The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice

Yugo Ando, Guo Xiang Yang, Masanobu Tsuda, Kazuhito Kawata, Weici Zhang, Takahiko Nakajima, Koichi Tsuneyama, Patrick S Leung, Zhe Xiong Lian, Kazuichi Okazaki, William M. Ridgway, Gary L. Norman, Aftab A. Ansari, Xiaosong He, Ross L. Coppel, M. Eric Gershwin

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32 Scopus citations

Abstract

Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19-/- dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19-/- mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A-/- dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23.

Original languageEnglish (US)
Pages (from-to)1418-1426
Number of pages9
JournalHepatology
Volume56
Issue number4
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Hepatology

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    Ando, Y., Yang, G. X., Tsuda, M., Kawata, K., Zhang, W., Nakajima, T., Tsuneyama, K., Leung, P. S., Lian, Z. X., Okazaki, K., Ridgway, W. M., Norman, G. L., Ansari, A. A., He, X., Coppel, R. L., & Gershwin, M. E. (2012). The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice. Hepatology, 56(4), 1418-1426. https://doi.org/10.1002/hep.25803