The Immunobiology of Colitis and Cholangitis in IL-23p19 and IL-17A Deleted dnTGFβRII Mice

• Type of Material: Article
• Authors: Yugo Ando, University of California; Guo-Xiang Yang, University of California; Masanobu Tsuda, University of California; Kazuhito Kawata, University of California; Weici Zhang, University of California; Takahiko Nakajima, University of Toyama; Koichi Tsuneyama, University of California; Patrick Leung, University of California; Zhe-Xiong Lian, University of California; Kazuichi Okazaki, Kansai Medical University; William M. Ridgway, University of Cincinnati; Gary L. Norman, INOVA Diagnostics, Inc.; Aftab A Ansari, Emory University; Xiao-Song He, University of California; Ross L. Coppel, Monash University; M. Eric Gershwin, University of California
• Language: English
• Date: 2012-10
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 by the American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.25803/abstract
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 56
• Issue: 4
• Start Page: 1418
• End Page: 1426
• Grant/Funding Information: Financial support provided by National Institutes of Health grant DK090019.
• Keywords: Primary biliary cirrhosis; cholangitis; colitis; murine models; autoimmunity
• Research Categories: Health Sciences, Pathology; Health Sciences, General; Health Sciences, Immunology

Abstract

dnTGFβRII mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis . We previously observed that deficiency in IL-12p40 led to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediated protection acted via 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 Th17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, while 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 the 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 while the colitis is caused by a direct effect of IL-23.