Differential modulation by IL-17A of Cholangitis versus Colitis in IL-2Rα deleted mice

Wei Yang, Yuan Yao, Yan Qing Yang, Fang Ting Lu, Liang Li, Yin Hu Wang, Takahiko Nakajima, Koichi Tsuneyama, William M. Ridgway, M. Eric Gershwin, Zhe Xiong Lian

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e105351
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Yang, W., Yao, Y., Yang, Y. Q., Lu, F. T., Li, L., Wang, Y. H., Nakajima, T., Tsuneyama, K., Ridgway, W. M., Gershwin, M. E., & Lian, Z. X. (2014). Differential modulation by IL-17A of Cholangitis versus Colitis in IL-2Rα deleted mice. PLoS One, 9(8), e105351. https://doi.org/10.1371/journal.pone.0105351