S, Kaplan CD, Tran EH, Crellin
NK, Spits H. Identification of a human
helper T cell population that has abundant
production of interleukin 22 and is distinct
from T(h)-17, T(h)1 and T(h)2 cells. Nat.
Immunol. 10(8), 864–871 (2009).
146 Zheng Y, Valdez PA, Danilenko DM et al.
Interleukin-22 mediates early host defense
against attaching and effacing bacterial
pathogens. Nat. Med. 14(3), 282–289
147 Aujla SJ, Chan YR, Zheng M et al. IL-22
mediates mucosal host defense against
Gram-negative bacterial pneumonia. Nat.
Med. 14(3), 275–281 (2008).
148 Ma HL, Liang S, Li J et al. IL-22 is
required for Th17 cell-mediated pathology
in a mouse model of psoriasis-like skin
inflammation. J. Clin. Invest. 118(2),
149 Radaeva S, Sun R, Pan HN, Hong F, Gao
B. Interleukin 22 (IL-22) plays a protective
role in T cell-mediated murine hepatitis:
IL-22 is a survival factor for hepatocytes via
STAT3 activation. Hepatology 39(5),
150 Zenewicz LA, Yancopoulos GD, Valenzuela
DM, Murphy AJ, Karow M, Flavell RA.
Interleukin-22 but not interleukin-17
provides protection to hepatocytes during
acute liver inflammation. Immunity 27(4),
151 Sugimoto K, Ogawa A, Mizoguchi E et al.
IL-22 ameliorates intestinal inflammation
in a mouse model of ulcerative colitis.
J. Clin. Invest. 118(2), 534–544 (2008).
152 Zenewicz LA, Yancopoulos GD,
Valenzuela DM, Murphy AJ, Stevens S,
Flavell RA. Innate and adaptive
interleukin-22 protects mice from
inflammatory bowel disease. Immunity
29(6), 947–957 (2008).
153 Andoh A, Zhang Z, Inatomi O et al.
Interleukin-22, a member of the IL-10
subfamily, induces inflammatory responses
in colonic subepithelial myofibroblasts.
Gastroenterology 129(3), 969–984 (2005).
154 Brand S, Beigel F, Olszak T et al. IL-22 is
increased in active Crohn’s disease and
promotes proinflammatory gene expression
and intestinal epithelial cell migration.
Am. J. Physiol. Gastrointest. Liver Physiol.
290(4), G827–G838 (2006).
155 Geremia A, Arancibia-Carcamo CV,
Fleming MP et al. IL-23-responsive innate
lymphoid cells are increased in
inflammatory bowel disease. J. Exp. Med.
208(6), 1127–1133 (2011).
156 Wolk K, Witte E, Hoffmann U et al. IL-22
induces lipopolysaccharide-binding protein
in hepatocytes: a potential systemic role of
IL-22 in Crohn’s disease. J. Immunol.
178(9), 5973–5981 (2007).
157 Knappe A, Hor S, Wittmann S,
Fickenscher H. Induction of a novel
cellular homolog of interleukin-10, AK155,
by transformation of T lymphocytes with
herpesvirus saimiri. J. Virol. 74(8),
158 Wolk K, Kunz S, Asadullah K, Sabat R.
Cutting edge: immune cells as sources and
targets of the IL-10 family members?
J. Immunol. 168(11), 5397–5402 (2002).
159 Sheikh F, Baurin VV, Lewis-Antes A et al.
Cutting edge: IL-26 signals through a
novel receptor complex composed of IL-20
receptor 1 and IL-10 receptor 2.
J. Immunol. 172(4), 2006–2010 (2004).
160 Hor S, Pirzer H, Dumoutier L et al.
The T-cell lymphokine interleukin-26
targets epithelial cells through the
interleukin-20 receptor 1 and
interleukin-10 receptor 2 chains. J. Biol.
Chem. 279(32), 33343–33351 (2004).
161 Dambacher J, Beigel F, Zitzmann K et al.
The role of the novel Th17 cytokine IL-26
in intestinal inflammation. Gut 58(9),
The IL-23/IL-17 pathway in inflammatory bowel disease
Expert Rev. Gastroenterol. Hepatol. 6(2), (2012)
162 Maloy KJ, Salaun L, Cahill R, Dougan G,
Saunders NJ, Powrie F. CD4+CD25+ T(R)
cells suppress innate immune pathology
through cytokine-dependent mechanisms.
J. Exp. Med. 197(1), 111–119 (2003).
163 Powrie F, Leach MW, Mauze S, Caddle
LB, Coffman RL. Phenotypically distinct
subsets of CD4+ T cells induce or protect
from chronic intestinal inflammation in
C. B-17 scid mice. Int. Immunol. 5(11),
164 Leach MW, Bean AG, Mauze S, Coffman
RL, Powrie F. Inflammatory bowel disease
in C.B-17 scid mice reconstituted with the
CD45RBhigh subset of CD4+ T cells.
Am. J. Pathol. 148(5), 1503–1515 (1996).
165 Morrissey PJ, Charrier K, Braddy S, Liggitt
D, Watson JD. CD4+ T cells that express
high levels of CD45RB induce wasting
disease when transferred into congenic
severe combined immune deficient mice.
Disease development is prevented by
cotransfer of purified CD4+ T cells. J. Exp.
Med. 178(1), 237–244 (1993).
166 Izcue A, Hue S, Buonocore S et al.
Interleukin-23 restrains regulatory T cell
activity to drive T cell-dependent colitis.
Immunity 28(4), 559–570 (2008).
167 Ahern PP, Schiering C, Buonocore S et al.
Interleukin-23 drives intestinal
inflammation through direct activity on
T cells. Immunity 33(2), 279–288 (2010).
168 Leppkes M, Becker C, Ivanov II et al.
RORg-expressing Th17 cells induce
murine chronic intestinal inflammation via
redundant effects of IL-17A and IL-17F.
Gastroenterology 136(1), 257–267 (2009).
169 Sonnenberg GF, Monticelli LA, Elloso
MM, Fouser LA, Artis D. CD4(+)
lymphoid tissue-inducer cells promote
innate immunity in the gut. Immunity
34(1), 122–134 (2011).
170 Geddes K, Rubino SJ, Magalhaes JG et al.
Identification of an innate T helper
Type 17 response to intestinal bacterial
pathogens. Nat. Med. 17(7), 837–844
171 Becker C, Dornhoff H, Neufert C et al.
Cutting edge: IL-23 cross-regulates IL-12
production in T cell-dependent
experimental colitis. J. Immunol. 177(5),
172 Duerr RH, Taylor KD, Brant SR et al.
A genome-wide association study identifies
IL23R as an inflammatory bowel disease
gene. Science 314(5804), 1461–1463
173 Barrett JC, Hansoul S, Nicolae DL et al.
Genome-wide association defines more
than 30 distinct susceptibility loci for
Crohn’s disease. Nat. Genet. 40(8),
174 Fisher SA, Tremelling M, Anderson CA
et al. Genetic determinants of ulcerative
colitis include the ECM1 locus and five loci
implicated in Crohn’s disease. Nat. Genet.
40(6), 710–712 (2008).
175 Franke A, Balschun T, Karlsen TH et al.
Replication of signals from recent studies of
Crohn’s disease identifies previously
unknown disease loci for ulcerative colitis.
Nat. Genet. 40(6), 713–715 (2008).
176 Anderson CA, Boucher G, Lees CW et al.
Meta-analysis identifies 29 additional
ulcerative colitis risk loci, increasing the
number of confirmed associations to 47.
Nat. Genet. 43(3), 246–252 (2011).
177 Di Meglio P, Di Cesare A, Laggner U et al.
The IL23R R381Q gene variant protects
against immune-mediated diseases by
impairing IL-23-induced Th17 effector
response in humans. PLoS One 6(2),
178 Pidasheva S, Trifari S, Phillips A et al.
Functional studies on the IBD
susceptibility gene IL23R implicate reduced
receptor function in the protective genetic
variant R381Q. PLoS One 6(10), e25038
179 Sarin R, Wu X, Abraham C. Inflammatory
disease protective R381Q IL23 receptor
polymorphism results in decreased primary
CD4+ and CD8+ human T-cell functional
responses. Proc. Natl Acad. Sci. USA
108(23), 9560–9565 (2011).
180 Schmechel S, Konrad A, Diegelmann J
et al. Linking genetic susceptibility to
Crohn’s disease with Th17 cell function:
IL-22 serum levels are increased in Crohn’s
disease and correlate with disease activity
and IL23R genotype status. Inflamm. Bowel
Dis. 14(2), 204–212 (2008).
181 Jurgens M, Laubender RP, Hartl F et al.
Disease activity, ANCA, and IL23R
genotype status determine early response to
infliximab in patients with ulcerative
colitis. Am. J. Gastroenterol. 105(8),
182 Cargill M, Schrodi SJ, Chang M et al.
A large-scale genetic association study
confirms IL12B and leads to the
identification of IL23R as psoriasis-risk
genes. Am. J. Hum. Genet. 80(2), 273–290
183 Burton PR, Clayton DG, Cardon LR et al.
Association scan of 14,500 nonsynonymous
SNPs in four diseases identifies
autoimmunity variants. Nat. Genet. 39(11),
184 Franke A, McGovern DP, Barrett JC et al.
Genome-wide meta-analysis increases to 71
the number of confirmed Crohn’s disease
susceptibility loci. Nat. Genet. 42(12),
185 Arisawa T, Tahara T, Shibata T et al. The
influence of polymorphisms of interleukin-
17A and interleukin-17F genes on the
susceptibility to ulcerative colitis. J. Clin.
Immunol. 28(1), 44–49 (2008).
186 Chen B, Zeng Z, Hou J, Chen M, Gao X,
Hu P. Association of interleukin-17F 7488
single nucleotide polymorphism and
inflammatory bowel disease in the Chinese
population. Scand. J. Gastroenterol. 44(6),
187 Seiderer J, Elben I, Diegelmann J et al. Role
of the novel Th17 cytokine IL-17F in
inflammatory bowel disease (IBD):
upregulated colonic IL-17F expression in
active Crohn’s disease and analysis of the
IL17F p.His161Arg polymorphism in IBD.
Inflamm. Bowel Dis. 14(4), 437–445
188 Schmidt C, Giese T, Ludwig B et al.
Expression of interleukin-12-related
cytokine transcripts in inflammatory bowel
disease: elevated interleukin-23p19 and
interleukin-27p28 in Crohn’s disease but not
in ulcerative colitis. Inflamm. Bowel Dis.
11(1), 16–23 (2005).
189 Fuss IJ, Becker C, Yang Z et al. Both
IL-12p70 and IL-23 are synthesized during
active Crohn’s disease and are down-
regulated by treatment with anti-IL-12 p40
monoclonal antibody. Inflamm. Bowel Dis.
12(1), 9–15 (2006).
190 Holtta V, Klemetti P, Sipponen T et al.
IL-23/IL-17 immunity as a hallmark of
Crohn’s disease. Inflamm. Bowel Dis. 14(9),
191 Fujino S, Andoh A, Bamba S et al. Increased
expression of interleukin 17 in inflammatory
bowel disease. Gut 52(1), 65–70 (2003).
192 Nielsen OH, Kirman I, Rudiger N, Hendel
J, Vainer B. Upregulation of interleukin-12
and -17 in active inflammatory bowel
disease. Scand. J. Gastroenterol. 38(2),
193 Kobayashi T, Okamoto S, Hisamatsu T
et al. IL23 differentially regulates the
Geremia & Jewell
www.expert-reviews.com Download full-text
Th1/Th17 balance in ulcerative colitis and
Crohn’s disease. Gut 57(12), 1682–1689
194 Kaser A, Ludwiczek O, Holzmann S et al.
Increased expression of CCL20 in human
inflammatory bowel disease. J. Clin.
Immunol. 24(1), 74–85 (2004).
195 Brand S, Olszak T, Beigel F et al. Cell
differentiation dependent expressed
CCR6 mediates ERK-1/2, SAPK/JNK,
and Akt signaling resulting in
proliferation and migration of colorectal
cancer cells. J. Cell. Biochem. 97(4),
196 Talley NJ, Abreu MT, Achkar JP et al.
An evidence-based systematic review on
medical therapies for inflammatory bowel
disease. Am. J. Gastroenterol. 106
(Suppl. 1), S2–S25 (2011).
197 Hueber W, Sands BE, Lewitzky S et al.;
for the Secukinumab in Crohn’s Disease
Study Group. Secukinumab, a human
anti-IL17A monoclonal antibody, for
moderate to severe Crohn’s disease:
randomized, double-blind placebo
controlled trial. Gut (2012) (In Press).
198 Hu Y, Shen F, Crellin NK, Ouyang W.
The IL-17 pathway as a major therapeutic
target in autoimmune diseases. Ann. NY
Acad. Sci. 1217, 60–76 (2011).
199 Hueber W, Sands BE, Vandemeulebroecke
M et al. Inhibition of IL-17A by
secukinumab is ineffective for Crohn’s
disease (CD). Presented at: 6th ECCO
Congress. Dublin, Ireland, 24–26
200 Noguchi D, Wakita D, Tajima M et al.
Blocking of IL-6 signaling pathway
prevents CD4+ T cell-mediated colitis in a
T(h)17-independent manner. Int. Immunol.
19(12), 1431–1440 (2007).
201 Zhang Z, Zheng M, Bindas J,
Schwarzenberger P, Kolls JK. Critical role
of IL-17 receptor signaling in acute
TNBS-induced colitis. Inflamm. Bowel Dis.
12(5), 382–388 (2006).
The IL-23/IL-17 pathway in inflammatory bowel disease