Immunity
Review
Functional Specialization
of Interleukin-17 Family Members
Yoichiro Iwakura,1,5,* Harumichi Ishigame,2 Shinobu Saijo,3 and Susumu Nakae4
1Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science,
The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan
2Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
3Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku,
Chiba 260-8673, Japan
4Frontier Research Initiative, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo,
108-8639, Japan
5Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
*Correspondence: iwakura@ims.u-tokyo.ac.jp
DOI 10.1016/j.immuni.2011.02.012
Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17
has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid
sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity,
inflammation, and tumors, and also plays important roles in the host defenses against bacterial and
fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25)
is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive.
In this review, we describe the identified functions of each IL-17 family member and discuss the potential of
these molecules as therapeutic targets.
Introduction
Interleukin-17A (IL-17A), also commonly called IL-17, is
produced by the T helper 17 (Th17) subset of CD4+ T cells. The
discovery of Th17 cells has been one of the most important
advances in T cell immunology since the discovery of Th1 and
Th2 cells by Mosmann, Coffman, and their colleagues more
than two decades ago (Mosmann et al., 1986). Th17 cells preferentially produce IL-17A, IL-17F, IL-21, and IL-22 (McGeachy and
Cua, 2008), whereas Th1 and Th2 cells mainly produce interferon-g (IFN-g) and IL-4, respectively. Recent progress in studies
of IL-17A and Th17 cells has revealed important roles for IL-17A
in the development of allergic and autoimmune diseases as well
as in protective mechanisms against bacterial and fungal infections, functions that were previously believed to be mediated
by Th1 or Th2 cells.
The Il17a gene, originally called the cytotoxic T lymphocyte
associated antigen 8 (Ctla8) gene, was first cloned from a murine
cytotoxic T lymphocyte (CTL) hybridoma cDNA library. Murine
IL-17A is a 21 kDa glycoprotein containing 147 amino acid residues that shares 63% amino acid identity with human IL-17A
(155 amino acids), and both mouse and human IL-17A are
secreted as disulfide-linked homodimers. Five additional structurally related cytokines were recently identified: IL-17B,
IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F to form
the IL-17 family (Kolls and Lindén, 2004; Weaver et al., 2007)
and each additional member of the IL-17 family shares 16%–
50% amino acid identity with IL-17A. Among the family members
(Table 1), IL-17A and IL-17F share the highest amino acid
sequence identity (50%), whereas IL-17E is the most divergent,
with 16% identity to IL-17A. Amino acid similarity is higher in the
C terminus and in five spatially conserved cysteine residues, four
of which form a cystine knot fold that differs from the canonical
cystine knot that is observed in transforming growth factor
(TGF)-b, bone morphogenic protein, and nerve growth factor
superfamilies as a result of the absence of two cysteine residues
(Gerhardt et al., 2009; Hymowitz et al., 2001). The sequences of
IL-17B, IL-17C, and IL-17E differ substantially from those of
IL-17A and IL-17F in the N terminus, with longer extensions for
the former three proteins. Furthermore, IL-17B is secreted as
a noncovalent dimer, suggesting that IL-17B, IL-17C, and
IL-17E may form a distinct subclass (Gerhardt et al., 2009;
Hymowitz et al., 2001). The Il17f gene is closely located to the
Il17a gene in both humans and mice (mouse chromosome 1,
human chromosome 6, respectively), whereas genes for the
other members are located on different chromosomes.
The IL-17 receptor (IL-17R) family includes five members
(IL-17RA to IL-17RE), which contain such conserved structural
characteristics as extracellular fibronectin III-like domains and
cytoplasmic similar expression to fibroblast growth factor,
IL-17R, and Toll-IL-1R family (SEFIR) domains (reviewed in
Gaffen, 2009). Functional receptors for IL-17 family cytokines
are thought to consist of homodimers or heterodimers (Figure 1).
For example, the heterodimer of IL-17RA and IL-17RC is a receptor for homodimers and heterodimers of IL-17A and IL-17F,
whereas the heterodimer consisting of IL-17RA and IL-17RB
serves as a receptor for IL-17E. Both IL-17B and IL-17E bind
to IL-17RB. IL-17C was recently reported to bind to IL-17RE
and activate NF-kB. IL-17RD, also called Sef, is preferentially expressed in endothelial, epithelial, and smooth muscle cells, but
not leukocytes. The ligands for this receptor, however, have
yet to be identified.
Of note, IL-17A, IL-17B, IL-17C, and IL-17F, but not IL-17E,
can induce the expression of proinflammatory cytokines such
as tumor necrosis factor (TNF) and IL-1b from fibroblasts and
peritoneal exudate cells and promote neutrophil migration, suggesting that these family members play similar roles in the
Immunity 34, February 25, 2011 ª2011 Elsevier Inc. 149
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Table 1. Mouse IL-17 Family Members
Percent
Homology
with IL-17A
Percent
Homology
with Human
Ligand
Receptor
Producer Cells
Target Cells
Proposed Functions
IL-17A
(IL-17)
IL-17RA
and IL-17RC
100
63
CD4+ T cell, CD8+ T cell, gd
T cell, NKT cell, LTi-like cell,
neutrophil and Paneth cell
epithelial cell, fibroblast,
keratinocyte, synoviocyte,
endothelial cell, T cell, B cell
and macrophage
proinflammatory cytokine
and chemokine induction;
neutrophil recruitment;
antimicrobial peptide
induction;
osteoclastogenesis;
angiogenesis; promotion of
T cell priming and Ab
production
IL-17B
IL-17RB
24
88
chondrocyte and neuron
monocyte and endothelial
cell
proinflammatory cytokine
induction; neutrophil
recruitment
IL-17C
IL-17RE
26
83
CD4+ T cell, DC,
macrophage and
keratinocyte
monocyte
proinflammatory cytokine
induction; neutrophil
recruitment
IL-17D
unknown
30
78
CD4+ T cell and B cell
endothelial cell and myeloid
progenitor
proinflammatory cytokine
induction
IL-17E
(IL-25)
IL-17RA
and IL-17RB
16
81
CD4+ cell, CD8+ T cell, mast
cell, eosinophil, epithelial cell
and endothelial cell
T cell, macrophage,
epithelial cell, NHC,
MMPtype2 cell, nuocyte, and
Ih2 cell
eosinophil recruitment;
promotion of Th2 and Th9
cell responses; suppression
of Th1 and Th17 cell
responses
IL-17F
IL-17RA
and IL-17RC
50
77
CD4+ cell, CD8+ T cell, gd
T cell, NKT cell, LTi-like cell,
and epithelial cell
epithelial cell, fibroblast,
keratinocyte, synoviocyte
and endothelial cell
proinflammatory cytokine
and chemokine induction;
neutrophil recruitment;
antimicrobial peptide
induction
LTi ; lymphoid tissue inducer, DC; dendritic cell, NHC ; natural helper cell, MMPtype2; multipotent progenitor type2, Ih2; innate type 2 helper.
development of certain diseases. Alternatively, IL-17E appears
to be involved in promoting Th2 cell-type immune responses.
However, the functional roles of other members of the IL-17
family have not been as well characterized as IL-17A. In this
review, we will summarize the recent progress of functional
studies of these IL-17 family cytokines in diseases and discuss
areas for future research.
IL-17F is a weaker inducer of proinflammatory cytokine expression and is produced by a wider range of cell types, including
innate immune cells and epithelial cells. Moreover, the tissue
distribution of IL-17RA and IL-17RC is different. These differences may result in some functional specialization of these
cytokines.
IL-17A and IL-17F
IL-17A and IL-17F are highly homologous and bind to the same
receptor. Furthermore, IL-17A and IL-17F can both be secreted
as disulfide-linked homodimers or heterodimers. Thus, these
two molecules are likely to have similar biological activities
(reviewed in Iwakura et al., 2008; Reynolds et al., 2010). Indeed,
both IL-17A and IL-17F are involved in the development of
inflammation and host defense against infection by inducing
the expression of genes encoding proinflammatory cytokines
(TNF, IL-1, IL-6, G-CSF, and GM-CSF), chemokines (CXCL1,
CXCL5, IL-8, CCL2, and CCL7), antimicrobial peptides (defensins and S100 proteins), and matrix metalloproteinases
(MMP1, MMP3, and MMP13) from fibroblasts, endothelial cells,
and epithelial cells (Figure 2). IL-17A also promotes SCF- and
G-CSF-mediated granulopoiesis and recruits neutrophils to the
inflammatory sites. IL-17A also induces the expression of intercellular cell adhesion molecule 1 (ICAM-1) in keratinocytes as
well as iNOS and cyclooxygenase-2 in chondrocytes. However,
IL-17A and IL-17F Producer Cells
IL-17A and IL-17F were initially reported to be predominantly
expressed in activated T cells. Linking IL-17A- and IL-17Fproducing CD4+ T cells to IL-23 effector function led to the
concept that Th17 cells belong to a distinct CD4+ T cell subset
(McGeachy and Cua, 2008). Th17 cell differentiation from naive
CD4+ T cells is controlled by several cytokines including
TGF-b, IL-6, and IL-21, which activate Stat3- and IRF4-dependent expression of retinoic acid receptor-related orphan
receptor-gt (RORgt) (reviewed in Hirahara et al., 2010; Korn
et al., 2009; Zhou and Littman, 2009). Other transcription factors,
such as RORa, basic leucine zipper transcription factor (Batf),
Runx1, and IkBz, also regulate Th17 cell differentiation in cooperation with RORgt. Both IL-1 and IL-23 are also critical for Th17
cell differentiation, growth, survival, and effector functions. In
humans, IL-1b, IL-21, IL-23, and TGF-b are required for the
development of Th17 cells expressing IL-17A, IL-17F, IL-22,
and RORgt, although the requirement for TGF-b in human
150 Immunity 34, February 25, 2011 ª2011 Elsevier Inc.
Immunity
Review
IL-17RC
Act1
Act1
TRAF6
?
IL-17RA
IL-17B
IL-17RB
Act1
TRAF3
Unknown
TRAF6
TAK1
FnIII
ERK
MAPK
AP-1
IL-17D
Act1
TRAF6
TAK1
IL-17C
IL-17RD
IL-17RA
IL-17E (IL-25)
Unknown
IL-17F
IL-17RE
IL-17A+F
IL-17RB
IL-17A
MAPK
NF-κB
C/EBP
AP-1
SEFIR
NF-κB
C/EBP
Figure 1. IL-17 and the IL-17 Receptor Families
Six IL-17 family cytokines (IL-17A to IL-17F) and five IL-17R family molecules (IL-17RA to IL-17RE) have been identified. After binding of an IL-17A or IL-17F
homodimer or heterodimer to IL-17R (the heterodimer of IL-17RA and IL-17RC), Act1 associates with IL-17RA and/or IL-17RC through its SEFIR domains.
Subsequently, the complex associates with TRAF6, leading to the activation of NF-kB, MAPK-AP-1, and C/EBP. Downstream of IL-17R, TRAF3 also associates
with Act1 to inhibit Act1-TRAF6-mediated activation of transcription factors. Act1-independent ERK activation also contributes to IL-17R signaling via an
unknown molecule (?). Similar to signaling via IL-17R, IL-17E (IL-25) binding to IL-25R (heterodimer of IL-17RA and IL-17RB) results in activation of NF-kB,
MAPK-AP-1, and C/EBP via recruitment of Act1 and TRAF6. IL-17RB, but not IL-17RA, contains an intracellular TRAF6-binding motif, which activates NF-kB,
but not AP-1, through TRAF6 binding. IL-17B and IL-17C bind to IL-17RB and IL-17RE, respectively; however, the downstream signaling pathway is unknown.
The ligand(s) for IL-17RD is also unknown. FnIII, fibronectin III-like domain; SEFIR, similar expression to FGF, IL-17R, and Toll-IL-1R family domain.
Th17 cell development still remains elusive (reviewed in Korn
et al., 2009).
The Th17 cell lineage is heterogeneous population. In addition
to IL-17A and IL-17F double-positive cells, populations that are
only IL-17A or IL-17F positive have been identified. The mechanisms that regulate IL-17A and IL-17F production also differ;
IL-17F is expressed earlier than IL-17A during Th17 cell development (Lee et al., 2009). Although underlying molecular mechanisms have not been described, it is likely that several mediators,
such as transcription factor or T cell receptor (TCR) signaling,
distinctly regulate the production of the cytokines. Indeed, deficiency of RORa selectively reduced IL-17A production (Yang
et al., 2008b), and IL-17A expression was more sensitive to the
strength of TCR signaling (Gomez-Rodriguez et al., 2009).
In addition to Th17 cells, a wide variety of T cells also produce
IL-17A and IL-17F. These cytokines are produced by cytotoxic
CD8+ T cells (Tc17) under conditions that are similar to those
required by Th17 cells, but different from those required by
IFN-g producing CD8+ T cells (Tc1). Similarly, distinct populations of gdT (gd-17) cells and NKT (NKT-17) cells produce
IL-17A and IL-17F (reviewed in Cua and Tato, 2010). However,
IL-23 and IL-1 can directly induce gd-17 cell development in
the absence of IL-6 and TCR ligation because, unlike naive
CD4+ and CD8+ T cells, these cells constitutively express
IL-23R, IL-1R, and RORgt. Likewise, NKT cells produce IL-17A
in the presence of IL-1 and IL-23 in combination with TCR stimulation. These two T cell populations (gd-17 and NKT-17) can
rapidly produce IL-17A and IL-17F in response to proinflammatory cytokine stimulation and may therefore provide an essential
initial source of these two cytokines.
More recently, innate lymphoid populations of neutrophils,
monocytes, natural killer cells, and lymphoid tissue inducer
(LTi)-like cells have been shown capable of rapidly producing
IL-17A and IL-17F (Cua and Tato, 2010). In addition, IL-17A is
produced by intestinal Paneth cells (Takahashi et al., 2008),
whereas IL-17F mRNA, but not IL-17A mRNA, is expressed in
colonic epithelial cells (Ishigame et al., 2009), suggesting that
IL-17A and IL-17F from nonlymphoid cells may also regulate
immune responses. Substantial efforts are underway to clarify
the mechanisms that control IL-17A and IL-17F production in
these cell types, and the relative contributions of the resulting
cytokines in immune responses.
Signaling Mechanism of IL-17A and IL-17F
Both Il17ra/ and Il17rc/ mice fail to respond to both IL-17A
and IL-17F, indicating that both IL-17RA and IL-17RC are
Immunity 34, February 25, 2011 ª2011 Elsevier Inc. 151
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T cells
Th17
Immune cells
Tc17
T cell
(Priming)
Antigen
APC
γδ-17
TGF-β
IL-6
IL-1
IL-23
Disease
development
B cell
(Antibody production)
RA, MS, IBD, psoriasis
CHS, DTH,
onatopic asthma
NKT-17
IL-17A
Innate immune cells
Macrophage
(Secrete IL-1, IL-6, TNF, IL-12)
Neutrophil
recruitment,
tissue destruction,
neovascularization
Tumor
Nonimmune cells
LTi-like cells
Host protection
IL-17F
Commensal
or pathogenic
organisms
Nonimmune cells
Paneth cell
Epithelial cell
Against fungi, bacteria
Epithelial cell, endothelial cell,
keratinocyte, synoviocyte, fibroblast
(Secrete IL-6, IL-8, TNF, G-CSF,
CXCL1, CXCL2, RANKL, MMP,
VEGF, antimicrobial peptides)
Figure 2. The Roles of IL-17A and IL-17F in the Development of Inflammatory Diseases and host Defense against Pathogens
IL-17A and IL-17F are produced by various cell types including T cells, innate immune cells, and nonimmune cells in response to cytokines such as TGF-b, IL-6,
IL-1, and IL-23, which are produced by antigen- or pathogen-stimulated antigen presenting cells (APCs). IL-17A and IL-17F activate immune cells such as T cells,
B cells, and macrophages to promote T cell priming, Ab production, and proinflammatory cytokine production, and nonimmune cells to induce many
proinflammatory mediators such as cytokines, chemokines, MMP, VEGF, RANKL, and antimicrobial peptides. These mediators induce neutrophil recruitment
at inflammatory sites, promote local tissue destruction, induce neovascularization in tumors, enhance osteoclastogenesis, and protect from pathogens, resulting
in disease development and host protection. IL-17A is mainly involved in autoimmune and allergic responses, tumor development, and host defense against
bacterial and fungal infections, whereas IL-17F plays important roles in the host defense against bacteria and inflammation in epithelial tissues.
involved in signal transduction (Figure 1) (reviewed in Gaffen,
2009). However, the expression profiles of IL-17RA and
IL-17RC are different among tissues and cell types; IL-17RA
distributed mostly immune cells, whereas IL-17RC is preferentially expressed in nonimmune cells (Ishigame et al., 2009;
Kuestner et al., 2007). In addition, the binding affinities of
IL-17A and IL-17F for these receptors are different; IL-17A has
higher affinity to IL-17RA, whereas IL-17F has higher affinity to
IL-17RC (Hymowitz et al., 2001; Kuestner et al., 2007). Therefore,
the distinct functions of IL-17A and IL-17F may reflect, at least in
part, differential expression of IL-17RA and IL-17RC, although
the precise structure of the receptors for IL-17A and IL-17F still
remains to be elucidated. Association between IL-17RA and
IL-17RC is not observed on the resting cell surface, and binding
of IL-17A to IL-17RA induces recruitment of IL-17RC to form the
IL-17RA-IL-17RC complex. The SEFIR domains of both IL-17RA
and IL-17RC are required to activate NF-kB, MAPK, and C/EBP
pathways in response to IL-17A or IL-17F (Ho et al., 2010; Hu
et al., 2010). The SEFIR domain-containing adaptor protein
Act1 (also called TRAF3IP3 and CIKS) directly associates with
IL-17RA and IL-17RC via interaction with each SEFIR domain,
resulting in the recruitment of TRAF6 and TAK1 to activate
NF-kB. Cxcl1 mRNA stabilization in response to IL-17A is dependent on Act1, but not TRAF6, whereas ERK activation is Act1
independent. TRAF3 in association with Act1 negatively regulates IL-17A-mediated NF-kB and MAPK activation (Figure 1)
(Zhu et al., 2010).
IL-17A and IL-17F in Autoimmune Diseases
Multiple sclerosis (MS) and rheumatoid arthritis (RA) have long
been believed to be a Th1 cell cytokine-mediated autoimmune
disease. Yet myelin oligodendrocyte glycoprotein (MOG)152 Immunity 34, February 25, 2011 ª2011 Elsevier Inc.
induced experimental autoimmune encephalomyelitis (EAE)
and collagen-induced arthritis (CIA) are much more severe in
mice lacking IL-12 or IFN-g activity (McGeachy and Cua,
2008), arguing against the importance of Th1 cells in these
diseases. Several studies demonstrated that IL-23 rather than
IL-12 is important for EAE and CIA development (Cua et al.,
2003; Murphy et al., 2003), suggesting involvement of Th17 cells.
Moreover, EAE and CIA development are attenuated in Il17a/
mice (Ishigame et al., 2009; Yang et al., 2008a). However, unlike
Il23a/ mice, Il17a/ mice still developed substantial inflammation after MOG immunization, suggesting that other IL-23induced mediators, such as IL-17F and IL-22, may also
contribute to the development of EAE. IL-17F, however, is not
required for EAE and CIA (Haak et al., 2009; Ishigame et al.,
2009; Yang et al., 2008a). Il22/ mice have substantially attenuated CIA (Geboes et al., 2009), whereas IL-22 is dispensable for
EAE development (Kreymborg et al., 2007). Furthermore, mice
deficient for both IL-17A and IL-17F showed no additional
suppression of these disorders (Ishigame et al., 2009), suggesting that IL-17F does not have substantial additive, synergistic, or
compensatory effects with IL-17A. It was reported that, in addition to Th17 cells, gd-17 cells are involved in the pathogenesis of
EAE and CIA (Petermann et al., 2010; Roark et al., 2007).
The roles of IL-17A have also been examined in several other
RA models. Deficient mice for IL-1 receptor antagonist (Il1rn/),
an endogenous antagonist for IL-1a and IL-1b, spontaneously
developed chronic inflammatory arthropathy, which was almost
completely suppressed in Il17a/ Il1rn/ mice, but only slightly
suppressed in Il17f/ Il1rn/ mice (Ishigame et al., 2009). The
development of arthritis was also markedly suppressed in
Il17a/ HTLV-I transgenic mice (Iwakura et al., 2008). IL-17A
plays a pathogenic role in arthritic mice carrying the Y759F
Immunity
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mutation in the gp130 subunit of the IL-6R, which disrupts
SOCS3-mediated negative feedback (Ogura et al., 2008). IL17A triggers a positive feedback loop of IL-6 signaling, including
activation of the NF-kB and Stat3 in fibroblasts, and the development of inflammation. The development of arthritis in SKG mice,
which carry a mutation in ZAP70 of the TCR complex, was also
suppressed by a lack of IL-17A (Hirota et al., 2007). The contributions of IL-17F to these disease models remain to be elucidated.
It is thought that IL-17A causes inflammation by inducing proinflammatory cytokine expression during the effector phase.
Neutralizing IL-17A signaling, however, did not affect K/BxN
serum-induced arthritis, in which autoantibodies for GPI activate
the alternative pathway of the complement activation pathway
and FcgRIII on mast cells to induce inflammatory cytokine expression (Jacobs et al., 2009). These results suggest that IL-17A is not
required during the effector phase in this setting. Because T cell
sensitization and antibody (Ab) production after immunization
with type II collagen were substantially reduced in Il17a/ mice
(Nakae et al., 2003), IL-17A may induce autoimmunity by directly
activating T cells and B cells during the sensitization phase
(Figure 2). In line with this idea, IL-17A is required for germinal
center formation and class switch recombination by directly acting
on B cells (Mitsdoerffer et al., 2010; Wu et al., 2010). A similar pathogenic role for IL-17A has been reported in systemic lupus erythematosus (SLE); IL-17A concentrations are elevated in patients
with SLE and IL-17A enhances survival, proliferation, and Ig class
switching in B cells (Doreau et al., 2009). However, the mechanism
of T cell sensitization has not been elucidated yet. Additionally,
Th17 cells also promote osteoclastogenesis as a result of RANKL
expression on the cell surface (Sato et al., 2006). The low activity of
IL-17F during autoimmune responses remains puzzling, but may
relate to weak proinflammatory cytokine-inducing activity (Yang
et al., 2008a) and limited distribution of IL-17RC in immune cells
(Ishigame et al., 2009; Kuestner et al., 2007).
Interestingly, the development of arthritis in Il1rn/, K/BxN,
and SKG mice depends on environmental factors, such as the
indigenous microbe Lactobacillus bifidus (Abdollahi-Roodsaz
et al., 2008), gut-residing segmented filamentous bacteria
(SFB) (Wu et al., 2010), and fungi (Yoshitomi et al., 2005). These
pathogens induce Th17 cell differentiation, which results in
arthritis, suggesting a link between innate immunity and autoimmune diseases.
In humans, IL-17A is detected in synovial fluids and synovium
from RA patients and induces proinflammatory cytokine production from synoviocytes (Chabaud et al., 1998). IL-17A mRNA is
also detected in cerebrospinal fluid mononuclear cells of MS
patients, and myelin peptide reactive Th17 cells are enriched in
MS patients (Venken et al., 2010). Th17 cells from MS patient
also produce IL-22 and IFN-g and preferentially cross the blood
brain barrier, suggesting involvement in the pathology (Kebir
et al., 2009).
Transferring CD4+CD45RBhi T cells into lymphopenic mice
provides a model of inflammatory bowel diseases (IBDs). IL-23
is essential for colitis development in this model, whereas neither
IL-17A nor IL-17F is required (Izcue et al., 2008; Leppkes et al.,
2009). Transferring Il17f/ CD4+CD45RBhi T cells together
with anti-IL-17A substantially reduced colitis, suggesting that
IL-17A and IL-17F play redundant roles during colitis development (Leppkes et al., 2009). In a recent study, however, mice
receiving Il17a/ CD4+ T cells displayed an accelerated wasting
disease, which was associated with increased Th1 cell-related
cytokine production, suggesting a protective role for IL-17A
(O’Connor et al., 2009). Alternatively, colitis was suppressed by
the adoptive transfer of CD4+CD45RBhi T cells that were deficient for IFN-g (Iwakura et al., 2008), highlighting the importance
of Th1 cells. Thus, both Th1 and Th17 cells are involved in the
pathogenesis of IBDs, although uncovering the precise roles of
these cells requires further elucidation. Recently, it was reported
that Helicobacter hepaticus-induced chronic colitis is associated
with IL-23-dependent production of IL-17A and IFN-g in the
colon by Thy1+SCA-1+RORgt+IL-23R+ innate lymphoid cells
(Buonocore et al., 2010). In humans, Th17 cells are detected in
the gut of Crohn’s disease patients and some of these additionally produce IFN-g (Annunziato et al., 2007). CD161+CD4+ T cells
in the gut produce IL-17A upon stimulation with IL-23, suggesting the involvement in Crohn’s disease (Kleinschek et al., 2009).
IL-17A-producing innate lymphoid cells are also found in
patients with IBDs (Buonocore et al., 2010).
The potential contribution of IL-17A to a dextran sodium
sulfate (DSS)-induced acute colitis model is controversial; one
study reported that Il17a/ mice displayed a substantially
reduced clinical score (Ito et al., 2008), whereas another study
demonstrated that mice lacking IL-17A or given anti-IL-17A
showed severe weight loss and colonic epithelial damage
(Ogawa et al., 2004; Yang et al., 2008a). Alternatively, Il17f/
mice developed attenuated colonic inflammation, which was
associated with reduced chemokine expression (Yang et al.,
2008a). Although the reason for the discrepancies in these
studies is not known at present, it is possible that intestinal
microbial flora may have differed in these studies and affected
the results. Interestingly, IL-22 has a protective role in both
DSS- and CD4+CD45RBhi T cell-induced colitis (Zenewicz
et al., 2008). This protective function of IL-22 in these models
appears to be mediated not only by CD4+ T cell-derived IL-22
but also by NK cell-derived IL-22.
Psoriasis is an inflammatory epidermal hyperproliferative skin
disease. Psoriasis-like epidermal hyperplasia was induced in
the ears of wild-type mice injected with IL-23, whereas little hyperplasia was observed in Il17a/ or Il22/ mice (Rizzo et al., 2011).
In contrast, psoriasiform dermatitis that spontaneously develops
in Il1rn/ mice was neither dependent on T cells nor IL-17A (Nakajima et al., 2010), suggesting an autoinflammatory mechanism.
Nonetheless, recent clinical studies suggest the involvement of
IL-17A in psoriasis (Hueber et al., 2010). Owing to a lack of spontaneous IL-17A-dependent psoriasis models, the precise roles of
IL-17A in this disorder remain obscure. In humans, the expression
of proinflammatory cytokines, including IL-17A, IL-22, and IL-23,
are elevated in psoriatic skins (Wilson et al., 2007), and the Tc17
and IL-22-producing CD8+ T cells (Tc22) are suggested to be
important for pathogenesis (Res et al., 2010). IL-17A in combination with TNF induces genes that are characteristic of psoriasis
from human keratinocytes. Polymorphisms in the IL23R gene
are associated with psoriasis, suggesting the involvement of
IL-23 in psoriasis (Nair et al., 2009).
IL-17A and IL-17F may also contribute to type I diabetes
mellitus (T1D). In vitro differentiated Th17 cells induce T1D in
nonobese diabetic (NOD)-severe combined immunodeficiency
(scid) mice (Bending et al., 2009). In this system, however, the
Immunity 34, February 25, 2011 ª2011 Elsevier Inc. 153
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development of diabetes was dependent on IFN-g, but not
IL-17A, suggesting that Th17 cells were reprogrammed into
Th1 cells under the lymphopenic conditions. In contrast,
adoptive transfer of IL-23-induced OTI Tc17 cells caused
IL-17A- and IL-17F-dependent diabetes in recipients that expressed OVA in b cells of the pancreas (Ciric et al., 2009). The
progression of diabetes in NOD mice was inhibited by anti-IL17A (Emamaullee et al., 2009), whereas the incidence of hyperglycemia in Il17a/ NOD mice was comparable to that in
Il17a+/+ NOD mice (Komiyama et al., 2006). Thus, the precise
role of IL-17A and IL-17F in T1D still remains to be elucidated.
IL-17A as a Target for Human Autoimmune Diseases
As pathogenic roles of IL-17A are suggested in most autoimmune diseases, clinical trials to inhibit Th17 cell development
or neutralize IL-17A have been carried out. An IL-6 receptor Ab
(tocilizumab, Hoffmann-La Roche and Chugai) is successfully
used for the treatment of RA and Crohn’s disease (Patel and
Moreland, 2010). Although the precise mechanism of the action
of this Ab is unknown, it is possible that the observed therapeutic
effects of this Ab are due, at least in part, to blockade of Th17 cell
differentiation.
A monoclonal Ab (ustekinumab) specific to p40 subunit of
IL-12 and IL-23 produced no substantial therapeutic effects in
a trial to treat patients with relapsing-remitting MS (Segal et al.,
2008). The reason for the discrepancy with the results obtained
in mouse EAE model is currently unclear, but improving an Ab
delivery system to the central nervous system may be useful.
Unlike the results for MS, the Ab to p40 subunit of IL-12 and
IL-23 improved symptoms of Crohn’s disease, similar to results
obtained by blocking IL-6 or TNF. This Ab also produced a positive result for psoriasis in a phase III trial and was substantially
superior to etanercept in another (Griffiths et al., 2010; Leonardi
et al., 2008). In addition, a phase II trial using a similar humanized
Ab to p40 subunit of IL-12 and IL-23, ABT-874, was also
successful (Kimball et al., 2011). Ustekinumab was also effective
in a phase II trial for psoriatic arthritis (Gottlieb et al., 2009).
IL-1 is also important for Th17 cell differentiation, particularly in
humans. An IL-1 receptor antagonist (anakinra) has been
successfully used for the treatment of RA (Geyer and Müller-Ladner, 2010). Because IL-1 is pleiotropic, further studies are
needed to elucidate the roles of IL-1 in the development of
arthritis and Th17 cell differentiation in humans.
Recently, a humanized IL-17A Ab, LY2439821, has been
developed to treat RA (Genovese et al., 2010). A group of 20
patients was administered once intravenously, and this was followed by an 8 week evaluation period. Another group of 77
patients received the Ab every 2 weeks for a total of five doses
with a total evaluation period of 16 weeks. Patients in both
groups showed substantial improvement. Another humanized
IL-17A Ab, AIN457, has also produced favorable results for the
treatment of RA, psoriasis, and uveitis (Hueber et al., 2010).
Groups of 36 patients with psoriasis, 52 patients with RA, and
16 patients with uveitis were given a single intravenous shots
of AIN457, and this was followed by a 6 week to 16 week evaluation period. In the RA trial, Ab-injected patients showed rapid
and substantial improvements as early as a week after the injection. Almost 75% of Ab-treated patients with psoriasis showed
improvement of their symptoms in comparison to 10% of
154 Immunity 34, February 25, 2011 ª2011 Elsevier Inc.
patients who received a placebo. Patients with uveitis showed
an amelioration of symptoms comparable to that observed in
patients treated with infliximab. Thus, blocking IL-17A is beneficial for the treatment of certain autoimmune diseases. The effect
of blocking other IL-17 family members including IL-17F has yet
to be evaluated in human diseases.
IL-17A and IL-17F in Allergic Diseases
Delayed-type hypersensitivity (DTH) and contact hypersensitivity (CHS)––two T cell-mediated type IV hypersensitive
responses––are attenuated in Il17a/ mice, but not Il17f/
mice, suggesting pathological roles of IL-17A in allergic
responses. The antigen-specific T cell population was reduced
in Il17a/ mice (Ishigame et al., 2009; Nakae et al., 2002), and
Tc17 cell-derived IL-17A induced local inflammation during the
elicitation phase of CHS (Iwakura et al., 2008).
In patients with atopic dermatitis, IL-17A expression increases in local lesions and the Th17 cell population expands
in peripheral blood (Koga et al., 2008). IL-17A may be beneficial
in this setting because IL-17A is important for the protection
against Staphylococcus aureus that aggravates the disease
(see below). Yet IL-17A may also promote disease progression
by facilitating local inflammation as has been reported for mice
lacking filaggrin, an important component of the skin barrier
and a predisposing factor for atopic dermatitis (Oyoshi et al.,
2009).
The pathogenesis of asthma is complex owing to its heterogeneity; e.g., atopic versus nonatopic, eosinophilic versus neutrophilic, and steroid-effective mild asthma versus steroid-resistant
severe asthma (Iwakura et al., 2008). Similar to their wild-type
littermates, Il17a/, Il17f/, and Il17a/ Il17f/ mice were
shown to develop OVA-induced airway eosinophilia (Ishigame
et al., 2009; Nakae et al., 2002). One study, however, has
suggested that IL-17A and IL-17F contribute positively and
negatively, respectively, to this chronic allergic response (Yang
et al., 2008a). Alternatively, overexpression of IL-17A and
IL-17F in the lungs causes increased proinflammatory cytokine
and chemokine expression, resulting in the inflammation associated with neutrophil infiltration (Yang et al., 2008a). IL-17A, but
not IL-17F, is required for OVA-induced airway neutrophilia in
DO11.10 mice (Ishigame et al., 2009; Nakae et al., 2002) and in
mice injected with DO11.10 Th17 cells (Liang et al., 2007). Airway
neutrophilia induced by house dust mite, a major asthma
allergen, is also dependent on IL-17A (Lajoie et al., 2010). The
population of IL-17A-producing Th2 cells, in addition to those
of Th2 cells and Th17 cells (Cosmi et al., 2010; Wang et al.,
2010b), was preferentially increased in the lungs of patients
with atopic asthma as well as of mice treated with certain
protease allergens such as Aspergillus-derived proteases and
papain and resulted in an influx of inflammatory leukocytes and
asthma exacerbation (Wang et al., 2010b). IL-17F, but not IL17A, mediates airway neutrophilia after inhalation of Aspergillus
proteases (Yang et al., 2008a), suggesting the involvement of
innate immune cell-derived IL-17F in this response. Th17 cells
also contribute to airway remodeling and neutrophilia during
chronic airway inflammation (Wang et al., 2010a). Overall, these
data suggest that IL-17A and IL-17F are involved in airway
neutrophilia, but not eosinophilia, during allergic asthma. The
detailed functional differences between IL-17A and IL-17F as
Immunity
Review
well as the roles of Th17 and IL-17A-producing Th2 cells in
asthma development remains to be elucidated.
IL-17A and IL-17F in Other Immune Cell-Mediated
Diseases
IL-17A-induced neutrophil recruitment to inflamed sites contributes to various diseases. For example, IL-17A is crucial for
neutrophil-mediated ischemia-reperfusion injury in the brain
(Shichita et al., 2009). NKT cell-derived IL-17A plays a role in
ozone-induced airway neutrophilia, a form of asthma independent of adaptive immunity (Pichavant et al., 2008). IL-17A, which
may be produced by gd T cells, is also involved in pulmonary
fibrosis and neutrophilia induced by bleomycin (Wilson et al.,
2010). Also, like many cytokines, IL-17A may play a role in sepsis
(Flierl et al., 2008; Freitas et al., 2009).
Rats transferred with soluble IL-17RA, but not Il17a/ mice,
showed reduced acute rejection of cardiac transplants (Gorbacheva et al., 2010; Li et al., 2006). This apparent discrepancy
suggests that IL-17F and/or IL-17E may also be involved in these
responses. IL-17A-mediated neutrophil recruitment accelerates
minor histocompatibility antigen-mismatched skin allograft
survival (Vokaer et al., 2010), yet IL-17A deficiency stimulates
corneal allograft rejection by promoting Th2 cell responses (Cunnusamy et al., 2010). The role of IL-17A in graft-versus-host
disease is controversial; IL-17A has been shown to be protective
(Yi et al., 2008), pathogenic (Kappel et al., 2009), and nonessential (Nakae et al., 2002), depending on the experimental protocols. IL-17F has not been examined in these diseases.
IL-17A and IL-17F in Tumor Development
Th17 cells infiltrate into tumor sites and draining lymph nodes in
cancer patients (reviewed in Zou and Restifo, 2010). The number
of IL-17A-producing cells correlates with poor survival in
patients with hepatocellular carcinoma, whereas the number
was decreased in patients with advanced ovarian cancer, lung
cancer, or non-Hodgkin’s lymphoma. Thus, Th17 cells and
IL-17A may play different roles depending on the tumor type
and stage.
Transplantation of IL-17A-overexpressing tumor cells into
immunodeficient mice induced angiogenesis through induction
of vascular endothelial growth factor (VEGF) expression, resulting in enhanced tumor growth (Numasaki et al., 2003). T cellderived IL-17A also dramatically increases the release of
angiogenic and chemoattractive IL-8 from tumor cells (Tartour
et al., 1999). Delayed growth of subcutaneously transplanted
B16 melanoma cells and MB49 bladder carcinoma cells was
observed in Il17a/ mice, whereas Ifng/ mice showed accelerated growth and augmented IL-17A production in the tumor
(Wang et al., 2009). In this case, IL-6 was expressed in response
to IL-17A-activated Stat3 in the tumor cells, upregulating the
expression of prosurvival and proangiogenic genes. IL-17A is
also involved in the development of colonic cancer in multiple
intestinal neoplasia (Min) mice, a model of familial adenomatous
polyposis (Chae et al., 2010). Interestingly, enterotoxigenic
Bacterioides fragilis (ETBF), an intestinal commensal bacteria,
can accelerate colonic inflammation and tumor formation in
Min mice (Wu et al., 2009). In this model, ETBF selectively
induced Th17 cell differentiation via Stat3 activation, and blocking IL-17A as well as IL-23R dramatically reduced tumor devel-
opment, indicating that a Stat3- and Th17 cell-dependent
pathway contributed to the disease.
Th17 cells have also been shown to inhibit tumor development. Lung metastasis of B16-F10 melanoma was increased in
Il17a/ mice, and adoptive transfer of tumor-specific Th17 cells
prevented tumor development associated with an activation of
tumor-specific CD8+ T cells (Martin-Orozco et al., 2009). Tc17
cells also suppressed established B16-F10 melanomas (Hinrichs
et al., 2009). Il17a/ mice showed increased tumor growth and
metastasis of MC38 cells in lung and subcutaneous tissues,
which was associated with reduced IFN-g-producing NK and
CD8+ T cells (Kryczek et al., 2009). These results suggest that
IL-17A indirectly stimulates antitumor immunity by promoting
type 1 immune responses. Thus, IL-17A has both protumor
and antitumor activity, depending on the types and stages of
tumors. Although the roles of other IL-17 family members
including IL-17F in tumor development have not been well
described, their potential contributions deserve consideration,
particularly in light of their distinct expression profiles. The
effects of blocking IL-17A or other IL-17 family members on
tumor growth in humans have yet to be examined.
IL-17A and IL-17F in Host Defense against Infection
In contrast to pathogenic roles of Th17 cytokines in autoimmune
diseases, Th17 cytokines protects hosts from pathogens at
epithelial and mucosal tissues including the skin, lung, and
intestine. Both IL-17A and IL-17F enhance protective immune
responses by inducing the production of CXC chemokines,
G-CSF, and antimicrobial peptides in epithelial cells and keratinocytes. Indeed, studies using cytokine- and receptor-deficient
mice showed that IL-17A and IL-17F were required for responses
to extracellular bacterium Klebsiella pneumoniae in the lungs,
Citrobacter rodentium in the colon, and Staphylococcus
aureus in the skin (Aujla et al., 2008; Ishigame et al., 2009).
Interestingly, Il17a/Il17f/ mice were highly susceptible
to spontaneous S. aureus infections compared with Il17f/
or Il17a/ mice, and Il17ra/ mice showed higher susceptibility
to K. pneumoniae infection than Il17a/ mice, suggesting that
IL-17A and IL-17F have overlapping roles in these models. On
the other hand, Il17a/ mice, Il17f/ mice, and Il17a/Il17f/
mice were similarly susceptible to C. rodentium (Ishigame et al.,
2009). The mechanisms underlying differential responses to
S. aureus and C. rodentium are not yet known. A recent study
using Il22/ and Il17rc/ mice claims that IL-22, but not
IL-17A and IL-17F, is essential for the early host response
against C. rodentium (Zheng et al., 2008). IL-22 is produced by
innate immune cells, including dendritic cells (DCs) and LTi-like
cells during C. rodentium infection and induces the expression
of Reg family antimicrobial proteins in colonic epithelial cells
(Sonnenberg et al., 2011; Zheng et al., 2008). IL-17A is also
required for host defense mechanisms against intracellular
pathogens in mice. Although Il17ra/ mice were not more susceptible to Mycobacterium tuberculosis infection (Aujla et al.,
2008), the IL-23-IL-17A pathway was required for Th1 cell-type
immune responses that protected the host against the intracellular pathogen Francisella tularensis (Lin et al., 2009).
In humans, hyper IgE syndrome patients, in which Th17 cell
differentiation is suppressed by a STAT3 mutation, are highly
susceptible to S. aureus, Candida albicans, and Streptococcus
Immunity 34, February 25, 2011 ª2011 Elsevier Inc. 155
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pneumoniae infection, resulting in the skin and lung inflammation
(reviewed in Milner et al., 2010). Furthermore, preferential depletion of Th17 cells in the intestine dramatically increases the
frequency of bacteremia, including nontyphoidal Salmonella
serotypes, in monkeys infected with simian immunodeficiency
virus, suggesting that a loss of Th17 cells may also cause
increased susceptibility to Salmonella in HIV-infected people
(Raffatellu et al., 2008). Therefore, in contrast to relatively minor
contribution of IL-17F to autoimmune and allergic diseases, both
IL-17A and IL-17F play protective roles for the defense against
some extracellular bacteria and fungi in the skin and mucoepithelial tissues. This may reflect the fact that IL-17F is produced
not only by Th17 cells and innate immune cells but also by
epithelial cells and that IL-17RC distributes widely in nonlymphoid tissues making a contrast to IL-17RA, although the
immune-activating activity of IL-17F is relatively low.
IL-17A is produced rapidly after microbial infection, and gd
T cells have been identified as a primary source during early
infections with several types of bacteria, including Listeria
monocytogenes and Escherichia coli infection (Hamada et al.,
2008; Shibata et al., 2007). These studies demonstrated that a
lack of IL-17A resulted in increased bacterial burden, suggesting
that gd T cell-derived IL-17A promotes neutrophil accumulation
to eradicate bacteria. Although NKT cells, LTi-like cells, epithelial
cells, and Paneth cells can also produce IL-17A and/or IL-17F,
the cell populations responsible for activating antibacterial
immunity depending on the pathogen, infected tissue, and time
after infection are unknown.
Th17 cells are enriched in the gastrointestinal tract under
steady-state conditions, and intestinal Th17 cell development
is largely dependent on commensal bacteria SFB (GaboriauRouthiau et al., 2009; Ivanov et al., 2009; Wu et al., 2010).
Adenosine 50 -triphosphate derived from commensal bacteria
or SFB-induced serum amyloid A stimulates DCs to produce
Th17 cell-inducing cytokines, including IL-6, IL-23, and TGF-b.
Notably, mice lacking Th17 cells because of the absence of
SFB showed increased susceptibility to C. rodentium (Ivanov
et al., 2009). Thus, intestinal commensal bacteria mediate the
development of Th17 cells as well as other IL-17A- and IL-17Fproducing cells, resulting in various effects on host immune
responses.
Il23a/ and Il17ra/, but not Il12a/, mice are highly
susceptible to oral candidiasis because of defective neutrophil
recruitment and antimicrobial peptide production (Conti et al.,
2009). Il22/ mice are only mildly susceptible to oral candidiasis, suggesting that IL-22 is dispensable for the host defense
in this model. IL-17A plays more important role than IL-17F in
systemic infection of C. albicans because only Il17a/ mice,
but not Il17f/ mice, show increased susceptibility (Saijo
et al., 2010). Interestingly, Th17 cell differentiation was strongly
induced in naive CD4+ T cells cultured in C. albicans-stimulated
bone marrow (BM)-derived DC (BMDC)-conditioned medium, an
effect mediated by high concentrations of IL-1 and IL-23 in the
medium. Th17 cell differentiation was substantially reduced
when dectin-2-deficient BMDC-conditioned medium were
used instead, indicating that dectin-2, the receptor for a fungal
cell wall component a-mannan, plays a major role for the differentiation of Th17 cells upon infection with C. albicans (Saijo et al.,
2010). Similarly, stimulation of dectin-1, the receptor for another
156 Immunity 34, February 25, 2011 ª2011 Elsevier Inc.
fungal cell wall component b-glucan, also induced Th17 cell
differentiation (LeibundGut-Landmann et al., 2007). IL-17A may
inhibit fungal growth by recruiting neutrophils, inducing b-defensins, and activating acquired immune system.
IL-17E
IL-17E enhances Th2 cell immune responses by inducing Th2
cell cytokines such as IL-4, IL-5, and IL-13 in auxiliary cells and
induces IgE production and eosinophilia, contributing to the
host defense against nematodes and allergic disorders (Figure 3).
The heterodimer consisting of IL-17RA and IL-17RB serves as
the receptor for IL-17E (Figure 1) (reviewed in Gaffen, 2009).
Although IL-17E binds only IL-17RB, but not IL-17RA, both
Il17rb/ and Il17ra/ mice fail to respond to IL-17E, suggesting
that both chains are involved in signal transduction. Like
IL-17RA, Act1 is recruited to the SEFIR domain of IL-17RB
through the interaction of SEFIR between IL-17RB and Act1 after
IL-17E bindings (Swaidani et al., 2009). In contrast to IL-17RA,
the cytoplasmic TRAF6-binding motif of IL-17RB directly associates with TRAF6 irrespective of IL-17E binding and activates
NF-kB upon IL-17E binding. IL-17E is produced by Th2 cells,
cecal patch CD4+ and CD8+ T cells, mast cells, and eosinophils
(reviewed in Reynolds et al., 2010). Alveolar macrophages and
endothelial and epithelial cells may also produce IL-17E in
rodents, and skin-resident and monocyte-derived DCs as well
as basophils produce IL-17E in humans. IL-17E promotes Th2
and Th9 cells activation, whereas IL-17E can induce IL-5- and
IL-13-mediated eosinophilia independently of T cells. Regarding
the latter cases, recently identified IL-17E-responsive novel
innate cell populations such as natural helper cells (NHCs), multipotent progenitor type2 (MMPtype2) cells, nuocytes, and innate
type 2 helper (Ih2) cells are focused on the T cell-independent
Th2-type immunity (Moro et al., 2010; Neill et al., 2010; Price
et al., 2010; Saenz et al., 2010b). Thus, IL-17E is considered to
be crucial for both acquired and innate immune responses.
IL-17E in Chronic Inflammatory Diseases
IL-17E ameliorates autoimmune diabetes (Emamaullee et al.,
2009). Like Ifng/ mice, IL-17E deficient (Il25/) mice were
susceptible to EAE, which was accompanied by increased
number of Th17 cells, whereas IL-17E suppressed EAE even in
Ifng/ mice by reducing the Th17 cell population in a manner
dependent on IL-13-IL-4Ra signaling (Kleinschek et al., 2007).
IL-17E attenuates peptideglycan (PGN)-induced, as well as
DSS-, 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-, and oxazolone-induced colitis, independently of IL-13 (Caruso et al., 2009;
Mchenga et al., 2008). IL-17E, which is expressed in epithelial
cells and macrophage-like cells of IBD patients, suppressed
IL-12p40 production in lipopolysaccharide (LPS)- and PGNstimulated mucosal CD14+ cells from IBD patients (Caruso
et al., 2009); this helped to ameliorate certain types of colitis
by reducing production of IFN-g (Figure 3). IL-17A- and IL-17Fproducing mast cells and neutrophils, but not T cells, and
IL-17E-expressing smooth muscle, endothelial and B cells are
suggested to be involved in the pathogenesis of atherosclerosis
(de Boer et al., 2010).
IL-17E activates IL-17RB+ NKT cells, IL-17RB+ CD11blo
CD11c+ F4/80+ macrophages, and airway epithelial cells to
secrete Th2 cell cytokines, resulting in airway eosinophilia
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Review
Antigen and
commensal
or pathogenic
organisms
Figure 3. The Roles of IL-17E in the
Development of Inflammatory Diseases
and Host Defense against Pathogens
T cells
NKT
(IL-4, IL-13)
Th2
(IL-4, IL-5,
IL-13)
Immune cells
Th9
(IL-9)
Th2 cytokines
Macrophage
Innate immune cells
DC
IL-17E
T cell
Promote:
Atopic asthma
Eosinophil
Macrophage, MPP-type 2 cell,
Ih2 cell, NHC, nuocyte
(IL-4, IL-5, IL-13)
Mast cell
Basophil
Non-immune cells
Non-immune cells
Paneth cell
Epithelial cell
Epithelial cell
(IL-4, IL-5, CCL11)
(Swaidani et al., 2009; Terashima et al., 2008). Airway eosinophilia was substantially decreased in mice treated with anti-IL17E or soluble IL-17RB-Fc proteins (Ballantyne et al., 2007; Tamachi et al., 2006) as well as in Il25/ mice because of impaired
Th2 cell and Th9 cell activation (Angkasekwinai et al., 2010).
On the other hand, airway eosinophilia induced by protease(s)
from Aspergillus oryzae was only partially reduced in Il25/
mice (Angkasekwinai et al., 2010). Thus, the roles of IL-17E in
airway inflammation are clearly different from those of IL-17A
and IL-17F, which are involved in airway neutrophilia, but not in
eosinophilia (Figure 3). Consistent with this notion, Il17ra/
mice, but not Il17a/ Il17f/ mice, are resistant to eosinophilic
acute airway inflammation induced by OVA plus alum (SchnyderCandrian et al., 2006).
IL-17E in Tumor Development
Administration of IL-17E to mice transplanted with various types
of tumor cell lines inhibited tumor growth. The antitumor effect of
IL-17E was abolished in scid mice, but not in nude mice, suggesting the involvement of IL-17E-mediated B cell activation
(Benatar et al., 2010). However, the role of IL-17E in tumorigenesis is poorly understood.
IL-17E in Host Defense against Infection
IL-17E is important for the protection against nematodes such as
Nippostrongylus brasiliensis and Trichuris muris by promoting
Th2 cell cytokine production (Figure 3) (Fallon et al., 2006;
Prevent:
Helminth infection
Block:
Th1 and Th17 cell
responses
IL-17E is crucial for both acquired and innate
immune responses. Upon antigen or pathogen
stimulation, various cells, such as T cells, innate
immune cells, and nonimmune cells, produce
IL-17E. IL-17E activates NKT cells, Th2 cells, and
Th9 cells to produce Th2 cytokines such as IL-4,
IL-5, and IL-13. Activated Th2 cells also produce
IL-17E, and it may further amplify T cell-mediated
acquired immune responses. IL-17E also
enhances type 2 immunity by directly acting on
innate immune cells, such as macrophages, multipotent progenitor type2 (MMPtype2) cells, innate
type 2 helper (Ih2) cells, natural helper cells
(NHCs), and nuocytes, which are the important
innate source of Th2 cytokines. In addition,
IL-17E promotes epithelial cell secretion of IL-4
and IL-5, and chemokines such as CCL11 to
recruit eosinophils. These IL-17E-indeced Th2
cytokines promote allergic disease development
as well as host protection against parasites. By
contrast, IL-17E directory and indirectory regulates autoimmunity by suppressing Th1 and Th17
responses.
Owyang et al., 2006; Zhao et al., 2010).
Recent studies have identified innate
immune cell populations such as NHC,
MMPtype2 cells, nuocytes, and Ih2 cells,
which can promote Th2 cell responses
in response to IL-17E (Moro et al., 2010;
Neill et al., 2010; Price et al., 2010; Saenz
et al., 2010b). Although the cell surface
phenotype and anatomical location are
different among these cell populations, they are elicited in the
absence of the adaptive immune system (reviewed in Saenz
et al., 2010a). The linage relationship between NHCs, MMPtype2
cells, nuocytes, and Ih2 cells, and the contributions of these
innate populations in other Th2 cell-related diseases remain to
be elucidated. It is also interesting to investigate the
relationship between non-B-non-T Lyn innate lymphoid cells
that produce IL-17A and IFN-g in response to IL-23 (Buonocore
et al., 2010) and those cells that produce Th2 cell cytokines in
response to IL-17E.
IL-17E produced by intestinal epithelial cells in response to
commensal bacteria limits intestinal Th17 cell expansion by inhibiting IL-23 production from macrophages (Zaph et al.,
2008). Thus, IL-17E may be involved in Th17 cell-mediated
host defense mechanisms against bacteria. Further investigations are needed to discriminate the roles of this cytokine from
other Th2 cytokines.
IL-17B, IL-17C, and IL-17D
IL-17B, IL-17C, and IL-17D were identified through database
searches a decade ago. Although these cytokines have similar
ability to induce inflammatory mediators as IL-17A and IL-17F,
their roles in the immune system remain largely unknown.
Although low IL-17B mRNA is detected in several organs, its
expression is high in chondrocytes and neurons (Lee et al.,
2001; Moseley et al., 2003; Shi et al., 2000). Like IL-17E,
IL-17B binds to IL-17RB with lower affinity than IL-17E (Figure 1)
Immunity 34, February 25, 2011 ª2011 Elsevier Inc. 157
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Review
(reviewed in Gaffen, 2009); however, the signal transduction
mechanisms of IL-17B-IL-17RB are unknown. IL-17C is expressed in CD4+ T cells, DCs, and macrophages at inflammatory
sites, but not in most normal tissues (Hwang and Kim, 2005;
Li et al., 2000; Yamaguchi et al., 2007). IL-17C binds to
IL-17RE and activates NF-kB (Gaffen, 2009; Starnes et al.,
2002). Similar to IL-17B, IL-17D mRNA is detected in several
tissues, whereas, in immune cells, its expression is observed
only in resting CD4+ T and B cells (Starnes et al., 2002). The
receptor(s) for IL-17D has not yet been identified.
Biological Functions of IL-17B, IL-17C, and IL-17D
Both IL-17B and IL-17C induce TNF and IL-1b expression from
a monocytic cell line and cause neutrophil infiltration (Li et al.,
2000; Shi et al., 2000). Elevated expression of IL-17B and
IL-17C was observed in local lesions of CIA. Adoptive transfer
of Il17b- or Il17c-gene-transduced CD4+ T cells exacerbated
CIA accompanied with increased TNF production, whereas the
disease was ameliorated in mice treated with IL-17B neutralizing
Ab (Yamaguchi et al., 2007). IL-17D, which is most homologous
to IL-17B, also induces the expression of IL-6, IL-8, and GM-CSF
in endothelial cells (Starnes et al., 2002), and inhibits hematopoietic progenitor colony formation, an activity shared by IL-17A,
IL-17F and IL-17E (Broxmeyer et al., 2006). Although the expression of IL-17D has been detected in rheumatoid nodules (Stamp
et al., 2008), potential pathogenic roles remain to be elucidated.
IL-17C mRNA expression was upregulated in cultured
epidermal keratinocytes subjected to S. aureus colonization
(Holland et al., 2009). Mycoplasma pneumoniae and the TLR5
agonist flagellin also induce IL-17C expression in lung and gut
tissues (Van Maele et al., 2010; Wu et al., 2007). Therefore,
IL-17B, IL-17C, and IL-17D may have similar activity to induce
inflammatory mediators, and contribute to inflammatory
responses like IL-17A and IL-17F. Future experiments using cytokine-blocking Abs or cytokine gene-targeted mice may help to
understand the functions of these cytokines in immune responses.
Concluding Remarks
Clinical studies have shown that blocking the activity of IL-12
and IL-23 (p40), IL-1, or IL-6, which are important for the development of Th17 cells and possibly innate IL-17A-producing
cells, is effective for the treatment of inflammatory diseases,
such as RA, MS, IBDs, and psoriasis. More recent clinical trials
have demonstrated that anti-IL-17A therapies may also be effective to treat some of these diseases. However, because IL-17A
plays important roles in the host defense against pathogens,
treatments using anti-IL-17A may also increase the risk of
opportunistic infections, as have been observed with therapies
targeting other cytokines. Thus, clinical application of these
approaches requires caution, with particular attention paid to
staphylococcus and candida infections. Because IL-17F is often
functionally redundant with IL-17A in host defenses against
infections and shows relatively lower proinflammatory activity,
anti-IL-17A treatment may be safer than other biological therapies. Nevertheless, for some pathogens both IL-17A and
IL-17F are required for the eradication. Because other IL-17
family members, especially IL-17E, are also proinflammatory
and may be involved in host defense responses, an understanding of the functions of these cytokines will allow the
158 Immunity 34, February 25, 2011 ª2011 Elsevier Inc.
development of more effective treatments for allergic and autoimmune disorders and tumors without compromising host
defense activity.
ACKNOWLEDGMENTS
We thank C. Cheng-Mayer for critical reading of the manuscript. This work is
supported by Grants-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, CREST, and the Promotion of Basic
Research Activities for Innovative Biosciences program (Y.I.) and the Program
for Improvement of Research Environment for Young Researchers, The
Special Coordination Funds for Promoting Science and Technology from the
Ministry of Education, Culture, Sports, Science and Technology, Japan (S.N.).
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