Inflammatory bowel diseases (IBD) are characterized by recurrent inflammation in the gastrointestinal tract. Infiltration of CD4+ lymphocytes and neutrophils is one of the predominant features in IBD. Recently, interleukin (IL)-23 and the downstream T-cell derived cytokine IL-17 have been found to be elevated in IBD patients. However, the role of IL-17 and IL-17 receptor (IL-17R) signaling in gastrointestinal inflammation is unknown. To examine their role, we investigated colonic inflammation in wild-type or IL-17R KO mice. Using a model of TNBS-induced colitis, we found that IL-17 was produced in colon tissue at 24 and 48 hours. IL-17R KO mice were significantly protected against TNBS-induced weight loss, IL-6 production, local MIP-2 induction, as well as colonic inflammation. This protection occurred in the presence of equivalent induction of local IL-23 and higher levels of IL-12p70 and IFN-gamma in IL-17R KO mice compared to wild-type mice. Moreover, IL-17R KO mice exhibited a reduced tissue neutrophil infiltration as assessed by myeloperoxidase activity. Furthermore, overexpression of an IL-17R IgG1 fusion protein significantly attenuated colonic inflammation after TNBS challenge. These results demonstrate that IL-17 and IL-17R signaling play a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.
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