P-207 The Role of IL-17C and IL-17RE in the Development of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a complex polygenic disorder causing a chronic relapsing inflammation and thought to result from a dysregulated and aberrant immune response to intestinal flora in a context of genetic predisposition. Recently, human IL17REL, a member of interleukin-17 receptor family, was identified through a genome-wide association study for ulcerative colitis. However, it is unknown how IL-17REL is involved in the development of ulcerative colitis. On the basis of the substantial homology between human IL-17REL and the extracellular domains of IL-17RE, it is likely that IL-17REL binds to the ligand of IL-17RE. We recently demonstrated IL-17RE is induced in a subset of CD4 helper T cells, Th17 cells, and is a receptor for a cytokine IL-17C. IL-17C-IL-17RE signaling plays a critical role to promote inflammation in chronic autoimmune disease. In addition, we reported IL-17C is crucial for the regulation of an acute experimental colitis by controlling the expression of the tight junction molecule occludin by colonic epithelial cells. Therefore, we hypothesize during chronic intestinal inflammation, induction of IL-17C in the inflamed intestine recruits Th17 cells via IL-17RE and IL-17C-IL-17RE signaling modulates Th17 cell function and play a pathogenic role in mediating inflammation. First, we found out that the expression of IL-17C and IL-17RE is increased in colon and small intestine of mice during chronic colitis. IL-17C expression was found in colonic epithelial cells and it was reduced upon antibiotic treatment, suggesting IL-17C expression is maintained by microbiota in the colon. IL-17RE expression, on the other hand, was not only found in Th17 cells but also in regulatory T cells isolated from colon and small intestine. Therefore, we adopted a CD4 transfer colitis model, where Il17re deficient CD45RBhi CD4+ cells or Il17re deficient CD25+CD4+ cells were transferred to Rag deficient mice to address the biological role of IL-17RE in Th17 cells and regulatory T cells. This study is directed to understand the contribution of novel cytokine-receptor pair, IL-17C-IL-17RE, in the pathogenesis of chronic inflammation in colon. Furthermore, this study will help us to understand complex nature of IBD development and provide a new platform to design therapy to block proinflammatory cytokine.