Deletion of IL-6 in dnTGF?RII Mice Improves Colitis but Exacerbates Autoimmune Cholangitis

• Type of Material: Article
• Authors: Weici Zhang, University of California; Masanobu Tsuda, University of California; Guo-Xiang Yang, University of California; Koichi Tsuneyama, University of Toyama; Guanghua Rong, University of California; William M. Ridgway, University of Cincinnati; Aftab A Ansari, Emory University; Richard A. Flavell, Yale University; Ross L. Coppel, Monash University; Zhe-Xiong Lian, University of Science and Technology of China; M. Eric Gershwin, University of California
• Language: English
• Date: 2010-07
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Association for the Study of Liver Diseases
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.23664/abstract
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 52
• Issue: 1
• Start Page: 215
• End Page: 222
• Grant/Funding Information: Financial support provided by National Institutes of Health grant DK077961.
• Keywords: TNF-α; Interleukin 6; Autoimmune cholangitis; Cholangiocyte proliferation; Colitis
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

The role of IL-6 in autoimmunity attracts attention because of the clinical usage of mAbs to IL-6R, designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 pathway is associated with modulating pathology in acute liver failure, liver regeneration and in the murine model of Concanavalin A-induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor β receptor (dnTGFβRII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6 deficient mice on a dnTGF-βRII background (dnTGFβRII IL-6−/−) and examined for the presence of anti-mitochondrial antibodies, levels of cytokines, histopathology and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti-IL6R in inflammatory bowel disease, dnTGFβRII IL-6−/− mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGFβRII IL-6−/− mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells and worsening hepatic pathology. The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti-IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti-IL6R antibody.