review article therapeutic potential of il-17-mediated...

Review ArticleTherapeutic Potential of IL-17-Mediated Signaling Pathway inAutoimmune Liver Diseases

Haiyan Zhang12 Francesca Bernuzzi1 Ana Lleo1 Xiong Ma2 and Pietro Invernizzi1

1Liver Unit and Center for Autoimmune Liver Diseases Humanitas Clinical and Research CenterVia Manzoni 56 Rozzano 20089 Milan Italy2State Key Laboratory for Oncogenes and Related Genes Key Laboratory of Gastroenterology and Hepatology Ministry of HealthDivision of Gastroenterology and Hepatology Ren Ji Hospital School of Medicine Shanghai Jiao Tong UniversityShanghai Cancer Institute Shanghai Institute of Digestive Disease 145 Middle Shandong Road Shanghai 200001 China

Correspondence should be addressed to Pietro Invernizzi pietroinvernizzihumanitasit

Received 27 February 2015 Accepted 20 May 2015

Academic Editor Jianfei Yang

Copyright copy 2015 Haiyan Zhang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Emerging evidence reveals that various cytokines and tissue microenvironments contribute to liver inflammation and autoimmu-nity and IL-17 family is one of highlights acknowledged Although the implication of IL-17 family in most common autoimmunediseases (such as psoriasis inflammatory bowel disease and rheumatoid arthritis) has been extensively characterized the role ofthis critical family in pathophysiology of autoimmune liver diseases (AILD) still needs to be clarified In the review we look intothe intriguing biology of IL-17 family and further dissect on the intricate role of IL-17-mediated pathway in AILD Consideringencouraging data from preclinical and clinical trials IL-17 targeted therapy has shown promises in several certain autoimmuneconditions However blocking IL-17-mediated pathway is just beginning and more fully investigation and reflection are requiredTaking together targeting IL-17-mediated responses may open up new areas of potential clinical treatment for AILD

1 Introduction

Liver is an immunological organ with unique properties ofimmune tolerance which can lead to systemic immune tol-erance Many genetically susceptible individuals suffer fromautoimmune liver diseases (AILD) while some unidentifiedenvironmental factors trigger the breach in immune toler-ance resulting liver as a victim However the exact pathogen-esis of AILD is still unknown Autoimmune hepatitis (AIH)primary biliary cirrhosis (PBC) primary sclerosing cholan-gitis (PSC) and autoimmune sclerosing cholangitis are themajor forms of AILD Besides a proportion of patients withinthe spectrum of AILDmay present with overlapping featuresof two classical disorders such as AIH PBC and PSC Thesepatients are often referred to as ldquooverlap syndromesrdquo [1 2]

AILD have fluctuating and progressive courses withalternating relapses and quiescences The spectrum of AILDis diverse ranging from insidious onset with abnormal liverfunction tests to fulminant hepatic failureThe causes of these

clinical conditions are complex and most likely heteroge-neous The mechanisms responsible for the progression ofAILD are yet to be fully clarified However recent studieshave demonstrated that cytokines play a pivotal role in theinduction of immune responses during the development andprogression of liver diseases Among them IL-17 family isone of the dominant pathogenic components in autoimmuneinflammatory diseases such asmultiple sclerosis (MS) psori-asis and rheumatoid arthritis (RA) [3ndash5] Of interest its rolein AILD still requires clarification On this basis this reviewaddresses the current data regarding the roles of IL-17 signal-ing in the pathogenesis ofAILD andprovides new insight intotherapeutic potential of targeting IL-17-mediated responses

2 General Features of Interleukin-17

21 IL-17 Family (Discovery Structure Resource and Func-tion) IL-17A (commonly referred to as IL-17) was firstidentified as a product of rodent activated T cells in 1993

Hindawi Publishing CorporationMediators of InflammationVolume 2015 Article ID 436450 12 pageshttpdxdoiorg1011552015436450

2 Mediators of Inflammation

and was initially known as cytotoxic T lymphocyte associatedantigen 8 (CTLA-8) [6] Since then other five members ofIL-17 family IL-17B IL-17C IL-17D IL-17E (also called IL-25) and IL-17F have been discovered based on homology inamino acid sequences [6ndash9]

IL-17A is the most well investigated member of the IL-17 family and acts on multiple cell types to enhance theproduction of various proinflammatory molecules includingcytokines (such as TNF and IL-6) chemokines (such asCXCL2 andMCP-1)mucins acute phase proteins andmatrixmetalloproteinases [10ndash16] Overall IL-17A exerts a widerange of functions in autoimmune diseases host defensetransplantation allergy and malignancy [17ndash21]

With the family IL-17F is the most homologous proteinto IL-17A (sim60) and resembles IL-17A in both the cellularsources and regulation function [22] Interestingly IL-17Aand IL-17F exist as homodimers [10] In addition IL-17A andIL-17F also form a heterodimeric cytokine (IL-17AF) withintermediate signaling potency [23]

Th17 a subset of CD4+T cells named for their abilityto preferentially produce IL-17 is recognized as the majorproducers of IL-17A and IL-17F [24] In addition severalinnate immune cell types are described as sources for IL-17including 120574120575T-cells natural killer (NK) cells natural killer T(NKT) cells dendritic cells (DCs) activatedmonocytes mastcells neutrophils and lymph tissue inducer (LTi) cells [25ndash28] Of note IL-17A is found to be approximately 10ndash30 timesmore potent than IL-17F [29] However IL-17F and IL-17Ahave overlapping yet distinct proinflammatory roles in hostimmune and defense mechanisms such as mucoepithelialbacterial infections inflammatory responses and allergicdiseases [30 31] For example genetic deletion of IL-17Fresulted in reduced experimental colitis caused by dextransulfate sodium whereas deletion of IL-17A inmice developedmore severe intestinal disease [32]

Unlike IL-17F IL-17E (IL-25) is the most distant cytokinefrom IL-17A in IL-17 family Recent studies show that IL-17E promotes Th2-mediated immune responses particularlycontributing to airway inflammation and allergic disease [33ndash35]

Far less is known about the cellular sources recep-torstarget cells and biological functions of the three remain-ing other IL-17 family cytokines IL-17B is expressed inmultiple organs including small intestine pancreas spinalcord and stomach [36] IL-17C was detected in keratinocytesand tracheal epithelial cells [37 38] Similar to IL-17B IL-17D is also expressed in a variety of organs and tissuesincluding heart pancreas and adipose tissue [22] Recentstudies from both human and animal models suggest thatthese IL-17 family members might possess an importantrole in inflammatory disease which highlights the need forfurther exploration For instance IL-17B was observed toparticipate in a murine model of collagen-induced arthritiswhereas treatment with IL-17B neutralizing antibody cansuccessfully suppress arthritis [39]

22 IL-17 Receptors (Discovery Structure Expression andSignaling) Interleukin-17RA (also known as IL17R) was thefirst receptor identified for IL-17A [40] IL-17RA is expressed

in considerable cell types including endothelial cells epithe-lial cells fibroblasts and myeloid cells However subsequentstudies have demonstrated additional receptor members arerequired to form a functional receptor complex for IL-17signaling [41] The IL-17 receptor family represents a groupof multimeric proteins that consists of four other moleculesIL-17RB (also known as IL17Rh1) IL-17RC (also known asIL17RL) IL-17RD and IL-17RE

Recent studies of IL-17RB revealed the expression inNKT cells memory Th2 cells macrophages lung epithelialcells airway smooth muscle cells and endothelial cells [42ndash44] IL-17RB can bind to both IL-17B and IL-17E in vitroand actively participate in Th2 immune responses via IL-17EndashIL-17RB interaction particularly in airway inflammation[33] Besides genetic and biochemical studies indicate IL-17RB binding to IL-17E recruits IL-17RA to the complex inmediating IL-17E function [45]

IL-17RC was initially identified based on sequencehomology to IL-17RA [46] IL-17RC was found to shareexpressionwith IL-17RA inmultiple cells including epithelialcells macrophages and fibroblasts but its expression onmyeloid cells is much lower [47] Of note the assembly ofa heterodimeric complex between IL-17RA and IL-17RC isrequired for the biological signaling of IL-17A and IL-17FNevertheless IL-17RCmay have some functions independentof IL-17RA for IL-17RC expression is elevated in someorgans and tissues such as small intestine and lung where theexpression of IL-17RA is absent [30]

IL-17RD and IL-17RE were also identified throughdatabase mining however little is currently known aboutthese two orphan receptors Studies have discovered theexpression of IL-17RD in epithelial cells and endothelial cellsMoreover IL-17RD can pair with IL-17RA to mediate IL-17A signaling while mutations of the IL-17RD cytoplasmicdomain can suppress IL-17A function [48] On one side IL-17RE RNA could be detected in lung testis kidney stomachand intestine on the other side the cellular expression of IL-17RE is poorly understood Further studies will be needed toaddress the significance of IL-17RE [49]

These single-pass receptors share minimal structuralhomology including a single transmembrane domain an ex-tracellular-fibronectin III-like (FnIII) domain and an intra-cellular SEFIL-17R (SEFIR) domain [29 50] As IL17R pro-teins possess the conserved SEFIR domain with IL17 familyligands binding this intracellular domain can directly inter-act with adaptor protein ACT1 (also known as TRAF3IP2)to initiate signaling cascades augmenting various inflamma-tory molecules that participate in immune responses Forinstance with the help of both ACT1 and TNF receptor asso-ciated factor 6 (TRAF6) the binding of IL-17A to IL-17RAcan activate nuclear factor-120581B (NF-120581B) signaling pathway[51] Additionally IL-17A can activate the CCAATenhancerbinding proteins (CEBPs)-CEBP120573 and CEBP120575 to inducethe transcription of inflammatory gene such as IL-6 [13]By contrast IL-17R-Act1-TRAF-NF-120581B pathway can be nega-tively regulated by the binding of TRAF3 to IL-17R resultingin suppression of downstream signaling [52]

Mediators of Inflammation 3

Table 1 Pathophysiological findings on IL-17 pathway in the development of AILD

Disease type Sources Main findings References

AIHPatients

Elevated levels of IL-17 and IL-23 in serum IncreasedTh17 cells inperipheral blood [53 54]

Infiltration of Th17 cells with enhanced ROR-120574t expression in liver [53]Increased expression of IL-17-related cytokines (IL-23 IL-21 IL-1120573 andIL-6) in liver [53]

Impairment of CD39posTregs to suppress IL-17 pathway [55]Greater proportions of IL-17+ and ROR120574+ cells in ngTregs [56]

Mouse models Elevated IL-17 levels in liver and serum [54]Blockade of IL-17 attenuate inflammatory liver injury [54]

PBC

Patients

Elevated levels of IL-17-related cytokines (IL-17 IL-23 IL-1120573 and IL-6) andenhanced gene expression of IL-17-mediated signalling pathway (IL-23 p19IL-23R and IL-17) in serum

[57 58]

Expansion of Th17 cells with enhanced ROR-120574t expression in peripheralblood [57]

Aggregation of Th17 cells around interlobular bile ducts [59ndash61]Enhanced expression of Th17-related cytokines and their cognate receptors(IL-23p19 IL-23p40 IL-17 and IL-23R) in liver [61]

Induction of inflammatory cytokines and chemokines (IL-6 IL-1120573IL-23p19 CXCL1 CXCL2 CXCL3 CXCL6 CXCL8 CCL2 and CCL20) byIL-17 in human BECs

[60]

Upregulation of MIP-3120572 in human BECs for further recruit of LCs [62]Mouse models

IL-12R120572minusminusmice Increased frequencies of IL-17 producing cells in liver [63]Induction of IL-17 responses by splenic CD4+ T cells cocultured with NPCs [59]

2OA-BSA-immunized mice Reduction of biliary damage in IL-17Aminusminusmice and IL-22minusminusmice Lowerlevels of AMA in IL-17Aminusminusmice [64]

dnTGF120573RII mice Lower titres of anti-gp210 antibodies in mice with deletions of IL-17-relatedcytokines (IL-12p40 IL-23p19 IL-17 IL-6 and TNF-120572) [65]

PSC

Patients

Infiltration of IL-17+ lymphocytes around damaged bile ducts and in areasof neoductular proliferation [66]

Increased frequencies of Th17 cells by stimulation of pathogen in peripheralblood [67]

Induction of Th17 cells by the selective stimulation of TLR 5 and TLR 7 [66]

Mouse models (BDL)

Elevated levels of IL-17A in serum [68]Increased gene levels of IL-17-related cytokines and receptors (IL-17 AIL-17F IL-17RA and IL-17RC) in liver [68]

Reduction of BDL-induced liver fibrosis in IL-17RAminusminusmice [68]Strong expression of IL-17-related cytokines and their receptors in liverresident cells (Kupffer cells HSC) [68 69]

Induction of TNF-120572 and TGF-120573 in Kupffer cells by IL-17 and in turnpromotion of IL-17 expressing cells differentiation [68 69]

AIH autoimmune hepatitis PBC primary biliary cirrhosis BEC biliary epithelial cells MIP-3120572 macrophage inflammatory protein-3120572 LC Langerhans cellsNPCs nonparenchymal cells AMA anti-mitochondrial antibodies dnTGF120573RII dominant-negative TGF-120573 receptor II PSC primary sclerosing cholangitisTLR Toll-like receptor BDL bile duct ligation HSC hepatic stellate cells 2OA 2-octynoic acid

3 Pathological Roles of IL-17 inAutoimmune Liver Diseases

Before the recognition of the distinct Th17 population itwas considered that Th1 Th2 and B cells were the dom-inant cellular components of pathology in autoimmunityHowever with the deepening of the studies about IL-17family IL-17 has been strongly implicated in the pathogenesis

of autoimmune diseases such as psoriasis inflammatorybowel disease (IBD) RA and systemic lupus erythematosus(SLE) [70ndash73] Nevertheless robust evidence demonstratesthat autoimmune liver diseases implicate the IL-17 pathway(Table 1)

31 Autoimmune Hepatitis AIH is a chronic inflamma-tory liver condition of unknown etiology that is putatively


initiated by the aberrant autoaggressive immunity againsthepatocyte-specific autoantigens [57] AIH is a progres-sive necroinflammatory disease characterized by elevatedaminotransferase levels hypergammaglobulinemia circulat-ing autoantibodies and histological evidence of interfacehepatitis [74] The abnormal autoimmune reactions in AIHare believed to be orchestrated by self-antigenic peptideactivated T cells that trigger the antibody-mediated cellularcytotoxicity and contribute to the pathogenesis of AIH [75]

Traditionally AIH has been associated with dysregula-tions of both innate and adaptive immunity Recently IL-17 pathway has caught the attention of hepatologists andimmunologists for IL-17 that is inimitably positioned atthe interface of both types of immunity A recent studyhas suggested that the serum levels of IL-17 and IL-23were significantly higher in patients with AIH compared topatients with chronic hepatitis B (CHB) and healthy controlsMoreover the frequency of circulating Th17 cells and thegene expression of IL-17 in the peripheral bloodmononuclearcells (PBMC) of AIH patients were also demonstrated tobe substantially elevated when detected by flow cytometryand real-time PCR [53 54] It is important to note thatthe number of Th17 cells and the gene expressions of IL-17specific transcription nuclear factor- retinoic-acid-receptor-related orphan nuclear receptor gamma (ROR-120574t) also weresignificantly increased in the liver of AIH patients comparedto those with CHB and healthy controls Interestingly hepaticTh17 cells in AIH patients are increased in a disease severitydependent manner In addition the expression of IL-17-related cytokines that is IL-23 IL-21 IL-1120573 and IL-6 wassignificantly augmented in the liver of AIH patients [53]

In mouse models of experimental autoimmune hepatitiscongruent findings reported that the expression of IL-17 inthe livers and sera of AIH mice were significantly elevatedcompared to the control mice It is noteworthy that admin-istration of IL-17A monoclonal neutralizing antibody couldmarkedly reduce histological hepatic necrosis and serumALTlevels compared to controls [54]These data suggest that IL-17pathway is likely to be a prime part of AIH pathogenesis

The mechanisms underlying the breakdown of self-tolerance leading to AIH have not been fully elucidatedthough numerous lines of evidence indicate that numer-ical and functional regulatory T-cell (Tregs) defects mayplay a permissive pathogenic role [76ndash78] Accordinglythe disrupted regulatory circuits of Tregs may accountfor the aberrant dysregulation of IL-17-mediated inflam-matory responses Within the Tregs group CD39posTregshave been shown to display specific suppression over IL-17 immunity compared to their CD39neg counterpart [79]More recently studies have reported that CD39posTregs notonly are decreased in frequency but also exhibit limitedadenosine triphosphateadenosine diphosphate hydrolysisactivity in AIH patients which in turn fail to suppressthe overactive IL-17 pathway by effector CD4+ T cells [55]These observations imply that impairment of CD39posTregsin AIH an inability to suppress IL-17 production and apropensity to convert to IL-17 producing effectors maycontribute to defected immunosuppression and autoimmune

liver condition Notably Tregs and Th17 cells share a com-mon progenitor though their developmental pathways differPrevious studies have reported that Tregs could be generatedfrom CD25minus (ngTreg) cells in AIH patients which suppressthe immune responses less efficiently than the freshly isolatedTregs [80] More importantly studies also demonstrated thatngTregs from AIH patients presented the greater propor-tions of IL-17+ and ROR120574+ cells than Tregs from healthycontrols Furthermore taking advantage of several differentapproaches for the removal of IL-17 influence ngTregs frompatients with AIH managed to differentiate into functionallystable immunosuppressive cells [56] These data highlightedthe crucial effect of IL-17 pathway on defeated function ofTreg in AIH and laid a solid foundation for immunothera-peutic strategies aiming at reestablishing immune tolerancethrough Treg infusion in combination with IL-17 abrogation

32 Primary Biliary Cirrhosis PBC is a chronic inflammatoryautoimmune disease thatmainly targets the cholangiocytes ofthe interlobular bile ducts in the liver [81] The diagnosis ofPBC is made when two of the three criteria are fulfilled thatis presence of serologically PBC-specific autoantibodies suchas anti-mitochondrial antibodies (AMA) abnormal changesin biochemical tests indicating cholestasis for longer than 6months and histologically chronic nonsuppurative destruc-tive cholangitis followed by progressive bile duct loss [82]There have been significant advances in the understanding ofthe immunobiology of PBC which is regarded as a classicalT cell-mediated autoimmune disease Intriguingly variouscytokines and tissuemicroenvironments were shown to exertcrucial roles in the regulation and propagation of autoim-mune inflammatory responses Accumulating evidence inmouse models and clinical studies has clearly demonstratedthe pivotal involvement of IL-17 signaling pathway in thepathogenesis of PBC

It has been well described that not only the serumconcentrations of IL-17 and IL-17-related cytokines suchas IL-23 IL-1120573 and IL-6 but also the mRNA expressionlevels of IL-17-mediated signaling pathway such as IL-23p19 IL-23R and IL-17 in PBMCs from PBC patients weresignificantly elevated compared to the healthy control [5758] Consistent with the IL-17 cytokines profile peripheralTh17 cell population and IL-17 specific ROR-120574t expression ofPBC patients were increased markedly compared to patientswith CHB On the contrary peripheral Treg cell populationand the expression of Treg specific transcription nuclearfactor FOXP3 were decreased dramatically in patients withPBC relative to CHB disease control [57]These observationsstrongly imply that the Th17Treg imbalance appears toexacerbate the breakdown of immune homeostasis in PBC

One of the intriguing questions in PBC is that theautoimmune attack is organ specific and the immunologicaldestruction is selective focus on small bile ducts Consistentwith this notion researchers concern more about the roleof IL-17 pathway in the liver of PBC patients Indeedseveral studies have revealed that PBC patients exhibit ele-vated levels of hepatic IL-17+ infiltrates as compared withhealthy livers [59 60] Of interest our recent results addressthe extensive IL-17-associated cytokines microenvironment


specifically in the livers of PBC and non-PBC control liverdisease patients Our observations have demonstrated thatTh17-related cytokines and their cognate receptors that is IL-23p19 IL-23p40 IL-17 and IL-23R were expressed by theinflammatory cells localized to the portal tracts with the IL-17+ cells aggregated around interlobular bile ducts intensivelyMore importantly Th17 skewing was more prominent inadvanced PBC patients [61] This direct association of Th17skewing with disease severity uncovers the significance ofthe IL-23Th17 pathway in the perpetuation of the so-calledtraditional IL-12Th1-mediated immunopathology in PBC

Of noted importance is that small biliary epithelial cells(BECs) are regarded as the target cells of the autoimmunedestruction in PBC [83] Thus numerous studies aim tounravel the contribution of IL-17 pathway on the patho-genesis of cholangiopathy Interestingly BECs possess IL-17-receptors (IL-17RA and IL-17RC) and also Act1 (an essen-tial adaptor protein in IL-17-mediated signaling) By takingadvantage of the cultured human BECs stimulation with IL-17 could induce the production of inflammatory cytokines(IL-6 IL-1120573 and IL-23p19) and chemokines (CXCL1 CXCL2CXCL3 CXCL6 CXCL8 CCL2 and CCL20) [60] Theseevidences have indicated that periductal secreton of IL-17facilitate the migration of various inflammatory cells includ-ingTh17 cells which in turn aggravate the chronic cholangitisand bile duct damage in PBC Moreover a subsequent studydemonstrated that Langerin+ Langerhans cells (LCs) whichwere dominantly scattered around or within biliary epitheliallayers of the damaged bile ducts served as periductal antigen-presenting cells in PBC [84] IL-17 managed to upregulate theexpression of macrophage inflammatory protein-3120572 (MIP-3120572) in human BECs dramatically while MIP-3120572 is the mainchemokine for attracting and recruiting LCs [62] Collec-tively IL-17 pathway exerts as an unneglectable componentof the periductal cytokinemilieu and biliary innate immunityin PBC

Detailed studies in several well-characterized murinemodels of PBC have further confirmed the importance of IL-17 signaling pathway in the development and progression ofPBC To beginwith IL-2 receptor120572 knockoutmice one of theidentified murine models manifesting characteristic clinicalfeatures of human PBC exhibits increased frequencies of IL-17 producing cells in the liver [63] Similar to PBC patientsIL-2R120572KOmice also demonstrate aggregative IL-17+ stainingin diseased portal areas compared to control Notably splenicCD4+ T cells cocultured with liver nonparenchymal cells(NPCs) fromwild-typemice could augment IL-17 productionapproximately 10-fold compared to T cells alone [59] Thesedata suggest a novel connection between the induction ofIL-17 responses and unique liver environment mediated byliver NPCs and IL-17-related cytokinemilieus in cases of liverautoimmunity

Secondly 2-octynoic acid-BSA-immunized mice thatdevelop an intense inflammatory cholangitis with similaritiesto humans with PBC are another classical PBC animalmodelIn some unique gene-deleted mice immunized with 2OA-BSA it is interesting to find that deletion of IL-17A and IL-22instead of IL-17F could attenuate biliary damage and inflam-mation Moreover reduced levels of AMA were detected in

IL-17A-knockout mice compared with controls [64] Thesefinding propose a potential therapeutic intervention of IL-17pathway for PBC

Additionally dominant-negative TGF-120573 receptor II(dnTGF120573RII) mice are also one of the well-establishedspontaneous models that exhibit histological features ofPBC with the same AMA specificity [85] It is important tonote that considerable patients with PBC have detectableserum ANA directed primarily against gp210 and sp100Upon further investigation it was revealed that sera fromdnTGF120573RII mice contained antibodies against gp210 andsp100 However mice with germline deletions of the genesencoding IL-17-related cytokines that is IL-12p40 IL-23p19IL-17 IL-6 and TNF-120572 had dramatically lower titres ofanti-gp210 antibodies but not anti-sp100 antibodies [65]In fact several lines of suggestive evidence mentioned thatpositive-anti-gp210 antibodies often predict a hepatic failuretype of progression in PBC [86 87] Deletion of thoseIL17-related cytokines that led to significantly lower serumanti-gp210 titres suggests thatTh17 cells appear to orchestrateanti-gp210 generation Taken together these observationsprovide a clue to further dissect the possible interactionbetween IL-17 inflammatory responses and the appearanceof PBC-specific autoreactivity

33 Primary Sclerosing Cholangitis PSC is a rare chroniccholestatic liver disease characterized by diffuse inflamma-tion destruction and fibrosis of multifocal bile ducts leadingto strictures predominantly in large- andmedium-sized ductsof the biliary tree [88 89] At present the critical etiologyor the conclusive pathogenic mechanisms underlying PSCremain unclear Numerous hypotheses have emerged andit has been widely accepted that abnormality of hepaticimmune response contribute to initiation and progressionof fibro-obliterative cholangiopathy [90 91] Recent evidencehas revealed that Th17 cells and its canonical cytokine IL-17 are served as critically important contributors of PSCpathogenesis

It has recently been described the numbers of IL-17+lymphocytes in liver were significantly increased in PSCpatients compared to AIH control patients AdditionallyIL-17A-expressing T cells aggregated around damaged bileducts and in areas of neoductular proliferation [66] Itis increasingly recognized that dysregulated responses topathogen stimulation especially bacteria and fungi maybe the proximal contributor to the immune activation inPSC [67 92] Of significance PBMCs from PSC patientsmanifested significantly increased frequencies of Th17 cellsafter pathogen stimulation compared to healthy controls andcholestatic controls Interestingly stimulation with Candidaalbicans which was shown to have a negative effect onprogression of disease gained the highest frequencies ofTh17cells than other pathogens in PSC patients [67] FurthermoreTh17 induction were noted by the selective stimulation ofToll-like receptors (TLR) 5 and 7 indicating that the patternrecognition receptors signaling pathways may intimately beinvolved in this response [66] These evidence points tothe speculation that aberrant exposure to pathogens in bilepotentially lead to a robust induction of IL-17 responses


which could initiate and then perpetuate portal and biliaryinflammation in PSC

By using several currently available animalmodels resem-bling some individual characteristic hallmarks of humanPSC researchers can therefore obtain a better knowledgeof IL-17 pathway Experimental biliary obstruction mod-els such as bile duct ligation (BDL) share the cardinalfeatures of obstructive cholestasis and biliary fibrosis withhuman PSC [93 94] Consistent with the reports from PSCpatients both the gene levels of IL-17-related cytokines andreceptors (IL-17 A IL-17F IL-17RA and IL- 17RC) in thelivers and sera concentration of circulating IL-17A in BDLmice were strongly upregulated compared with their shamcontrol More importantly BDL-induced liver fibrosis wasapparently inhibited in IL-17RAminusminus mice compared withtheir wild-type counterparts manifested by a sharp decreaseof collagen deposition 120572-SMA+ myofibroblasts number andmRNA expression of fibrogenic gene and so forth [68]Intriguingly liver resident cells such as Kupffer cells andhepatic stellate cells (HSC) can also show strong expressionof IL-17 cytokines and their receptors in addition to Th17Furthermore IL-17 could stimulate the production of TNF-120572 and TGF-120573 from Kupffer cells which then regulate theHSC activation via the Stat-3 signaling pathway and inturn promote the differentiation of IL-17 expressing cells[68 69] To date however there is no ideal single animalmodel that can demonstrate that all the characteristic of PSCpatients existsTherefore wewill rather call formore differentmodels to elucidate the particular immune role of IL17IL17Rsignaling within the pathogenetic steps of PSC

4 Therapeutic Potential of IL-17-MediatedSignaling Pathway in AutoimmuneLiver Diseases

As the studies mentioned above excessive IL-17 responseshave been proven to be a key mediator and potent drivers ofliver-specific autoimmune diseases With these comments inmind targeting dysregulated IL-17 signaling pathway seemsto be a new area of promising immunotherapy for AILDpatients especially for those patients who failed to respondto conventional therapy However detailed studies on thepotential of adjusting violent IL-17 responses in AILD remainlimited On the other hand it is also clear that pathologicalIL-17-mediated signaling is generally involved in many otherhuman autoimmune conditions such as psoriasis IBD RASLE andMS to name a few [3 95ndash98] Inspiringly numerousclinical studies have examined the feasibility and effective-ness of reconstituting IL-17-mediated pathways includingtargeting IL-17-related cytokinesreceptors regulating theexpression of IL-17 cytokines and IL-17IL-17R downstreamsignaling for therapeutic purposes (Figure 1)

41 Blocking IL-17IL-17 Receptors Among different optionsfor targeting IL-17 pathway blocking IL-17 or IL-17R familytend to be the most direct strategy Thus accumulatingevidences stem from cellular animal and human studies

uncovered the beneficial anti-inflammatory effect of blockingIL-17IL-17 receptors on attenuating autoimmune diseases[99] These encouraging results of targeting IL-17IL-17Rattract the attention of many medicine companies and thepredominant studies prefer to focus on IL-17A and IL-17RA Blocking agents that neutralize IL-17A (eg secuk-inumabAIN457 ixekizumabLY2439821) and IL-17RA (egbrodalumabAMG-827) are on track to Phase IIIII clinicaltrials with satisfactory data Taking treating psoriasis patientsfor example all the published Phase II randomized double-blind placebo-controlled studies results from these threehumanized monoclonal antibodies offer encouragementwith the majority of (82 for secukinumab versus 9 forplacebo 119875 lt 0001 828 for ixekizumab versus 77for placebo 119875 lt 0001 863 for brodalumab versus160 for placebo 119875 lt 0001) patients obtaining at least75 improvement from baseline in the Psoriasis Area andSeverity Index score (PASI 75) after 12 weeks of treatment[100ndash102] Furthermore Phase III results demonstrated thatsecukinumab not only significantly improved the clinicalsymptoms of psoriasis at 12 weeks but also offer fasteryet longer efficacy than etanercept (TNF inhibitor) andplacebo control [103] Favorable findings were also reportedin the clinical trial of secukinumab and ixekizumab withsatisfactory relief of symptoms and safety in various IL-17-related autoimmune disease states such as RA ankylosingspondylitis and noninfectious uveitis [104ndash107] However itis noteworthy that secukinumab is ineffective and has higherrates of adverse events for treating patients with moderate tosevere Crohnrsquos disease [108] This unfavorable data alarm usto give more cautious consideration on IL-17 antibody beforecomprehensive clinical application

Regarding targeting IL-17IL-17R family there are othermembers under the consideration In the light of threedifferent forms of IL-17 complex exist that are IL-17AIL-17A homodimer IL-17FIL-17F homodimer and IL-17AIL-17F IL-17AIL-17A heterodimer Researchers aim to targetboth IL-17A and IL-17F by using the same antibody RG7624(Roche) to assess the efficacy and safety in the clinical trialHowever to the best of our knowledge there have not beenany published data from RG7624 Phase I trial Concerningtargeting IL-17 receptor IL-17RC is believed to be anotherpotential strategy in addition to IL-17RA As IL-17RA and IL-17RC heterodimer function as the indispensable componentof IL-17A and IL-17F signaling pathway [109] the therapeutictool blocking both IL-17 RA and IL-17RC gains the attentionIn concordance previous study demonstrated that both IL-17RA and IL-17RC were implicated in the IL-17-triggeredinflammatory cascade and blockade of both receptors bysilencing interfering RNA or specific inhibitors was essen-tially needed to downregulate IL-17 pathogenic responsesin RA [110] Nevertheless targeting IL-17RA may lead toundesirable effect on the IL-17E-mediated responses with IL-17RAIL-17RB heterodimer as receptor for IL-17E [111] Inview of anti-inflammatory effect of IL-17E in inflammatoryautoimmune disorders thus targeting IL-17RCmay be amorespecific and efficient strategy


Th 17 cell

IL-17AIL-17A

IL-6

IL-1120573

IL-1120573

IL-23

IL-23p19 p40

IL-23

R

IL-12

R1205731

TYK2JAK2

IL-6

Gp1

30

Gp1

30

IL-6

RJAK2 JAK2

Naiumlve CD4+ T cell

ROR120574t

IL-17AIL-17F

IL-17FIL-17F

IL-17RAIL-17RC

ACT1

TRAF-6

NK-120581B

IL-17 target cellIL-17

IL-6 receptor antagonisttocilizumab

ROR120574t inhibitorsSR1001 SR2211

IL-17A-targeted antibodiessecukinumabAIN457 ixekizumabLY2439821

IL-17A and IL-17F-targeted antibodiesRG7624

IL-17RA receptor antagonistbrodalumabAMG-827

Inhibitors of IL-17R signal transductionCCrsquo loop decoy peptide

STAT-4

STAT-3

STAT-3

STAT-3P P

STAT-4STAT-3

Innate IL-17 producing cell

IL-1 receptor antagonistanakinra

Antigen presenting cell

Antigen

STAT-3STAT-3

P P

IL-1R

IL-23IL-12 p40-targeted antibodiesustekinumab briakinumab

IL-23 p19-targeted antibodiesSCH900222MK-3222 LY2525623

Figure 1 Therapeutic potential of targeting IL-17-mediated pathway Several novel strategies in which members of the IL-17 family canbe targeted are already in use for preclinical and clinical trials including inhibitors blocking the differentiation of TH17 cells IL-17 familycytokines or their cognate receptors-targeted antibodies and small molecule inhibitors blocking transduction of IL-17-mediated signaling intarget cells

42 Targeting Upstream of IL-17 New therapies inhibitingupstream of IL-17-mediated pathways have been proposedas attractive avenues of investigation Several proinflam-matory cytokines IL-23 IL-6 and IL-1120573 in particular arecrucial for the development of IL-17-expressing cells andthus provoke the induction of IL-17 cytokines Accordinglyclinical trials hold promise for targeting of these cytokines ortheir receptors as therapies of certain autoimmune diseasesFirst of all neutralization antibody against the p40 chainof IL-23IL-12 (ustekinumab and briakinumab) presentedsatisfactory efficacy and sustained safety in Phase IIIII clin-ical trials for treating patients with active psoriatic arthritisor refractory Crohnrsquos disease [112 113] More importantlyustekinumab yielded desirable long-term safety in patientswith moderate-to-severe psoriasis up to 5 years of follow-upin large approved Phase III trials [114 115] Given the factthat the p40 subunit is shared by IL-23 and IL-12 antibod-ies (SCH900222MK-3222 and LY2525623) aiming at IL-23unique subunit p19 should be more specific Presently theclinical trials of these two antibodies are still in process [116]

Secondly IL-6 also participates in the induction ofTh17 cells which are major source of IL-17A and IL-17FAntagonistical antibody against the interleukin 6 receptor(tocilizumab) demonstrates significant clinical efficacy andsatisfying safety hence tocilizumab has been approved inmany countries for the treatment of certain inflammatoryautoimmune diseases such as RA and juvenile idiopathicarthritis (JIA) [117 118] In addition IL-1120573 is another crucialcytokine for IL-17 induction Of significant IL-1 receptor

antagonist (anakinra) has emerged as a promising clinicaltreatment for RA [119]

It has been widely accepted that ROR120574t serve as the mas-ter regulator for Th17 differentiation Therefore this rendersus a clue that ROR120574t has the potential to be a promisingtherapeutic target for autoimmune disease Actually ROR120574t-specific inhibitors are on the way to become one of themost competitive biological drugs among all therapeuticfields Emerging studies have focus on the drug targetwith several favorable candidates for further development[120ndash122] Of relevance SR1001 a high-affinity dual ROR120572and ROR120574 inverse agonist has been proved to effectivelysuppress the clinical severity of experimental autoimmuneencephalomyelitis (a well-characterized model of multiplesclerosis) through its inhibition on TH17 cell differentia-tion [123] It is noteworthy that ROR120572 and ROR120574 exertextra functions outside of the immune system and are theimportant modulators of hepatic metabolism As ROR120572 isthe positive regulator of hepatic metabolic gene such asRev-erb120572 PAI-1 and Cyp7b1 administration of SR1001 mayhave broad implications in metabolic homeostasis [123ndash126]Therefore new inhibitors that are more specific to ROR120574tshould be thoughtfully selected before further usage inautoimmune liver disease treatment In concordance SR2211a potent ROR120574 modulator which demonstrate selectivelyinhibitory effect on the production of IL-17 in cells is seenas a potentially viable approach for treating autoimmunedisorders [127]


43 Targeting Downstream Signaling of IL-17 Downstreamtargets of IL-17IL-17R initiated signaling pathways arealso promising candidates to inhibit their proinflammatoryactivity Of note the genetic variation of the Act1 gene(TRAF3IP2) which is the key adaptor to propagate IL-17-mediated downstream signaling is associated with suscep-tibility to psoriasis and psoriatic arthritis by genome-wideassociation studies (GWAS) [128 129] As a first step totarget Act1 for therapeutic strategies recent study reportedthat blocking the interaction between Act1 and IL-17RA witha CC1015840 loop decoy peptide significantly attenuated IL-17-Aand IL-17E-associated inflammation [130] These observa-tions suggest the potential of blocking Act1 for managementof IL-17-induced autoimmune diseases Moreover crucialtranscription factors such as NF-120581B CEBP and AP-1 [131]involved in regulating IL-17 signaling events deserve moreattention and further investigation as the next generation ofefficacious therapies targets

5 Conclusions

IL-17 family has been shown to play active and essentialroles in the pathogenesis of AILD by controlling numerousimmune mediators and cellular events Therefore blockingIL-17-induced responses at an early stage should prevent theseinflammatory events to occur or exacerbate The discoveryof IL-17 target therapy has opened up new areas of potentialclinical treatment with several clinical trials showing encour-aging results However given the complexity of immunolog-ical interactions more intensive investigation and cautiousreflection are required Nevertheless there are still many keyquestions remaining with regard to other members of IL-17family besides IL-17A and IL-17F Of noted importance is thatinhibition of IL-17 similar to blockade of TNF-120572 cytokinecould raise the potential risks of serious infection and otherunexpected conditionsTherefore the optimal blockade placeof IL-17 pathway should properly balance therapeutic benefitsand side effects in human autoimmune disease management

Abbreviations

AILD Autoimmune liver diseasesAIH Autoimmune hepatitisPBC Primary biliary cirrhosisPSC Primary sclerosing cholangitisCHB Chronic hepatitis BMS Multiple sclerosisRA Rheumatoid arthritisNK Natural killerDCs Dendritic cellsLti Lymph tissue inducerBEC Biliary epithelial cellsMIP-3120572 Macrophage inflammatory protein-3120572LC Langerhans cellsNPCs Nonparenchymal cellsAMA Anti-mitochondrial antibodiesdnTGF120573RII Dominant-negative TGF-120573 receptor IITLR Toll-like receptorBDL Bile duct ligation

HSC Hepatic stellate cells2OA 2-Octynoic acidTRAF6 TNF receptor associated factor 6NF-120581B Nuclear factor-120581BIBD Inflammatory bowel diseaseSLE Systemic lupus erythematosus

Conflict of Interests

The authors declare that no financial conflict of interestsexists

References

[1] O Chazouilleres D Wendum L Serfaty S MontembaultO Rosmorduc and R Poupon ldquoPrimary biliary cirrhosis-autoimmune hepatitis overlap syndrome clinical features andresponse to therapyrdquo Hepatology vol 28 no 2 pp 296ndash3011998

[2] K M Boberg R W Chapman G M Hirschfield A WLohse M P Manns and E Schrumpf ldquoOverlap syndromes theInternational Autoimmune Hepatitis Group (IAIHG) positionstatement on a controversial issuerdquo Journal of Hepatology vol54 no 2 pp 374ndash385 2011

[3] J S Tzartos M A Friese M J Craner et al ldquoInterleukin-17production in central nervous system-infiltrating T cells andglial cells is associated with active disease in multiple sclerosisrdquoThe American Journal of Pathology vol 172 no 1 pp 146ndash1552008

[4] M A Lowes T Kikuchi J Fuentes-Duculan et al ldquoPsoriasisvulgaris lesions contain discrete populations of Th1 andTh17 Tcellsrdquo Journal of Investigative Dermatology vol 128 no 5 pp1207ndash1211 2008

[5] G Azizi F Jadidi-Niaragh and A Mirshafiey ldquoTh17 Cells inImmunopathogenesis and treatment of rheumatoid arthritisrdquoInternational journal of rheumatic diseases vol 16 no 3 pp243ndash253 2013

[6] E Rouvier M-F Luciani M-G Mattei F Denizot and P Gol-stein ldquoCTLA-8 cloned from an activated T cell bearing AU-rich messenger RNA instability sequences and homologous toaHerpesvirus saimiri generdquo Journal of Immunology vol 150 no12 pp 5445ndash5456 1993

[7] T Starnes H E Broxmeyer M J Robertson and R HromasldquoCutting edge IL-17D a novel member of the IL-17 familystimulates cytokine production and inhibits hemopoiesisrdquo TheJournal of Immunology vol 169 no 2 pp 642ndash646 2002

[8] J Lee W-H Ho M Maruoka et al ldquoIL-17E a novel proinflam-matory ligand for the IL-17 receptor homolog IL-17Rh1rdquo TheJournal of Biological Chemistry vol 276 no 2 pp 1660ndash16642001

[9] S G Hymowitz E H Filvaroff J Yin et al ldquoIL-17s adopt acystine knot fold structure and activity of a novel cytokine IL-17F and implications for receptor bindingrdquoThe EMBO Journalvol 20 no 19 pp 5332ndash5341 2001

[10] F Fossiez O Djossou P Chomarat et al ldquoT cell interleukin-17 induces stromal cells to produce proinflammatory andhematopoietic cytokinesrdquo Journal of Experimental Medicinevol 183 no 6 pp 2593ndash2603 1996

[11] S C Liang X-Y Tan D P Luxenberg et al ldquoInterleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively


enhance expression of antimicrobial peptidesrdquo The Journal ofExperimental Medicine vol 203 no 10 pp 2271ndash2279 2006

[12] M B M Teunissen C W Koomen R de Waal Malefyt EA Wierenga and J D Bos ldquoInterleukin-17 and interferon-120574 synergize in the enhancement of proinflammatory cytokineproduction by human keratinocytesrdquo Journal of InvestigativeDermatology vol 111 no 4 pp 645ndash649 1998

[13] F Shen Z Hu J Goswami and S L Gaffen ldquoIdentification ofcommon transcriptional regulatory elements in interleukin-17target genesrdquo The Journal of Biological Chemistry vol 281 no34 pp 24138ndash24148 2006

[14] S Dragon M S Rahman J Yang H Unruh A J Halayko andA S Gounni ldquoIL-17 enhances IL-1120573-mediated CXCL-8 releasefromhuman airway smoothmuscle cellsrdquoTheAmerican Journalof PhysiologymdashLung Cellular andMolecular Physiology vol 292no 4 pp L1023ndashL1029 2007

[15] W H Faour A Mancini Q W He and J A Di Battista ldquoT-cell-derived interleukin-17 regulates the level and stability ofcyclooxygenase-2 (COX-2) mRNA through restricted activa-tion of the p38 mitogen-activated protein kinase cascade Roleof distal sequences in the 31015840-untranslated region of COX-2mRNArdquoThe Journal of Biological Chemistry vol 278 no 29 pp26897ndash26907 2003

[16] M Laan Z-H Cui H Hoshino et al ldquoNeutrophil recruitmentby human IL-17 via C-X-C chemokine release in the airwaysrdquoThe Journal of Immunology vol 162 no 4 pp 2347ndash2352 1999

[17] Y Komiyama S Nakae T Matsuki et al ldquoIL-17 plays an impor-tant role in the development of experimental autoimmuneencephalomyelitisrdquo Journal of Immunology vol 177 no 1 pp566ndash573 2006

[18] H R Conti F Shen N Nayyar et al ldquoTh17 cells and IL-17receptor signaling are essential formucosal host defense againstoral candidiasisrdquo Journal of ExperimentalMedicine vol 206 no2 pp 299ndash311 2009

[19] H Chen W Wang H Xie et al ldquoA pathogenic role of IL-17 at the early stage of corneal allograft rejectionrdquo TransplantImmunology vol 21 no 3 pp 155ndash161 2009

[20] W J Burlingham R B Love E Jankowska-Gan et al ldquoIL-17-dependent cellular immunity to collagen type V predisposesto obliterative bronchiolitis in human lung transplantsrdquo TheJournal of Clinical Investigation vol 117 no 11 pp 3498ndash35062007

[21] N Martin-Orozco P Muranski Y Chung et al ldquoT helper 17cells promote cytotoxic T cell activation in tumor immunityrdquoImmunity vol 31 no 5 pp 787ndash798 2009

[22] T Starnes M J Robertson G Sledge et al ldquoCutting edgeIL-17F a novel cytokine selectively expressed in activated Tcells andmonocytes regulates angiogenesis and endothelial cellcytokine productionrdquo Journal of Immunology vol 167 no 8 pp4137ndash4140 2001

[23] S H Chang andC Dong ldquoA novel heterodimeric cytokine con-sisting of IL-17 and IL-17F regulates inflammatory responsesrdquoCell Research vol 17 no 5 pp 435ndash440 2007

[24] S Aggarwal N Ghilardi M-H Xie F J de Sauvage andA L Gurney ldquoInterleukin-23 promotes a distinct CD4 T cellactivation state characterized by the production of interleukin-17rdquo Journal of Biological Chemistry vol 278 no 3 pp 1910ndash19142003

[25] S Hue P Ahern S Buonocore et al ldquoInterleukin-23 drivesinnate and T cell-mediated intestinal inflammationrdquo Journal ofExperimental Medicine vol 203 no 11 pp 2473ndash2483 2006

[26] A V Rachitskaya A M Hansen R Horai et al ldquoCutting edgeNKT cells constitutively express IL-23 receptor and ROR120574tand rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashionrdquo Journal of Immunology vol 180 no 8 pp5167ndash5171 2008

[27] H H Uhlig B S McKenzie S Hue et al ldquoDifferential activityof IL-12 and IL-23 in mucosal and systemic innate immunepathologyrdquo Immunity vol 25 no 2 pp 309ndash318 2006

[28] D J Cua and C M Tato ldquoInnate IL-17-producing cells thesentinels of the immune systemrdquo Nature Reviews Immunologyvol 10 no 7 pp 479ndash489 2010

[29] S L Gaffen ldquoStructure and signalling in the IL-17 receptorfamilyrdquo Nature Reviews Immunology vol 9 no 8 pp 556ndash5672009

[30] H Ishigame S Kakuta T Nagai et al ldquoDifferential roles ofinterleukin-17A and -17F in host defense against mucoepithelialbacterial infection and allergic responsesrdquo Immunity vol 30no 1 pp 108ndash119 2009

[31] N Hizawa M Kawaguchi S-K Huang and M NishimuraldquoRole of interleukin-17F in chronic inflammatory and allergiclung diseaserdquo Clinical and Experimental Allergy vol 36 no 9pp 1109ndash1114 2006

[32] X O Yang S H Chang H Park et al ldquoRegulation ofinflammatory responses by IL-17Frdquo Journal of ExperimentalMedicine vol 205 no 5 pp 1063ndash1075 2008

[33] Y-H Wang P Angkasekwinai N Lu et al ldquoIL-25 augmentstype 2 immune responses by enhancing the expansion andfunctions of TSLP-DC-activatedTh2memory cellsrdquoThe Journalof Experimental Medicine vol 204 no 8 pp 1837ndash1847 2007

[34] T Sharkhuu K I Matthaei E Forbes et al ldquoMechanism ofinterleukin-25 (IL-17E)-induced pulmonary inflammation andairways hyper-reactivityrdquoClinical and Experimental Allergy vol36 no 12 pp 1575ndash1583 2006

[35] J L Barlow and A N J McKenzie ldquoIL-25 a key requirementfor the regulation of type-2 immunityrdquo BioFactors vol 35 no2 pp 178ndash182 2009

[36] H Li J Chen A Huang et al ldquoCloning and characterizationof IL-17B and IL-17C two new members of the IL-17 cytokinefamilyrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 97 no 2 pp 773ndash778 2000

[37] L vanMaele C Carnoy D Cayet et al ldquoTLR5 signaling stimu-lates the innate production of IL-17 and IL-22 byCD3119899119890119892CD127+immune cells in spleen and mucosardquo Journal of Immunologyvol 185 no 2 pp 1177ndash1185 2010

[38] D B Holland R A Bojar M D Farrar and K T Hol-land ldquoDifferential innate immune responses of a living skinequivalent model colonized by Staphylococcus epidermidis orStaphylococcus aureusrdquo FEMSMicrobiology Letters vol 290 no2 pp 149ndash155 2009

[39] Y Yamaguchi K Fujio H Shoda et al ldquoIL-17B and IL-17C are associated with TNF-120572 production and contribute tothe exacerbation of inflammatory arthritisrdquo The Journal ofImmunology vol 179 no 10 pp 7128ndash7136 2007

[40] Z Yao W C Fanslow M F Seldin et al ldquoHerpesvirus Saimiriencodes a new cytokine IL-17 which binds to a novel cytokinereceptorrdquo Immunity vol 3 no 6 pp 811ndash821 1995

[41] Z Yao M K Spriggs J M J Derry et al ldquoMolecular charac-terization of the human interleukin (IL)-17 receptorrdquo Cytokinevol 9 no 11 pp 794ndash800 1997


[42] Y Sonobe H Takeuchi K Kataoka et al ldquoInterleukin-25expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase C120576-dependent man-nerrdquo The Journal of Biological Chemistry vol 284 no 46 pp31834ndash31842 2009

[43] S Lajoie-Kadoch P Joubert S Letuve et al ldquoTNF-120572 and IFN-120574inversely modulate expression of the IL-17E receptor in airwaysmooth muscle cellsrdquo The American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 290 no 6 ppL1238ndashL1246 2006

[44] A Terashima H Watarai S Inoue et al ldquoA novel subset ofmouse NKT cells bearing the IL-17 receptor B responds toIL-25 and contributes to airway hyperreactivityrdquo Journal ofExperimental Medicine vol 205 no 12 pp 2727ndash2733 2008

[45] E A Rickel L A Siegel P Y Bo-Rin et al ldquoIdentification offunctional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activitiesrdquo The Journal of Immunology vol 181 no6 pp 4299ndash4310 2008

[46] R E Kuestner D W Taft A Haran et al ldquoIdentification of theIL-17 receptor related molecule IL-17RC as the receptor for IL-17FrdquoThe Journal of Immunology vol 179 no 8 pp 5462ndash54732007

[47] D Ge and Z You ldquoExpression of interleukin-17RC protein innormal human tissuesrdquo International Archives of Medicine vol1 no 1 article 19 2008

[48] Z Rong A Wang Z Li et al ldquoIL-17RD (Sef or IL-17RLM)interacts with IL-17 receptor and mediates IL-17 signalingrdquo CellResearch vol 19 no 2 pp 208ndash215 2009

[49] T-S Li X-N Li Z-J Chang X-Y Fu and L Liu ldquoIdentifi-cation and functional characterization of a novel interleukin 17receptor a possible mitogenic activation through rasmitogen-activated protein kinase signaling pathwayrdquo Cellular Signallingvol 18 no 8 pp 1287ndash1298 2006

[50] T A Moseley D R Haudenschild L Rose and A HReddi ldquoInterleukin-17 family and IL-17 receptorsrdquoCytokine andGrowth Factor Reviews vol 14 no 2 pp 155ndash174 2003

[51] A Hot and P Miossec ldquoEffects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytesrdquo Annals of theRheumatic Diseases vol 70 no 5 pp 727ndash732 2011

[52] S Zhu W Pan P Shi et al ldquoModulation of experimentalautoimmune encephalomyelitis through TRAF3-mediated sup-pression of interleukin 17 receptor signalingrdquo The Journal ofExperimental Medicine vol 207 no 12 pp 2647ndash2662 2010

[53] L Zhao Y Tang Z You et al ldquoInterleukin-17 contributes tothe pathogenesis of autoimmune hepatitis through inducinghepatic interleukin-6 expressionrdquo PLoS ONE vol 6 no 4Article ID e18909 2011

[54] H Yu J Huang Y Liu et al ldquoIL-17 contributes to autoimmunehepatitisrdquo Journal of Huazhong University of Science and Tech-nology [Medical Sciences] vol 30 no 4 pp 443ndash446 2010

[55] C R Grant R Liberal B S Holder et al ldquoDysfunctionalCD39119875119874119878 regulatory T cells and aberrant control of T-helpertype 17 cells in autoimmune hepatitisrdquo Hepatology vol 59 no3 pp 1007ndash1015 2014

[56] M S Longhi R Liberal B Holder et al ldquoInhibition ofinterleukin-17 promotes differentiation of CD25minus cells intostable T regulatory cells in patients with autoimmune hepatitisrdquoGastroenterology vol 142 no 7 pp 1526e6ndash1535e6 2012

[57] M P Manns A J Czaja J D Gorham et al ldquoDiagnosis andmanagement of autoimmune hepatitisrdquo Hepatology vol 51 no6 pp 2193ndash2213 2010

[58] C Qian T Jiang W Zhang et al ldquoIncreased IL-23 and IL-17expression by peripheral blood cells of patients with primarybiliary cirrhosisrdquo Cytokine vol 64 no 1 pp 172ndash180 2013

[59] R Y Z Lan T L Salunga K Tsuneyama et al ldquoHepatic IL-17 responses in human and murine primary biliary cirrhosisrdquoJournal of Autoimmunity vol 32 no 1 pp 43ndash51 2009

[60] K Harada S Shimoda Y Sato K Isse H Ikeda and YNakanuma ldquoPeriductal interleukin-17 production in associa-tion with biliary innate immunity contributes to the pathogen-esis of cholangiopathy in primary biliary cirrhosisrdquoClinical andExperimental Immunology vol 157 no 2 pp 261ndash270 2009

[61] C-Y Yang X Ma K Tsuneyama et al ldquoIL-12Th1 and IL-23Th17 biliary microenvironment in primary biliary cirrhosisimplications for therapyrdquo Hepatology vol 59 no 5 pp 1944ndash1953 2014

[62] K Harada S Shimoda H Ikeda et al ldquoSignificance ofperiductal Langerhans cells and biliary epithelial cell-derivedmacrophage inflammatory protein-3120572 in the pathogenesis ofprimary biliary cirrhosisrdquo Liver International vol 31 no 2 pp245ndash253 2011

[63] W Hsu W Zhang K Tsuneyama et al ldquoDifferential mech-anisms in the pathogenesis of autoimmune cholangitis versusinflammatory bowel disease in interleukin-2R120572minusminus micerdquo Hep-atology vol 49 no 1 pp 133ndash140 2009

[64] K Kawata M Tsuda G-X Yang et al ldquoIdentification ofpotential cytokine pathways for therapeutic intervention inmurine primary biliary cirrhosisrdquo PLoS ONE vol 8 no 9Article ID e74225 2013

[65] C-Y Yang P S C Leung G-X Yang et al ldquoEpitope-specificanti-nuclear antibodies are expressed in a mouse model ofprimary biliary cirrhosis and are cytokine-dependentrdquo Clinicaland Experimental Immunology vol 168 no 3 pp 261ndash267 2012

[66] J Katt D Schwinge T Schoknecht et al ldquoIncreased T helpertype 17 response to pathogen stimulation in patients withprimary sclerosing cholangitisrdquo Hepatology vol 58 no 3 pp1084ndash1093 2013

[67] H Kulaksiz G Rudolph P Kloeters-Plachky P Sauer H Geissand A Stiehl ldquoBiliary candida infections in primary sclerosingcholangitisrdquo Journal of Hepatology vol 45 no 5 pp 711ndash7162006

[68] F Meng K Wang T Aoyama et al ldquoInterleukin-17 signalingin inflammatory Kupffer cells and hepatic stellate cells exacer-bates liver fibrosis in micerdquo Gastroenterology vol 143 no 3 pp765ndash776 2012

[69] M Hara H Kono S Furuya K Hirayama M Tsuchiya andH Fujii ldquoInterleukin-17A plays a pivotal role in cholestatic liverfibrosis in micerdquo Journal of Surgical Research vol 183 no 2 pp574ndash582 2013

[70] Y Zheng D M Danilenko P Valdez et al ldquoInterleukin-22 aT11986717 cytokine mediates IL-23-induced dermal inflammation

and acanthosisrdquo Nature vol 445 no 7128 pp 648ndash651 2007[71] A Ogawa A Andoh Y Araki T Bamba and Y Fujiyama

ldquoNeutralization of interleukin-17 aggravates dextran sulfatesodium-induced colitis in micerdquo Clinical Immunology vol 110no 1 pp 55ndash62 2004

[72] E Lubberts M I Koenders B Oppers-Walgreen et al ldquoTreat-ment with a neutralizing anti-murine interleukin-17 antibodyafter the onset of collagen-induced arthritis reduces jointinflammation cartilage destruction and bone erosionrdquo Arthri-tis and Rheumatism vol 50 no 2 pp 650ndash659 2004


[73] H-C Hsu P Yang J Wang et al ldquoInterleukin 17-producingT helper cells and interleukin 17 orchestrate autoreactive ger-minal center development in autoimmune BXD2 micerdquoNatureImmunology vol 9 no 2 pp 166ndash175 2008

[74] M S Longhi Y Ma G Mieli-Vergani and D VerganildquoAetiopathogenesis of autoimmune hepatitisrdquo Journal ofAutoimmunity vol 34 no 1 pp 7ndash14 2010

[75] I N Crispe ldquoThe liver as a lymphoid organrdquo Annual Review ofImmunology vol 27 pp 147ndash163 2009

[76] M S Longhi M J Hussain R RMitry et al ldquoFunctional studyof CD4+CD25+ regulatory T cells in health and autoimmunehepatitisrdquoThe Journal of Immunology vol 176 no 7 pp 4484ndash4491 2006

[77] S Ferri M S Longhi C de Molo et al ldquoA multifacetedimbalance of T cells with regulatory function characterizes type1 autoimmunehepatitisrdquoHepatology vol 52 no 3 pp 999ndash10072010

[78] S Sakaguchi K Fukuma K Kuribayashi and T MasudaldquoOrgan-specific autoimmune diseases induced in mice by elim-ination of T cell subset I Evidence for the active participationof T cells in natural self-tolerance deficit of a T cell subsetas a possible cause of autoimmune diseaserdquo The Journal ofExperimental Medicine vol 161 no 1 pp 72ndash87 1985

[79] J M Fletcher R Lonergan L Costelloe et al ldquoCD39+Foxp3+regulatory T cells suppress pathogenic Th17 cells and areimpaired in multiple sclerosisrdquo Journal of Immunology vol 183no 11 pp 7602ndash7610 2009

[80] M S Longhi F Meda P Wang et al ldquoExpansion and denovo generation of potentially therapeutic regulatory T cells inpatients with autoimmune hepatitisrdquo Hepatology vol 47 no 2pp 581ndash591 2008

[81] P Invernizzi C Selmi andM EGershwin ldquoUpdate on primarybiliary cirrhosisrdquo Digestive and Liver Disease vol 42 no 6 pp401ndash408 2010

[82] K D Lindor M E Gershwin R Poupon M Kaplan NV Bergasa and E J Heathcote ldquoPrimary biliary cirrhosisrdquoHepatology vol 50 no 1 pp 291ndash308 2009

[83] G Syal M Fausther and J A Dranoff ldquoAdvances in cholan-giocyte immunobiologyrdquoThe American Journal of PhysiologymdashGastrointestinal and Liver Physiology vol 303 no 10 ppG1077ndashG1086 2012

[84] G Ballardini M Fallani F B Bianchi and E Pisi ldquoAntigenpresenting cells in liver biopsies from patients with primarybiliary cirrhosisrdquo Autoimmunity vol 3 no 2 pp 135ndash144 1989

[85] S Oertelt Z-X Lian C-M Cheng et al ldquoAnti-mitochondrialantibodies and primary biliary cirrhosis in TGF-120573 receptor IIdominant-negative micerdquo The Journal of Immunology vol 177no 3 pp 1655ndash1660 2006

[86] M Nakamura H Kondo T Mori et al ldquoAnti-gp210 andanti-centromere antibodies are different risk factors for theprogression of primary biliary cirrhosisrdquoHepatology vol 45 no1 pp 118ndash127 2007

[87] S Itoh T Ichida T Yoshida et al ldquoAutoantibodies against a 210kDa glycoprotein of the nuclear pore complex as a prognosticmarker in patients with primary biliary cirrhosisrdquo Journal ofGastroenterology and Hepatology vol 13 no 3 pp 257ndash2651998

[88] Y-M Lee and M M Kaplan ldquoPrimary sclerosing cholangitisrdquoThe New England Journal of Medicine vol 332 no 14 pp 924ndash933 1995

[89] P Angulo and K D Lindor ldquoPrimary sclerosing cholangitisrdquoHepatology vol 30 no 1 pp 325ndash332 1999

[90] J E Eaton J A Talwalkar K N Lazaridis G J Gores and KD Lindor ldquoPathogenesis of primary sclerosing cholangitis andadvances in diagnosis and managementrdquo Gastroenterology vol145 no 3 pp 521ndash536 2013

[91] GMHirschfield T H Karlsen K D Lindor andDH AdamsldquoPrimary sclerosing cholangitisrdquoThe Lancet vol 382 no 9904pp 1587ndash1599 2013

[92] G Rudolph D Gotthardt P Kloters-Plachky H Kulaksiz DRost and A Stiehl ldquoInfluence of dominant bile duct stenosesand biliary infections on outcome in primary sclerosing cholan-gitisrdquo Journal of Hepatology vol 51 no 1 pp 149ndash155 2009

[93] P Fickert G Zollner A Fuchsbichler et al ldquoUrsodeoxycholicacid aggravates bile infarcts in bile duct-ligated and Mdr2knockout mice via disruption of cholangiolesrdquo Gastroenterol-ogy vol 123 no 4 pp 1238ndash1251 2002

[94] M J PollheimerMTrauner andP Fickert ldquoWill we evermodelPSCmdashlsquoitrsquos hard to be a PSC modelrsquordquo Clinics and Research inHepatology and Gastroenterology vol 35 no 12 pp 792ndash8042011

[95] A Chiricozzi E Guttman-YasskyM Suarez-Farıas et al ldquoInte-grative responses to IL-17 and TNF-120572 in human keratinocytesaccount for key inflammatory pathogenic circuits in psoriasisrdquoJournal of Investigative Dermatology vol 131 no 3 pp 677ndash6872011

[96] S Fujino A Andoh S Bamba et al ldquoIncreased expression ofinterleukin 17 in inflammatory bowel diseaserdquo Gut vol 52 no1 pp 65ndash70 2003

[97] S Kotake N Udagawa N Takahashi et al ldquoIL-17 in synovialfluids from patients with rheumatoid arthritis is a potent stimu-lator of osteoclastogenesisrdquoThe Journal of Clinical Investigationvol 103 no 9 pp 1345ndash1352 1999

[98] G Dong R Ye W Shi et al ldquoIL-17 induces autoantibodyoverproduction and peripheral blood mononuclear cell over-expression of IL-6 in lupus nephritis patientsrdquo Chinese MedicalJournal vol 116 no 4 pp 543ndash548 2003

[99] S Zhu and Y Qian ldquoIL-17IL-17 receptor system in autoim-mune disease mechanisms and therapeutic potentialrdquo ClinicalScience vol 122 no 11 pp 487ndash511 2012

[100] K A Papp R G Langley B Sigurgeirsson et al ldquoEfficacyand safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis a randomized double-blind placebo-controlled phase II dose-ranging studyrdquo British Journal ofDermatology vol 168 no 2 pp 412ndash421 2013

[101] C Leonardi RMatheson C Zachariae et al ldquoAnti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoria-sisrdquo The New England Journal of Medicine vol 366 no 13 pp1190ndash1191 2012

[102] K A Papp C Leonardi A Menter et al ldquoBrodalumab ananti-interleukin-17-receptor antibody for psoriasisrdquo The NewEngland Journal of Medicine vol 366 no 13 pp 1181ndash1189 2012

[103] M T Tse ldquoIL-17 antibodies gain momentumrdquo Nature ReviewsDrug Discovery vol 12 no 11 pp 815ndash816 2013

[104] M C Genovese P Durez H B Richards et al ldquoEfficacy andsafety of secukinumab in patients with rheumatoid arthritisa phase II dose-finding double-blind randomised placebocontrolled studyrdquo Annals of the Rheumatic Diseases vol 72 no6 pp 863ndash869 2013

[105] D Baeten X Baraliakos J Braun et al ldquoAnti-interleukin-17Amonoclonal antibody secukinumab in treatment of ankylosingspondylitis a randomised double-blind placebo-controlledtrialrdquoThe Lancet vol 382 pp 1705ndash1713 2013


[106] ADDick I Tugal-Tutkun S Foster et al ldquoSecukinumab in thetreatment of noninfectious uveitis results of three randomizedcontrolled clinical trialsrdquo Ophthalmology vol 120 no 4 pp777ndash787 2013

[107] M C Genovese M Greenwald C S Cho et al ldquoA phaseII randomized study of subcutaneous ixekizumab an anti-interleukin-17 monoclonal antibody in rheumatoid arthritispatients who were naive to biologic agents or had an inadequateresponse to tumor necrosis factor inhibitorsrdquo Arthritis ampRheumatism vol 66 no 7 pp 1693ndash1704 2014

[108] W Hueber B E Sands S Lewitzky et al ldquoSecukinumaba human anti-IL-17A monoclonal antibody for moderate tosevere Crohnrsquos disease Unexpected results of a randomiseddouble-blindplacebo-controlled trialrdquo Gut vol 61 no 12 pp1693ndash1700 2012

[109] D Toy D Kugler M Wolfson et al ldquoCutting edge interleukin17 signals through a heteromeric receptor complexrdquo Journal ofImmunology vol 177 no 1 pp 36ndash39 2006

[110] S Zrioual M-L Toh A Tournadre et al ldquoIL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXCchemokine expression in synoviocytes and are overexpressed inrheumatoid bloodrdquo Journal of Immunology vol 180 no 1 pp655ndash663 2008

[111] R Pappu V Ramirez-Carrozzi N Ota W Ouyang and Y HuldquoThe IL-17 family cytokines in immunity and diseaserdquo Journalof Clinical Immunology vol 30 no 2 pp 185ndash195 2010

[112] C Ritchlin P Rahman A Kavanaugh et al ldquoEfficacy and safetyof the anti-IL-1223 p40 monoclonal antibody ustekinumab inpatients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy6-month and 1-year results of the phase 3 multicentre double-blind placebo-controlledrdquo Annals of the Rheumatic Diseasesvol 73 no 6 pp 990ndash999 2014

[113] W J SandbornCGasink L-LGao et al ldquoUstekinumab induc-tion and maintenance therapy in refractory Crohnrsquos diseaserdquoThe New England Journal of Medicine vol 367 no 16 pp 1519ndash1528 2012

[114] C E M Griffiths B E Strober P van de Kerkhof et alldquoComparison of ustekinumab and etanercept for moderate-to-severe psoriasisrdquoTheNew England Journal of Medicine vol 362no 2 pp 118ndash128 2010

[115] K A Papp C E M Griffiths K Gordon et al ldquoLong-termsafety of ustekinumab in patients with moderate-to-severepsoriasis final results from 5 years of follow-uprdquo British Journalof Dermatology vol 168 no 4 pp 844ndash854 2013

[116] P Miossec and J K Kolls ldquoTargeting IL-17 and T11986717 cells in

chronic inflammationrdquo Nature Reviews Drug Discovery vol 11no 10 pp 763ndash776 2012

[117] A Shetty R Hanson P Korsten et al ldquoTocilizumab in thetreatment of rheumatoid arthritis and beyondrdquo Drug DesignDevelopment andTherapy vol 8 pp 349ndash364 2014

[118] J E Frampton ldquoTocilizumab a review of its use in the treatmentof juvenile idiopathic arthritisrdquoPediatricDrugs vol 15 no 6 pp515ndash531 2013

[119] M Geyer and U Muller-Ladner ldquoActual status ofantiinterleukin-1 therapies in rheumatic diseasesrdquo CurrentOpinion in Rheumatology vol 22 no 3 pp 246ndash251 2010

[120] J R Huh E E Englund H Wang et al ldquoIdentification ofpotent and selective diphenylpropanamide ROR120574 inhibitorsrdquoACS Medicinal Chemistry Letters vol 4 no 1 pp 79ndash84 2013

[121] P M Khan B E-D M El-Gendy N Kumar et al ldquoSmallmolecule amides as potent ROR-120574 selective modulatorsrdquo Bioor-ganic and Medicinal Chemistry Letters vol 23 no 2 pp 532ndash536 2013

[122] S C P Williams ldquoFlurry of deal-making surrounds newautoimmunity targetrdquo Nature Medicine vol 19 no 9 article1078 2013

[123] L A Solt N Kumar P Nuhant et al ldquoSuppression of TH17differentiation and autoimmunity by a synthetic ROR ligandrdquoNature vol 472 no 7344 pp 491ndash494 2011

[124] P Delerive W W Chin and C S Suen ldquoIdentification ofReverb120572 as a novel ROR120572 target generdquo Journal of BiologicalChemistry vol 277 no 38 pp 35013ndash35018 2002

[125] J Wang L Yin and M A Lazar ldquoThe orphan nuclear receptorRev-erb120572 regulates circadian expression of plasminogen activa-tor inhibitor type 1rdquoThe Journal of Biological Chemistry vol 281no 45 pp 33842ndash33848 2006

[126] T Wada S K Hong M Angers et al ldquoIdentification ofoxysterol 7120572-hydroxylase (Cyp7b1) as a novel retinoid-relatedorphan receptor120572 (ROR120572) (NR1F1) target gene and a functionalcross-talk between ROR120572 and liver X receptor (NR1H3)rdquoMolecular Pharmacology vol 73 no 3 pp 891ndash899 2008

[127] N Kumar B Lyda M R Chang et al ldquoIdentification of SR2211a potent synthetic ROR120574-selective modulatorrdquo ACS ChemicalBiology vol 7 no 4 pp 672ndash677 2012

[128] E ELinghaus D ELinghaus P E Stuart et al ldquoGenome-wideasociation study identifies a psoriasis susceptibility locus atTRAF3IP2rdquo Nature Genetics vol 42 no 11 pp 991ndash995 2010

[129] U Huffmeier S Uebe A B Ekici et al ldquoCoMon variants atTRAF3IP2 are aSociated with susceptibility to psoriatic arthritisand psoriasisrdquoNatureGenetics vol 42 no 11 pp 996ndash999 2010

[130] C Liu S Swaidani W Qian et al ldquoA CCrsquo loop decoy peptideblocks the interaction between Act1 and IL-17RA to attenuateIL-17- and IL-25-induced inflammationrdquo Science Signaling vol4 no 197 article ra72 2011

[131] F Shen and S L Gaffen ldquoStructure-function relationships inthe IL-17 receptor implications for signal transduction andtherapyrdquo Cytokine vol 41 no 2 pp 92ndash104 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


and was initially known as cytotoxic T lymphocyte associatedantigen 8 (CTLA-8) [6] Since then other five members ofIL-17 family IL-17B IL-17C IL-17D IL-17E (also called IL-25) and IL-17F have been discovered based on homology inamino acid sequences [6ndash9]

IL-17A is the most well investigated member of the IL-17 family and acts on multiple cell types to enhance theproduction of various proinflammatory molecules includingcytokines (such as TNF and IL-6) chemokines (such asCXCL2 andMCP-1)mucins acute phase proteins andmatrixmetalloproteinases [10ndash16] Overall IL-17A exerts a widerange of functions in autoimmune diseases host defensetransplantation allergy and malignancy [17ndash21]

With the family IL-17F is the most homologous proteinto IL-17A (sim60) and resembles IL-17A in both the cellularsources and regulation function [22] Interestingly IL-17Aand IL-17F exist as homodimers [10] In addition IL-17A andIL-17F also form a heterodimeric cytokine (IL-17AF) withintermediate signaling potency [23]

Th17 a subset of CD4+T cells named for their abilityto preferentially produce IL-17 is recognized as the majorproducers of IL-17A and IL-17F [24] In addition severalinnate immune cell types are described as sources for IL-17including 120574120575T-cells natural killer (NK) cells natural killer T(NKT) cells dendritic cells (DCs) activatedmonocytes mastcells neutrophils and lymph tissue inducer (LTi) cells [25ndash28] Of note IL-17A is found to be approximately 10ndash30 timesmore potent than IL-17F [29] However IL-17F and IL-17Ahave overlapping yet distinct proinflammatory roles in hostimmune and defense mechanisms such as mucoepithelialbacterial infections inflammatory responses and allergicdiseases [30 31] For example genetic deletion of IL-17Fresulted in reduced experimental colitis caused by dextransulfate sodium whereas deletion of IL-17A inmice developedmore severe intestinal disease [32]

Unlike IL-17F IL-17E (IL-25) is the most distant cytokinefrom IL-17A in IL-17 family Recent studies show that IL-17E promotes Th2-mediated immune responses particularlycontributing to airway inflammation and allergic disease [33ndash35]

Far less is known about the cellular sources recep-torstarget cells and biological functions of the three remain-ing other IL-17 family cytokines IL-17B is expressed inmultiple organs including small intestine pancreas spinalcord and stomach [36] IL-17C was detected in keratinocytesand tracheal epithelial cells [37 38] Similar to IL-17B IL-17D is also expressed in a variety of organs and tissuesincluding heart pancreas and adipose tissue [22] Recentstudies from both human and animal models suggest thatthese IL-17 family members might possess an importantrole in inflammatory disease which highlights the need forfurther exploration For instance IL-17B was observed toparticipate in a murine model of collagen-induced arthritiswhereas treatment with IL-17B neutralizing antibody cansuccessfully suppress arthritis [39]

22 IL-17 Receptors (Discovery Structure Expression andSignaling) Interleukin-17RA (also known as IL17R) was thefirst receptor identified for IL-17A [40] IL-17RA is expressed

in considerable cell types including endothelial cells epithe-lial cells fibroblasts and myeloid cells However subsequentstudies have demonstrated additional receptor members arerequired to form a functional receptor complex for IL-17signaling [41] The IL-17 receptor family represents a groupof multimeric proteins that consists of four other moleculesIL-17RB (also known as IL17Rh1) IL-17RC (also known asIL17RL) IL-17RD and IL-17RE

Recent studies of IL-17RB revealed the expression inNKT cells memory Th2 cells macrophages lung epithelialcells airway smooth muscle cells and endothelial cells [42ndash44] IL-17RB can bind to both IL-17B and IL-17E in vitroand actively participate in Th2 immune responses via IL-17EndashIL-17RB interaction particularly in airway inflammation[33] Besides genetic and biochemical studies indicate IL-17RB binding to IL-17E recruits IL-17RA to the complex inmediating IL-17E function [45]

IL-17RC was initially identified based on sequencehomology to IL-17RA [46] IL-17RC was found to shareexpressionwith IL-17RA inmultiple cells including epithelialcells macrophages and fibroblasts but its expression onmyeloid cells is much lower [47] Of note the assembly ofa heterodimeric complex between IL-17RA and IL-17RC isrequired for the biological signaling of IL-17A and IL-17FNevertheless IL-17RCmay have some functions independentof IL-17RA for IL-17RC expression is elevated in someorgans and tissues such as small intestine and lung where theexpression of IL-17RA is absent [30]

IL-17RD and IL-17RE were also identified throughdatabase mining however little is currently known aboutthese two orphan receptors Studies have discovered theexpression of IL-17RD in epithelial cells and endothelial cellsMoreover IL-17RD can pair with IL-17RA to mediate IL-17A signaling while mutations of the IL-17RD cytoplasmicdomain can suppress IL-17A function [48] On one side IL-17RE RNA could be detected in lung testis kidney stomachand intestine on the other side the cellular expression of IL-17RE is poorly understood Further studies will be needed toaddress the significance of IL-17RE [49]

These single-pass receptors share minimal structuralhomology including a single transmembrane domain an ex-tracellular-fibronectin III-like (FnIII) domain and an intra-cellular SEFIL-17R (SEFIR) domain [29 50] As IL17R pro-teins possess the conserved SEFIR domain with IL17 familyligands binding this intracellular domain can directly inter-act with adaptor protein ACT1 (also known as TRAF3IP2)to initiate signaling cascades augmenting various inflamma-tory molecules that participate in immune responses Forinstance with the help of both ACT1 and TNF receptor asso-ciated factor 6 (TRAF6) the binding of IL-17A to IL-17RAcan activate nuclear factor-120581B (NF-120581B) signaling pathway[51] Additionally IL-17A can activate the CCAATenhancerbinding proteins (CEBPs)-CEBP120573 and CEBP120575 to inducethe transcription of inflammatory gene such as IL-6 [13]By contrast IL-17R-Act1-TRAF-NF-120581B pathway can be nega-tively regulated by the binding of TRAF3 to IL-17R resultingin suppression of downstream signaling [52]




AIHPatients





PBC

Patients


[57 58]




[60]





PSC

Patients




Mouse models (BDL)




































Th 17 cell

IL-17AIL-17A

IL-6

IL-1120573

IL-1120573

IL-23

IL-23p19 p40

IL-23

R

IL-12

R1205731

TYK2JAK2

IL-6

Gp1

30

Gp1

30

IL-6

RJAK2 JAK2


ROR120574t

IL-17AIL-17F

IL-17FIL-17F

IL-17RAIL-17RC

ACT1

TRAF-6

NK-120581B








STAT-4

STAT-3

STAT-3

STAT-3P P

STAT-4STAT-3




Antigen

STAT-3STAT-3

P P

IL-1R










5 Conclusions


Abbreviations





References
















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















AIHPatients





PBC

Patients


[57 58]




[60]





PSC

Patients




Mouse models (BDL)




































Th 17 cell

IL-17AIL-17A

IL-6

IL-1120573

IL-1120573

IL-23

IL-23p19 p40

IL-23

R

IL-12

R1205731

TYK2JAK2

IL-6

Gp1

30

Gp1

30

IL-6

RJAK2 JAK2


ROR120574t

IL-17AIL-17F

IL-17FIL-17F

IL-17RAIL-17RC

ACT1

TRAF-6

NK-120581B








STAT-4

STAT-3

STAT-3

STAT-3P P

STAT-4STAT-3




Antigen

STAT-3STAT-3

P P

IL-1R










5 Conclusions


Abbreviations





References
















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































Th 17 cell

IL-17AIL-17A

IL-6

IL-1120573

IL-1120573

IL-23

IL-23p19 p40

IL-23

R

IL-12

R1205731

TYK2JAK2

IL-6

Gp1

30

Gp1

30

IL-6

RJAK2 JAK2


ROR120574t

IL-17AIL-17F

IL-17FIL-17F

IL-17RAIL-17RC

ACT1

TRAF-6

NK-120581B








STAT-4

STAT-3

STAT-3

STAT-3P P

STAT-4STAT-3




Antigen

STAT-3STAT-3

P P

IL-1R










5 Conclusions


Abbreviations





References
















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 Conclusions


Abbreviations





References
















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article therapeutic potential of il-17-mediated...

Documents