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Interleukin-17C Promotes Th17 Cell Responses and Autoimmune Disease Via Interleukin-17 Receptor E

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Interleukin-17C Promotes Th17 Cell Responses and Autoimmune Disease Via Interleukin-17 Receptor E View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity Article Interleukin-17C Promotes Th17 Cell Responses and Autoimmune Disease via Interleukin-17 Receptor E Seon Hee Chang,1,2 Joseph M. Reynolds,1,2 Bhanu P. Pappu,1 Guangjie Chen,1 Gustavo J. Martinez,1 and Chen Dong1,* 1Department of Immunology and Center for Inflammation and Cancer, MD Anderson Cancer Center, Houston, TX 77054-1901, USA 2These authors contributed equally to this work *Correspondence: [email protected] DOI 10.1016/j.immuni.2011.09.010 SUMMARY IL-23 (Langrish et al., 2005) for their differentiation and cytokine expression. Although several interleukin-17 (IL-17) family Th17 cells, via production of IL-17A and IL-17F, promote the members and their receptors have been recently development of autoimmune diseases while protecting the appreciated as important regulators in inflammatory host against bacterial and fungal infections (Kolls and Linde´ n, diseases, the function of other IL-17 cytokines and 2004). IL-17A and IL-17F signal through the IL-17 receptor A IL-17 receptor-like molecules is unclear. Here we (IL-17RA)-IL-17RC complex (Hu et al., 2010; Toy et al., 2006). show that an IL-17 cytokine family member, IL-17C, Although IL-17RA is expressed ubiquitously, IL-17RC expres- sion is dominant in nonhematopoietic cells (Kuestner et al., was induced in a Th17 cell-dependent autoimmune 2007). IL-17A and IL-17F target epithelial cells or fibroblasts to disease and was required for its pathogenesis. produce arrays of cytokines and chemokines including IL-6 IL-17C bound to IL-17RE, a member of IL-17 receptor and CXCL1 (Chang and Dong, 2009; Gaffen, 2008). A distant family whose full-length isoform was selectively ex- member of IL-17 family cytokine, IL-25 (IL-17E), is involved in pressed in Th17 cells and signaled via an IL-17RA- allergic diseases and host defense against parasitic helminthes RE receptor complex and the downstream adaptor (Chang and Dong, 2009; Kolls and Linde´ n, 2004; Pappu et al., Act1. IL-17C-IL-17RE induced the expression of a 2008). Recently, it was shown that IL-25 utilized IL-17RA and nuclear IkappaB family member, IkBz, in Th17 cells IL-17RB as a receptor complex (Angkasekwinai et al., 2010; to potentiate the Th17 cell response. Thus, our work Rickel et al., 2008). IL-17RB is expressed in Th2 (Angkasekwinai has identified a cytokine-receptor pair with important et al., 2007; Wang et al., 2007) and Th9 (Angkasekwinai et al., function in regulating proinflammatory responses. 2010) cells as well as a subset of NKT cells (Terashima et al., 2008). IL-25 induces the production of IL-4, IL-5, IL-13, and This pathway may be targeted to treat autoimmune IL-9 in these target cell types. IL-17RA, IL-17RC, and IL-17RB diseases. recruit Act1 (Chang et al., 2006; Claudio et al., 2009; Qian et al., 2007), an intracellular adaptor molecule sharing homology with the cytoplasmic domain of the IL-17R family (Novatchkova INTRODUCTION et al., 2003), to mediate downstream signaling. Although IL-17 family members IL-17A, IL-17F, and IL-25 (as Interleukin-17 (IL-17) family cytokines have recently emerged as well as IL-17 receptor family members IL-17RA, IL-17RC, and important players in inflammatory responses. IL-17A and IL-17F, IL-17RB) have been relatively well studied in immune responses which are most highly related among IL-17 family cytokines, are and inflammatory diseases, the function of other IL-17 family expressed by a distinct T cell subset, Th17 cells (Dong, 2008). cytokines and IL-17R-like molecules is unclear. IL-17C was iden- The cytokines TGF-b and IL-6 or IL-21 have been shown to be tified along with IL-17B by a homology search of IL-17-like cyto- critical in generation of Th17 cells (Bettelli et al., 2006; Korn kines and reported to stimulate THP, a monocytic cell line, to et al., 2007; Mangan et al., 2006; Nurieva et al., 2007; Veldhoen produce TNF-a and IL-1b (Yamaguchi et al., 2007). Adenoviral et al., 2006), leading to the expression of lineage-specific tran- delivery of IL-17C to lung triggers neutrophil recruitment (Hurst scription factors, RORgt(Ivanov et al., 2006) and RORa (Yang et al., 2002). IL-17C-overexpressing CD4+ T cells exacerbate et al., 2008c). RORgt and RORa are retinoic-acid-receptor- collagen-induced arthritis in recipient mice (Yamaguchi et al., related orphan receptors that are induced by activation of the 2007). These results suggest that IL-17C may have an important STAT3 pathway by IL-6 (Yang et al., 2007). Other transcription proinflammatory function. factors are also reported to promote Th17 cell differentiation. IL-17RE belongs to the IL-17R family and was originally iden- Most recently, IkBz, a nuclear IkappaB family member, was iden- tified based on searches for IL-17R homologous sequences tified to be induced by STAT3 and promote Th17 cell differenti- (Li et al., 2006). The closest related molecule of IL-17RE is ation by cooperating with RORgt and RORa (Okamoto et al., IL-17RC. IL-17RE shares 18% of amino acid sequence identity 2010). Th17 cells also express IL-1R and IL-23R, rendering the with IL-17RC and the two genes encoding these receptors are cells to selectively respond to IL-1 (Chung et al., 2009) and located adjacent to each other on human chromosome 3 and Immunity 35, 611–621, October 28, 2011 ª2011 Elsevier Inc. 611 Immunity IL-17C and IL-17RE in Th17 Cell Regulation mouse chromosome 6. The Il17re gene encodes a protein IL-17A+ or IL-17A+IFN-g+ cells were not different (Figures 1B carrying a single transmembrane domain with various short iso- and 1C). We then directly examined cytokines and chemokines forms ranging from 34 to 70 kD. However, little is known on the expressed at the sites of inflammation. IL-17C deficiency re- specific ligands and signaling functions of these proteins. It sulted in significant decreases in the Th17 cell-related mediators was previously reported that IL-17RE has mitogenic activity in Il17a, Il17f, Il22, Ccr6, and Ccl20 (p < 0.05) (Figures 1D). Interest- a ligand-independent manner (Li et al., 2006). A recent ingly, we also observed a noticeable decrease in Ifng mRNA genome-wide association study revealed that IL17REL, a close expression in the CNS of Il17cÀ/À mice. In addition to the CNS, homolog of IL17RE, is a risk locus for ulcerative colitis (Franke splenocytes from EAE mice were restimulated with MOG35-55 et al., 2010). peptide to analyze cytokine expression. WT and Il17cÀ/À CD4+ In this study, we have studied the function of IL-17C and iden- T cells were found to proliferate similarly (data not shown) and tified IL-17RE as its receptor in regulation of Th17 cell differenti- the cytokine response to MOG35-55 peptide was similar between ation and autoimmune diseases. IL-17C-IL-17RE signaling may WT and Il17cÀ/À mice by intracellular cytokine staining (Fig- be a promising target in the treatment of chronic autoimmune ure 1E). Thus, IL-17C appears to be necessary for the pathogen- diseases. esis of EAE disease and for CNS inflammation in this model. RESULTS IL-17C Binds to IL-17RE To identify the mechanism whereby IL-17C mediates proinflam- IL-17C Is Necessary for Pathogenesis of EAE matory function in EAE disease, we first searched for the As a first step to understand the function of IL-17C, we gener- receptor of IL-17C among IL-17R family members and the target ated Il17cÀ/À mice by gene targeting. A LacZ-coding sequence cells for IL-17C. 293T cells were transfected with various IL-17R was inserted into exon 2 to disrupt the expression of Il17c (see family members, and an IL-17C-hIg fusion protein we generated Figures S1A and S1B available online). These mice developed was used to detect the binding. Compared to cells transfected normally and did not exhibit any pronounced immunological with an empty vector, substantial increases in binding of IL- deficiency. Normal development of lymphocytes was observed: 17C-hIg was observed in 293T cells transfected with IL-17RE CD4+ and CD8+ T cells in spleen and draining lymph nodes are (Figure 2A). We did not detect any measurable binding of comparable between WT (wild-type) and Il17cÀ/À mice (Fig- IL-17C-hIg to IL-17RA or other members of the IL-17 receptor ure S1C). Also, the number of regulatory T cells in Il17cÀ/À family by the same system (Figure 2B). Expression of IL-17 mice was similar to that in WT mice (Figure S1C). When spleno- receptor molecules was confirmed in this system via binding of cytes were restimulated with PMA plus ionomycin, the amount of positive control IL-17 cytokine fusion proteins and through IL-17A and IFN-g production was comparable between Il17cÀ/À real-time RT-PCR (Figure S2). and WT CD4+ and CD8+ T cells (Figure S1D). To explore the role of IL-17C in inflammatory diseases, we IL-17RE Is Highly Expressed in Th17 Cells analyzed IL-17C expression in different tissues and found that To understand how IL-17C-IL-17RE regulates pathogenesis of its expression was increased by approximately 15-fold in the autoimmune disease, we further examined the expression of central nervous system (CNS) of mice induced with experimental Il17re mRNA by RT-PCR. Based on the previous literature (Li autoimmune encephalomyelitis (EAE) compared to the normal et al., 2006), IL-17RE is predicted to have multiple isoforms.
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