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4 CRITICAL ROLE OF INTERLEUKIN-17 AND INTERLEUKIN-17 RECEPTOR SIGNALING IN Trinitrobenzene Sulfonic Acid-INDUCED COLITIS.
  1. Z. Zhang1,
  2. M. Zheng2,
  3. J. Bindas2,
  4. P. Schwarzenberger3,
  5. J. K. Kolls2
  1. 1Oregon Health & Science University
  2. 2Children's Hospital of Pittsburgh
  3. 3Louisiana State University Health Sciences Center

Abstract

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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