1. Differential Modulation by IL-17A of Cholangitis versus Colitis in IL-2Rα Deleted Mice.
- Author
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Yang, Wei, Yao, Yuan, Yang, Yan-Qing, Lu, Fang-Ting, Li, Liang, Wang, Yin-Hu, Nakajima, Takahiko, Tsuneyama, Koichi, Ridgway, William M., Gershwin, M. Eric, and Lian, Zhe-Xiong
- Subjects
COLITIS ,INTERLEUKIN-17 ,INTERLEUKIN-2 ,LABORATORY mice ,IMMUNOLOGY ,CIRRHOSIS of the liver - Abstract
IFN-γ is a signature Th1 cell associated cytokine critical for the inflammatory response in autoimmunity with both pro-inflammatory and potentially protective functions. IL-17A is the hallmark of T helper 17 (Th17) cell subsets, produced by γδT, CD8+ T, NK and NKT cells. We have taken advantage of our colony of IL-2Rα
−/− mice that spontaneously develop both autoimmune cholangitis and inflammatory bowel disease. In this model CD8+ T cells mediate biliary ductular damage, whereas CD4+ T cells mediate induction of colon-specific autoimmunity. Importantly, IL-2Rα−/− mice have high levels of interferon γ (IFN-γ), and interleukin-17A (IL-17A). We produced unique double deletions of mice that were either IL-17A−/− IL-2Rα−/− or IFN-γ−/− IL-2Rα−/− to specifically address the precise role of these two cytokines in the natural history of autoimmune cholangitis and colitis. Of note, deletion of IL-17A in IL-2Rα−/− mice led to more severe liver inflammation, but ameliorated colitis. In contrast, there were no significant changes in the immunopathology of double knock-out IFN-γ−/− IL-2Rα−/− mice, compared to single knock-out IL-2Rα−/− mice with respect to cholangitis or colitis. Furthermore, there was a significant increase in pathogenetic CD8+ T cells in the liver of IL-17A−/− IL-2Rα−/− mice. Our data suggest that while IL-17A plays a protective role in autoimmune cholangitis, it has a pro-inflammatory role in inflammatory bowel disease. These data take on particular significance in the potential use of anti-IL-17A therapy in humans with primary biliary cirrhosis. [ABSTRACT FROM AUTHOR]- Published
- 2014
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