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Rheumatology Advance Access originally published online on January 31, 2008
Rheumatology 2008 47(6):771-776; doi:10.1093/rheumatology/kem352
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Signalling, inflammation and arthritis

Crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity

V. Paunovic, H. P. Carroll, K. Vandenbroeck and M. Gadina

Centre for Cancer Research and Cell Biology. Queen's University Belfast, UK.

Correspondence to: M. Gadina, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK. E-mail: m.g.gadina{at}qub.ac.uk


   Abstract
Top
 Abstract
Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
 References
 
Autoimmune diseases such as rheumatoid arthritis are the consequence of a persistent imbalance between pro- and anti-inflammatory immune mechanisms leading to chronic inflammation. The action of several cytokines is at the basis of this complex process. This review is focused on the signalling events triggered by two major groups of cytokines, namely the IL-12 and IL-17 families, which in the past few years have been shown to have a prominent role in the pathogenesis of such diseases. In particular, we will focus on the signalling cascades set in motion by such cytokines and how this may relate to the pathogenesis of human immune and inflammatory disorders as knowledge of such cascades may help in the development of novel therapeutic approaches for such diseases.

KEY WORDS: Inflammation, Autoimmunity, Rheumatoid arthritis, Cytokines, Interleukins, Interferons, T helper, Signal transduction, Jak–STAT pathway, Animal models


   Introduction
Top
 Abstract
 Introduction
Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
 References
 
The autoimmune inflammatory response occurring in diseases such as RA is the consequence of the action of a diverse cell population that includes B cells, T cells, macrophages and synovial fibroblasts, which results in decreased functionality of the affected joints. The presence of synovial fibroblasts results in the gradual destruction of the joint and promotes the production of pro-inflammatory cytokines. In fact, it is the persistent imbalance between pro- and anti-inflammatory immune mechanisms that leads to chronic inflammation and subsequent joint destruction. Several cytokines are involved in this complex process. This review will focus on the signalling events triggered by two major groups of cytokines, namely the IL-12 and IL-17 families, which have a prominent role in the pathogenesis of autoimmune diseases. We will focus on the signalling cascades set in motion by such cytokines and how these may relate to the pathogenesis of human immune and inflammatory disorders as knowledge of such cascades may help in the development of novel therapeutic approaches for such diseases.


   Interleukin-12
Top
 Abstract
 Introduction
 Interleukin-12
Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
 References
 
Among the pro-inflammatory cytokines that are involved in the pathogenesis of several autoimmune diseases, IL-12 is the main stimulator of IFN-{gamma} production and of the development of T helper (Th) 1 autoimmune response. In patients with RA, levels of IL-12 are elevated in serum and synovial fluids with a direct correlation with disease activity [1].

IL-12 is the prototype of a unique family of heterodimeric cytokines. It is composed of two disulphide-linked subunits designated p35 and p40 [2]. Due to its dimeric nature IL-12 (and other IL-12-related cytokines) has been classified as a separate class of cytokines. On the other hand, early reports showed a high homology between the p40 subunit and the extracellular portion of the IL-6 receptor [3]. Taking into account recent information about other members of the family such as IL-27 it has been suggested that they could all be regrouped in the even bigger IL-6-related cytokine family.

IL-12 is produced by monocytes, macrophages, dendritic cells (DCs), neutrophils and B cells. Toll-like receptor (TLR) signalling induces T cell-independent production of IL-12 [4], whereas T cell-dependent production of IL-12 is induced through the engagement of CD40 on antigen-presenting cells and CD40L on T cells [5]. IL-12 production is also positively regulated by IFN-{gamma}, which is induced by IL-12 itself. Conversely, IL-12 production is inhibited by IL-10, IL-11, IL-13 and type I IFNs.

The IL-12 receptor (IL-12R) consists of two subunits, β1 and β2, which are homologous to gp130 and are required for the generation of human high-affinity IL-12-binding sites. The β2 subunit functions as the primary signal transducing component and recruits signalling molecules, such as the tyrosine kinases, Janus kinase (Jak)2 and Tyrosine kinase (Tyk)2 and signal transducers and activators of transcription (STAT)3, STAT4 and STAT5 [6–8] (Fig. 1). IL-12Rβ1 has no known signalling functions but is required for high affinity binding of the cytokine. Both subunits are expressed on T cells, NK cells and DCs. Their expression is tightly controlled and up-regulated upon T-cell activation. IFN-{gamma} stimulation also results in up-regulation of the transcription factor T box transcription factor (T-bet), which in turn, maintains IL-12Rβ2 expression [9]. Conversely, IL-4 has been shown to down-regulate IL-12Rβ2 expression [10, 11]. Regulation of IL-12 receptor expression by IFN-{gamma} and IL-4 is therefore an important control mechanism for Th cell differentiation. IL-12 induces production of IFN-{gamma} by T and NK cells and this production is further enhanced by IL-18. The combination of these cytokines is highly synergistic and can also induce IFN-{gamma} production in macrophages. IL-12 potentiates the cytolytic activity of NK and T cells inducing their proliferation and also acts on DCs to induce further production of IL-12 [12]. IL-12 and IFN-{gamma} antagonize Th2 differentiation and the production of IL-4, IL-5 and IL-13.


Figure 1
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  		FIG. 1. Signal transduction events following IL-12, IL-23, IL-27 and IL-17 binding to their respective receptors. The IL-12 receptor is composed of two subunits, IL-12R{alpha} and IL-12Rβ. Ligand binding results in Jak2 and Tyk2 phosphorylation and the subsequent activation of the receptor. STAT3 and STAT4 are then recruited and phosphorylated, STAT4 homodimers shuttle to the nucleus where they induce IFN-{gamma} gene transcription. P38 MAPK is also activated upon IL-12 binding and is essential for IFN-{gamma} gene transcription in T cells. IL-23 also activates the Jak/STAT pathway. STAT3 and STAT4 heterodimers are the main mediators of signalling and their activity can be inhibited by SOCS-3. IL-23 also activates the NF-{kappa}B pathway in Th17 cells. IL-27 activates Jak1/2, Tyk 2 and a number of STATs. Phosphorylated STAT1 homodimers and STAT3 homodimers travel to the nucleus and stimulate gene transcription. Like IL-12, IL-27 also activates the p38 MAPK pathway. In cells expressing the IL-17R complex, IL-17 causes the activation of TRAF 6 and the recruitment of TAK1 through the adaptor protein Act1, which interacts with the SEFIR domain of IL-17RA. IL-17 also induces the activation of MAPK and PI3K ultimately leading to NF-{kappa}B and C/EBP-dependent transcription of its target genes.

 
The inhibition of tyrosine kinases has become a reality after the successes obtained with the breakpoint cluster region (BCR)-Abelson leukaemia (ABL) inhibitor imatinib. Jak kinases have also been subjects of intense studies and, in fact, some excellent pre-clinical results have been obtained by targeting Jak3, which is activated by all the cytokines utilizing the common {gamma} chain of the IL-2 receptor complex [13]. On the other hand, kinases such as the IL-12-activated Jak2 and Tyk2 are less likely to be good targets due to Jak2 critical involvement in erythropoietin signalling and Tyk2 contribution in IFN signalling.

Besides activating the Jak/STAT pathway, IL-12 activates several other signalling cascades, some of which are cell specific. IL-12, and possibly other IL-12 family members, activates the mitogen-activated protein kinase (MAPK) cascade. In particular, the p38 MAPK is enzymatically active upon IL-12 stimulation of T cells and activation of this MAPK is critical for IFN-{gamma} production in response to IL-12 [14–16]. This was shown in vitro using chemical inhibitors as well as in vivo in a dominant negative p38 transgenic mouse model [17]. The function of p38 is critical for STAT4 serine phosphorylation, which is required for optimal IFN-{gamma} production in T cells [18]. How IL-12 turns on the p38 MAPK cascade is still unclear. Molecules such as GADD45β and {gamma} and the GTPase Rac2 have been suggested to play a role [19–21]. Taking into account the importance that IFN-{gamma}-producing cells still have in many autoimmune diseases, the IL-12 family activation of the MAPK family has already attracted attention for possible molecular intervention although none of the inhibitors developed so far has demonstrated clinical good efficacy in humans [22].

Negative regulation of IL-12 signalling occurs primarily through the suppressor of cytokine signalling (SOCS) family of proteins. SOCS-1 and SOCS-3 have been proposed to inhibit IL-12 signalling leading to decreased IFN-{gamma} production [23–25]. Interestingly, SOCS-3 deletion in T cells does not affect IL-12-dependent STAT4 phosphorylation, but instead acts as a major regulator of IL-23-mediated STAT3 phosphorylation, which is required for the generation of IL-17-secreting Th cells (Th17 cells) [26] (see subsequently). Indeed, SOCS-3–/{triangleup}vav mice, in which SOCS-3 is deleted in haematopoietic and endothelial cells, develop severe joint inflammation as well as increased osteoclast generation and bone destruction. The absence of SOCS-3 resulted in enhanced CD4+ T-cell activation and IL-17 production [27]. Despite their role as classical feedback inhibitors of cytokine signalling, no clinical interventions exploiting the SOCS pathway exist at present.

The importance of IL-12 in autoimmune diseases has been known for quite a few years. Early evidence for a crucial role of IL-12 in the pathogenesis of RA surfaced from experiments carried out in the mouse models of arthritis, such as collagen-induced arthritis (CIA). Co-administration of type II collagen with IL-12 to DBA/1 mice strongly enhanced anti-collagen immune response and led to massive local inflammation characterized by polymorphonuclear cell infiltration as well as cartilage and bone destruction [28, 29]. However, neutralization of endogenously produced IFN-{gamma} prevented development of CIA in IL-12-treated mice [30]. When established CIA was treated with IL-12 for a prolonged period of time, the arthritis score was suppressed and cartilage breakdown was reduced. Therefore IL-12 has both early pro-inflammatory and late anti-inflammatory effects in arthritis-like autoimmune disease [29].

In the IFN-{gamma}R knockout CIA model, disease is more severe than in the wild-type counterparts, and in this model anti-IL-12 appeared both to reduce symptoms of arthritis and to down-regulate Th1 and humoral autoimmune responses [31]. These findings illustrated that endogenous IL-12 can induce Th1-dependent pathological reactions in the CIA model, both dependent and independent of IFN-{gamma} production. While these studies bestow a critical role for IL-12 in the pathogenesis of murine arthritis-like autoimmune disease, it is also evident that some of the findings were based on the use of anti-IL-12 antibodies, which act via the neutralization of the p40 subunit, and consequently need to be reinterpreted since such antibodies cannot discriminate between IL-12 and the later discovered IL-23. Interestingly, patients with Crohn's disease, another typical autoimmune disease, have been administered anti-p40 antibody with minimal side-effects and relatively good clinical responses [32]. If such a response is due to IL-12 or IL-23 blockade is still unclear.


   Interleukin-23
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
 References
 
With the discovery of p19, a protein homologous to IL-12p35, in early 2000, an additional layer of complexity was added to the biological role of IL-12 and a family of cytokines was born. The p19 is produced by macrophages, DCs, T cells and endothelial cells, and heterodimerizes with p40 to form the cytokine now designated IL-23 [33]. Like IL-12, IL-23 was also initially shown to induce the production of IFN-{gamma} by human T cells in vitro. However, in contrast to IL-12, which is important for differentiation of naive T cells, IL-23 was reported to induce proliferation of memory T cells [34]. It has now emerged that the role of IL-23 is to sustain the development of pro-inflammatory, IL-17-secreting CD4+ memory T cells (Th17 cells) [35].

IL-23 binds a receptor composed of IL-12Rβ1 and a second subunit designated IL-23R that is normally expressed at low levels on T cells, NK cells, monocytes and DCs. The IL-23R contains seven intracellular tyrosine residues potentially involved in signalling. Like IL-12, IL-23 utilizes Jak kinases such as Tyk2 and Jak2 to phosphorylate and activate STAT3 and STAT4, which that are the major mediators of IL-23 signalling (Fig. 1). Development of Th17 cells has been shown to be dependent on both STAT3 and STAT4. In particular, STAT3 is required for the expression of IL-17A, IL-17F and the transcription factor retinoid-related orphan receptor (ROR){gamma}t in Th17 cultures. Retroviral transduction of constitutively active STAT3 in transforming growth factor-β (TGF-β) plus IL-6-primed T cells regulates IL-17 production. Therefore, STAT3 activation downstream of the IL-23R complex and gp130 are essential for Th17 development (gp130/IL-6-driven) and proliferation (IL-23 driven) at least in mice (see subsequently) [36]. STAT4 on the other hand is only partially required for the development of IL-23-primed Th17 cells but is essential for IL-17 secretion in response to IL-23 plus IL-18 stimulation [37]. It must be noted that some of the aforementioned studies were performed using chemical inhibitors or overexpression systems. In the future, it would be important to confirm these results using more appropriate biochemical and genetic approaches as details about the whole signalling programme that IL-23 can induce in different cell types are still ill defined. In addition to the Jak–STAT pathway IL-23 can also activate the PI3K/AKT and nuclear factor (NF)-{kappa}B pathways [38] as it was shown in a model of spontaneous arthritis such as the IL-1Ra-deficient mice.

A role for SOCS-3 in the control of IL-23 signal transduction has already been mentioned above but we cannot exclude a possible role for other molecules such as the protein inhibitor of activated STAT (PIAS) [39].

A clearer picture of IL-23's biological role has emerged in the past few years. Using a p35 and p19 knock-out CIA model, Murphy and colleagues [40] demonstrated that IL-23 is essential in joint autoimmune inflammation and that IL-12, contrary to expectation, mediates protection from the disease. Deletion of the p35 chain aggravated the course of the disease while p19-deficient mice were resistant to disease and unable to generate IL-17-producing CD4+ T cells (Th17). Therefore, it was suggested that, while IL-12 induces IFN-{gamma} production, the inflammatory effects of IL-23 are at least partially mediated via development of Th17 cells [35, 40]. It is therefore possible to speculate that the IL-23-driven autoimmune response in CIA does not proceed via the classical IFN-{gamma}-Th1 pathway. Notably, the Th17 subset of cells was identified as an osteoclastogenic link between T cell activation and bone resorption [41] once again underscoring the crucial role of this subset of Th cells in the pathogenesis of joint diseases.


   Interleukin-27
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
The IL-17 family
 Conclusions
 Acknowledgement
 References
 
IL-27, the most recent addition to the IL-12 family, is a heterodimeric cytokine [42] comprising two subunits designated Epstein–Barr-induced molecule 3 (EBI3), which is homologous to IL-12p40 [43, 44] and a novel protein, p28. Like IL-12, IL-27 is expressed in Toll-like receptor-activated monocytes and macrophages and is also produced by monocyte-derived DCs upon exposure to Gram-positive bacteria. Its expression is also induced by IFNs and initial studies suggested that it was involved in early initiation of Th1 responses by inducing proliferation of naive T cells, promoting Th1 polarization and IFN-{gamma} production.

IL-27 binds a receptor composed of WSX-1/TCCR, a type I cytokine receptor, and gp130, which serves as a common signal transduction receptor for all the IL-6-related family members. WSX-1 is mainly expressed in lymphoid cells such as T cells and NK cells with the highest levels found on effector and memory T cells and control of the expression of the IL-27 receptor is mainly achieved via regulation of WSX-1 expression as gp130 is basally expressed in several tissues [45]. Mice nullizygous for WSX-1 had been generated prior to the discovery of its ligand and showed impaired Th1 development and IFN-{gamma} production in response to antigen stimulation [46, 47].

IL-27 binding to its receptor results in activation of Jak1, Jak2, Tyk2 as well as STAT1, STAT2, STAT3, STAT4 and STAT5 (Fig. 1). IL-27-triggered STAT1 activation is crucial for many effects of this cytokine. Via STAT1, IL-27 promotes Th1 cell differentiation, IL-12 and IFN-{gamma} production and expression of MHC class I [11, 48, 49]. These effects seem to occur through two distinct pathways, one going through p38MAPK and T-bet and another via intercellular adhesion molecule (ICAM)-1/lymphocyte function associated antigen (LFA-1) and extracellular signal-regulated kinases (ERKs) 1/2 activation [50]. STAT3 phosphorylation has been proposed to be required for T-cell proliferation but another report has shown that lack of STAT3 in fully activated cells results in impaired IL-27 functions [51]. We still do not know how important STAT4 and STAT2 really are in IL-27 signalling and our knowledge is undoubtedly still very limited. This is surely an area of research that needs to receive a lot of attention in the immediate future as we still do not know if IL-27 is capable to induce activation of other pathways or how its receptor-derived signals are kept under control.

T cells from WSX-1-deficient mice produce lower levels of IFN-{gamma} when stimulated in vitro and have increased susceptibility to intracellular pathogens like Listeria monocytogenes, higher levels of IL-4 and an augmented Th2 response. Disruption of the WSX-1 gene also resulted in changes in the pathology associated with the MRL/lpr mice and absence of the IL-27 receptor resulted in a disease similar to the human membranous glomerulonephritis with reduced levels of IFN-{gamma} and increased IL-4 expression, the loss of WSX-1 therefore resulting in a change of the disease from a Th1 to a Th2 autoimmune response [52].

Besides its role as a Th1 cytokine, IL-27 also attenuates the inflammatory response induced by protozoan infections. WSX-1-deficient mice injected with the T-cell mitogen Concanavalin A or infected with Toxoplasma gondii showed a normal protective Th1 response. However, in the absence of IL-27 signalling, these mice developed increased numbers of activated and proliferating CD4+ and CD8+ T cells with higher levels of serum IL-2 and IFN-{gamma} and the mice eventually succumbed to T cell-dependent inflammatory disease.

The mechanisms by which IL-27 exerts this inhibition though, are not completely clear. IL-27 inhibits IL-2 production upon TCR engagement and this is again dependent on STAT1 but not on STAT3, STAT4 or T-bet. Up-regulation of SOCS-3 by IL-27 could be a possible mechanism since overexpression of anti-sense SOCS-3 or a dominant negative form of this inhibitor reversed the IL-27-mediated block of IL-2 production [53].

Another major effect of IL-27 is the suppression of Th17 development. Mice defective for WSX-1 showed increased susceptibility to experimental autoimmune encephalomyelitis (EAE) and had higher levels of circulating Th17 cells. Furthermore, IL-27 directly inhibits the IL-6 plus TGF-β-driven differentiation of this subset of Th cells. These effects were dependent on STAT1, but independent of IFN-{gamma} or SOCS-3 [36, 54]. Altogether, these studies helped clarify the anti-inflammatory activity of IL-27.

Despite its clear anti-inflammatory activity, a role of IL-27 in autoimmunity has been suggested by experiments on adjuvant-induced arthritis in rats and EAE in mice. In adoptive transfer experiments, Goldberg and colleagues [55, 56] showed that anti-IL-27 suppresses disease by affecting the proliferative response and IFN-{gamma} production. Moreover, severity of the disease in EAE can be reduced by using IL-27-neutralizing antibodies.

Altogether, the IL-12 family of cytokines plays a pivotal role in several autoimmune inflammatory pathologies but, in the past few years, it has become clear that this family is not acting alone. The definition of a new subset of Th cells that mainly secrete IL-17 has been a milestone in our understanding of autoimmune diseases and this family of cytokines is now the focus of several studies.


   The IL-17 family
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
Conclusions
 Acknowledgement
 References
 
The IL-17 is a group of cytokines and shares little homology with other cytokines. Six family members have been identified to date, designated as IL-17A–F [57]. Despite their initial discovery over a decade ago, the IL-17 family has not received much attention until recently [57]. As mentioned above, the discovery that IL-17A is a hallmark cytokine of the novel Th cell subset Th17 has altered the Th1/Th2 paradigm that dominated immune biology for many years, and has brought this family back into the spotlight [58, 59].

IL-17A and IL-17F are the two most studied members. They are produced by activated T cells (both CD4+ and CD8+) with memory phenotype and their transcription is regulated by cooperation between nuclear factor of activated T-cells (NFAT) and STAT3 transcription factors [60–63]. The other family members have more ubiquitous patterns of expression, suggesting distinct biological roles. Both IL-17B and IL-17D are expressed in various tissues and in resting CD4+ T cells, and have pro-inflammatory activity as they can induce secretion of IL-6, IL-8 and GM-CSF [64] while IL-17E (more commonly known as IL-25) is expressed in human brain, lungs, testis and prostate, and mouse CD4+ T cells with Th2 profile [65, 66].

IL-17A stimulates the production of numerous cytokines and chemokines involved in inflammatory responses and for protection against infection from extracellular bacterial pathogens such as Klebsiella pneumoniae, Borrelia burgdorferi, Bordetella pertussis and Citrobacter rodentium [67–70].

The members of the IL-17 family of cytokines bind to a unique class of cytokine receptors. IL-17RA has no apparent homology with any other receptor proteins [60, 71]. It exists as a multimeric pre-formed receptor complex with IL-17RC, which undergoes a conformational change upon ligand binding [72, 73]. Bioinformatics analysis has revealed a domain within the intracellular portion of IL-17RA (and IL17RC), termed the SEFIR domain, with homology to the Toll-like and IL-1 receptor (TIR) domain. However, unlike the TIR domain, the SEFIR domain mediates IL17RA signalling independently of MyD88 and TRIF [74]. The SEFIR domain of the receptor is essential for activation of NF-{kappa}B, ERK and CCAAT-enhancer-binding proteins (C/EBPs) and subsequent transcription of IL-17 target genes. It has recently been shown that IL-17RA-induced NF-{kappa}B activation is dependent on the adaptor protein Act1, which is a known activator of NF-{kappa}B (Fig. 1). Act1 fails to bind to IL-17RA with a deletion of the SEFIR domain resulting in severe impairment of gene transcription [75, 76]. Act1 deficiency in astroglial and epithelial cells abolishes the IL-17-dependent induction of the c/EBP family of transcription factors, cytokine and chemokine production as well as activation of TRAF6 and NF-{kappa}B [77, 78]. Furthermore, Act1-deficient mice present with diminished inflammation in two different models of autoimmune diseases: experimental autoimmune encephalomyelitis and dextran sulphate-induced colitis [76]. Altogether, given the apparent specificity of Act1 for the IL-17-mediated signalling events, blocking the complexes that are dependent on this adaptor could be an interesting therapeutic approach.

A growing body of evidence also supports a role for MAPK family members ERK1/2, c-Jun N terminal kinase (JNK) and p38 downstream of the IL-17RA receptor. MAPK activation has been implicated in the regulation of mRNA stability, as it has been shown that p38 mediates increased stability of COX-2 reporter gene mRNA and protein synthesis via distal regions of the 3'-untranslated region and in activation of AP-1 transcription factor complexes [79, 80]. Moreover, IL-17RA also activates the PI3K/AKT signalling pathway upstream of IL-6 and IL-8 gene expression in synoviocytes [81]. IL-17RA also induces up-regulation of IL-23p19 expression in RA synovial fibroblasts through a PI3K/NF-{kappa}B and p38-dependent pathways [82].

Despite its clear importance for the mounting of an appropriate immune response against pathogens and in several autoimmune diseases, our knowledge of the signalling cascade downstream of the IL-17 receptor is still poor. We still do not know how signalling is kept under control and if proteins such as SOCS or PIAS are involved.

Much more is known about the biology of IL-17. In vivo studies have highlighted a role of IL-17 in RA. IL-17-deficient mice have suppressed allergic cellular and humoral responses upon antigen-specific T-cell sensitization, as well as markedly suppressed development of CIA implicating IL-17 in priming collagen-specific T cells, and in production of collagen-specific IgG2a antibodies [83, 84]. Similarly, studies on streptococcal cell wall-induced arthritis in IL-17RA-deficient mice revealed a critical role for IL-17/IL17RA signalling in inducing both IL-1 and different metalloproteinases in T cells [85].

Development and differentiation of Th17 cells require a complex network of cytokines. Studies in mice have highlighted the fundamental role of IL-6, TGF-β and IL-21 [70, 86–88]. Other cytokines such as IL-2, IL-12, IL-27 and IFNs can inhibit Th17 differentiation [54, 89, 90]. Very recently it has been shown in humans that TGF-β inhibits rather than potentiates Th17 development. Instead IL-1β produced by macrophages activated through TLRs is critical for the differentiation of this subset of Th cells whereas the role of IL-23 in humans remains controversial [91, 92] (Fig. 2).


Figure 2
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  		FIG. 2. Cytokine-mediated induction of synovial inflammation depends on Th17 cells. Differentiation of Th0 into Th17 cells is mediated by IL-23 and IL-6 released from myeloid DCs, by IL-1 and IL-6 from macrophages as well as by IL-21 from activated T cells. The cytokines IL-2, IL-12, IL-27 and IFNs counteract this process. TGF-β actions differ between mice, where it is crucial for Th17 development, and humans, where it acts as a negative regulator. IL-17, released from Th17 cells, affects several cell populations of the inflamed synovium such as chondrocytes, osteoblasts, synovial fibroblasts, mast cells and neutrophils. Cytokines such as IL-1, M-CSF and TNF are released both by macrophages and articular cells (e.g. synovial fibroblasts) to enhance inflammatory processes and tissue degradation. For the sake of clarity, only the key cytokine pathways are depicted, with emphasis on the role of IL-17.

 
IL-17A has been most extensively investigated especially for its role in the development of several autoimmune diseases, such as RA, multiple sclerosis, inflammatory bowel disease and psoriasis [93]. IL-17A and F are secreted in response to TCR engagement and IL-23 stimulation [35, 94–96]. In addition, it was shown that IL-17A was spontaneously produced by RA synovial membrane cultures in T cell rich areas [97] and high levels of IL-17A were found in the synovial fluid from RA patients [98, 99].

IL-17 not only contributes to the inflammatory process within the joint, but also directly impacts on the cartilage and bone. IL-17 inhibits chondrocyte metabolism, causes proteoglycan breakdown, stimulates induction of metalloproteinases and causes cartilage destruction (Fig. 2). Osteoclastogenesis is also triggered by IL-17 through the up-regulation of receptor activator of nuclear factor {kappa}B ligand (RANKL) on osteoblasts and the interaction between RANKL and receptor activator of nuclear factor {kappa}B (RANK) is critical for osteoclastogenesis and bone erosion [100]. In addition, in IL-17 and IL-23p19 knockout mice, lipopolysaccharide (LPS)-induced arthritis resulted in reduced osteoclast formation and consequently reduced bone destruction [41].


   Conclusions
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
Acknowledgement
 References
 
Current RA therapy, including blockade of tumour necrosis factor-{alpha} (TNF-{alpha}) and IL-1, is efficient in relieving pain and reducing inflammation. However, it does not prevent many other damaging events such as cartilage and bone destruction in the joints. The studies on the two families of cytokines discussed in this review have undoubtedly helped in the definition of possible therapeutic approaches. For example, the establishment of the IL-23–IL-17 axis in the pathogenesis and persistence of RA and the definition of a new subset of Th cells has revealed new potential therapeutic targets. Indeed studies that tested neutralization of IL-17 in animal models achieved very promising results in reducing signs of inflammation and disease development in both CIA and EAE models. On the other hand, the diverse regulation of Th17 development between mice, where we can easily manipulate truly naive T cells, and humans, where this is obviously not possible, has put a brake on the direct translation of the successes of animal studies into human therapy. Our knowledge of T-cell biology, especially in humans, has dramatically expanded in the past few years but for some of the more recently defined subsets we still have very little information. Similarly, the inter-crossing of signals generated by different cytokines, sometimes stemming from different receptors, has added several layers of complexity and we are just now starting to define some of the key molecules that are ultimately responsible for several biological responses.

Nonetheless, our understanding of the signalling cascades set into motion by some of the aforementioned cytokines is still limited and should be the focus of future studies aimed at defining new and more effective tools for the treatment of RA and other autoimmune pathologies.

Formula


   Acknowledgement
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
References
 
This article is dedicated to the memory of Anna Malgaroli Gadina.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Interleukin-12
 Interleukin-23
 Interleukin-27
 The IL-17 family
 Conclusions
 Acknowledgement
 References
 

  1. Kim W, Min S, Cho M, et al. The role of IL-12 in inflammatory activity of patients with rheumatoid arthritis (RA). Clin Exp Immunol (2000) 119:175–81.[CrossRef][Web of Science][Medline]
  2. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol (2003) 3:133–46.[CrossRef][Web of Science][Medline]
  3. Gearing DP, Cosman D. Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor. Cell (1991) 66:9–10.[CrossRef][Web of Science][Medline]
  4. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol (2001) 2:675–80.[CrossRef][Web of Science][Medline]
  5. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med (1996) 184:747–52.[Abstract/Free Full Text]
  6. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med (1995) 181:399–404.[Abstract/Free Full Text]
  7. Jacobson NG, Szabo SJ, Weber-Nordt RM, et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med (1995) 181:1755–62.[Abstract/Free Full Text]
  8. Ahn HJ, Tomura M, Yu WG, et al. Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation. J Immunol (1998) 161:5893–900.[Abstract/Free Full Text]
  9. Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA (2001) 98:15137–42.[Abstract/Free Full Text]
  10. Szabo SJ, Dighe AS, Gubler U, Murphy KM. Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med (1997) 185:817–24.[Abstract/Free Full Text]
  11. Afkarian M, Sedy JR, Yang J, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol (2002) 3:549–57.[CrossRef][Web of Science][Medline]
  12. Micallef MJ, Ohtsuki T, Kohno K, et al. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol (1996) 26:1647–51.[Web of Science][Medline]
  13. Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science (2003) 302:875–8.[Abstract/Free Full Text]
  14. Visconti R, Gadina M, Chiariello M, et al. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood (2000) 96:1844–52.[Abstract/Free Full Text]
  15. Zhang S, Kaplan MH. The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression. J Immunol (2000) 165:1374–80.[Abstract/Free Full Text]
  16. Gollob JA, Schnipper CP, Murphy EA, Ritz J, Frank DA. The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. J Immunol (1999) 162:4472–81.[Abstract/Free Full Text]
  17. Rincon M, Enslen H, Raingeaud J, et al. Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J (1998) 17:2817–29.[CrossRef][Web of Science][Medline]
  18. Morinobu A, Gadina M, Strober W, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci USA (2002) 99:12281–6.[Abstract/Free Full Text]
  19. Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM. IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol (2001) 2:157–64.[CrossRef][Web of Science][Medline]
  20. Lu B, Yu H, Chow C, et al. GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity (2001) 14:583–90.[CrossRef][Web of Science][Medline]
  21. Li B, Yu H, Zheng W, et al. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science (2000) 288:2219–22.[Abstract/Free Full Text]
  22. Dodeller F, Schulze-Koops H. The p38 mitogen-activated protein kinase signaling cascade in CD4 + T cells. Arthritis Res Ther (2006) 8:205.[CrossRef][Medline]
  23. Alexander WS, Starr R, Fenner JE, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell (1999) 98:597–608.[CrossRef][Web of Science][Medline]
  24. Eyles JL, Metcalf D, Grusby MJ, Hilton DJ, Starr R. Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. J Biol Chem (2002) 277:43735–40.[Abstract/Free Full Text]
  25. Yamamoto K, Yamaguchi M, Miyasaka N, Miura O. SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit. Biochem Biophys Res Commun (2003) 310:1188–93.[CrossRef][Web of Science][Medline]
  26. Chen Q, Coffey A, Bourgoin SG, Gadina M. Cytohesin binder and regulator augments T cell receptor-induced nuclear factor of activated T cells. AP-1 activation through regulation of the JNK pathway. J Biol Chem (2006) 281:19985–94.[Abstract/Free Full Text]
  27. Wong PK, Egan PJ, Croker BA, et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest (2006) 116:1571–81.[CrossRef][Web of Science][Medline]
  28. Germann T, Szeliga J, Hess H, et al. Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA (1995) 92:4823–7.[Abstract/Free Full Text]
  29. Joosten LA, Lubberts E, Helsen MM, van den Berg WB. Dual role of IL-12 in early and late stages of murine collagen type II arthritis. J Immunol (1997) 159:4094–102.[Abstract]
  30. Germann T, Rude E, Schmitt E. The influence of IL12 on the development of Th1 and Th2 cells and its adjuvant effect for humoral immune responses. Res Immunol (1995) 146:481–6.[CrossRef][Web of Science][Medline]
  31. Matthys P, Vermeire K, Mitera T, Heremans H, Huang S, Billiau A. Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice. Eur J Immunol (1998) 28:2143–51.[CrossRef][Web of Science][Medline]
  32. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med (2004) 351:2069–79.[Abstract/Free Full Text]
  33. 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 (2000) 13:715–25.[CrossRef][Web of Science][Medline]
  34. Belladonna ML, Renauld JC, Bianchi R, et al. IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J Immunol (2002) 168:5448–54.[Abstract/Free Full Text]
  35. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 + T cell activation state characterized by the production of interleukin-17. J Biol Chem (2003) 278:1910–4.[Abstract/Free Full Text]
  36. Stumhofer JS, Laurence A, Wilson EH, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol (2006) 7:937–45.[CrossRef][Web of Science][Medline]
  37. Mathur AN, Chang HC, Zisoulis DG, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol (2007) 178:4901–7.[Abstract/Free Full Text]
  38. Cho ML, Kang JW, Moon YM, et al. STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol (2006) 176:5652–61.[Abstract/Free Full Text]
  39. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol (2005) 5:593–605.[CrossRef][Web of Science][Medline]
  40. 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 (2003) 198:1951–7.[Abstract/Free Full Text]
  41. Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med (2006) 203:2673–82.[Abstract/Free Full Text]
  42. Pflanz S, Timans JC, Cheung J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity (2002) 16:779–90.[CrossRef][Web of Science][Medline]
  43. Devergne O, Hummel M, Koeppen H, et al. A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J Virol (1996) 70:1143–53.[Abstract]
  44. Devergne O, Birkenbach M, Kieff E. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc Natl Acad Sci USA (1997) 94:12041–6.[Abstract/Free Full Text]
  45. Villarino AV, Larkin J III, Saris CJ, et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J Immunol (2005) 174:7684–91.[Abstract/Free Full Text]
  46. Chen Q, Ghilardi N, Wang H, et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature (2000) 407:916–20.[CrossRef][Medline]
  47. Yoshida H, Hamano S, Senaldi G, et al. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity (2001) 15:569–78.[CrossRef][Web of Science][Medline]
  48. Lucas S, Ghilardi N, Li J, de Sauvage FJ. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci USA (2003) 100:15047–52.[Abstract/Free Full Text]
  49. Kamiya S, Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T. An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells. J Immunol (2004) 173:3871–7.[Abstract/Free Full Text]
  50. Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T. IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J Immunol (2006) 177:7579–87.[Abstract/Free Full Text]
  51. Yoshimura T, Takeda A, Hamano S, et al. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. J Immunol (2006) 177:5377–85.[Abstract/Free Full Text]
  52. Shimizu S, Sugiyama N, Masutani K, et al. Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1). J Immunol (2005) 175:7185–92.[Abstract/Free Full Text]
  53. Owaki T, Asakawa M, Kamiya S, et al. IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3. J Immunol (2006) 176:2773–80.[Abstract/Free Full Text]
  54. Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol (2006) 7:929–36.[CrossRef][Web of Science][Medline]
  55. Goldberg R, Wildbaum G, Zohar Y, Maor G, Karin N. Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J Immunol (2004) 173:1171–8.[Abstract/Free Full Text]
  56. Goldberg R, Zohar Y, Wildbaum G, Geron Y, Maor G, Karin N. Suppression of ongoing experimental autoimmune encephalomyelitis by neutralizing the function of the p28 subunit of IL-27. J Immunol (2004) 173:6465–71.[Abstract/Free Full Text]
  57. Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol (2002) 71:1–8.[Abstract/Free Full Text]
  58. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol (2005) 6:1123–32.[CrossRef][Web of Science][Medline]
  59. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 + T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol (2005) 6:1133–41.[CrossRef][Web of Science][Medline]
  60. Yao Z, Painter SL, Fanslow WC, et al. Human IL-17: a novel cytokine derived from T cells. J Immunol (1995) 155:5483–6.[Abstract]
  61. Shin HC, Benbernou N, Esnault S, Guenounou M. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine (1999) 11:257–66.[CrossRef][Web of Science][Medline]
  62. Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol (2003) 170:2106–12.[Abstract/Free Full Text]
  63. Chen Z, Laurence A, Kanno Y, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA (2006) 103:8137–42.[Abstract/Free Full Text]
  64. Gaffen SL, Kramer JM, Yu JJ, Shen F. The IL-17 cytokine family. Vitam Horm (2006) 74:255–82.[Web of Science][Medline]
  65. Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity (2001) 15:985–95.[CrossRef][Web of Science][Medline]
  66. Lee J, Ho WH, Maruoka M, et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem (2001) 276:1660–4.[Abstract/Free Full Text]
  67. Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol (2000) 165:6107–15.[Abstract/Free Full Text]
  68. Fedele G, Stefanelli P, Spensieri F, Fazio C, Mastrantonio P, Ausiello CM. Bordetella pertussis-infected human monocyte-derived dendritic cells undergo maturation and induce Th1 polarization and interleukin-23 expression. Infect Immun (2005) 73:1590–7.[Abstract/Free Full Text]
  69. Happel KI, Dubin PJ, Zheng M, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med (2005) 202:761–9.[Abstract/Free Full Text]
  70. Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature (2006) 441:231–4.[CrossRef][Medline]
  71. Yao Z, Spriggs MK, Derry JM, et al. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine (1997) 9:794–800.[CrossRef][Web of Science][Medline]
  72. Kramer JM, Yi L, Shen F, et al. Evidence for ligand-independent multimerization of the IL-17 receptor. J Immunol (2006) 176:711–5.[Abstract/Free Full Text]
  73. Toy D, Kugler D, Wolfson M, et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol (2006) 177:36–9.[Abstract/Free Full Text]
  74. Maitra A, Shen F, Hanel W, et al. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci USA (2007) 104:7506–11.[Abstract/Free Full Text]
  75. Chang SH, Park H, Dong C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem (2006) 281:35603–7.[Abstract/Free Full Text]
  76. Qian Y, Liu C, Hartupee J, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol (2007) 8:247–56.[CrossRef][Web of Science][Medline]
  77. Awane M, Andres PG, Li DJ, Reinecker HC. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol (1999) 162:5337–44.[Abstract/Free Full Text]
  78. Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med (2000) 191:1233–40.[Abstract/Free Full Text]
  79. Faour WH, Mancini A, He QW, Di Battista JA. T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade: role of distal sequences in the 3'-untranslated region of COX-2 mRNA. J Biol Chem (2003) 278:26897–907.[Abstract/Free Full Text]
  80. Henness S, Johnson CK, Ge Q, Armour CL, Hughes JM, Ammit AJ. IL-17A augments TNF-alpha-induced IL-6 expression in airway smooth muscle by enhancing mRNA stability. J Allergy Clin Immunol (2004) 114:958–64.[CrossRef][Web of Science][Medline]
  81. Hwang SY, Kim JY, Kim KW, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther (2004) 6:R120–8.[CrossRef][Web of Science][Medline]
  82. 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-kappaB- and p38 MAPK-dependent signalling pathways. Rheumatology (2007) 46:57–64.[Abstract/Free Full Text]
  83. Nakae S, Komiyama Y, Nambu A, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity (2002) 17:375–87.[CrossRef][Web of Science][Medline]
  84. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol (2003) 171:6173–7.[Abstract/Free Full Text]
  85. Lubberts E, Koenders MI, Oppers-Walgreen B, et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum (2004) 50:650–9.[CrossRef][Web of Science][Medline]
  86. Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol (2006) 7:1151–6.[CrossRef][Web of Science][Medline]
  87. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature (2006) 441:235–8.[CrossRef][Medline]
  88. 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 (2007) 8:967–74.[CrossRef][Web of Science][Medline]
  89. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity (2007) 26:371–81.[CrossRef][Web of Science][Medline]
  90. Hoeve MA, Savage ND, de Boer T, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol (2006) 36:661–70.[CrossRef][Web of Science][Medline]
  91. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol (2007) 8:942–9.[CrossRef][Web of Science][Medline]
  92. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol (2007) 8:950–7.[CrossRef][Web of Science][Medline]
  93. Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol (2006) 18:670–5.[CrossRef][Web of Science][Medline]
  94. Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med (1996) 183:2593–603.[Abstract/Free Full Text]
  95. Happel KI, Zheng M, Young E, et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol (2003) 170:4432–6.[Abstract/Free Full Text]
  96. Liu XK, Clements JL, Gaffen SL. Signaling through the murine T cell receptor induces IL-17 production in the absence of costimulation, IL-23 or dendritic cells. Mol Cells (2005) 20:339–47.[Web of Science][Medline]
  97. Chabaud M, Garnero P, Dayer JM, Guerne PA, Fossiez F, Miossec P. Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. Cytokine (2000) 12:1092–9.[CrossRef][Web of Science][Medline]
  98. Ziolkowska M, Koc A, Luszczykiewicz G, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol (2000) 164:2832–8.[Abstract/Free Full Text]
  99. Kotake S, Udagawa N, Takahashi N, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest (1999) 103:1345–52.[Web of Science][Medline]
  100. McClung MR. Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Curr Osteoporos Rep (2006) 4:28–33.[CrossRef][Medline]
Submitted 18 May 2007; revised version accepted 30 November 2007.
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