IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy

• Type of Material: Article
• Authors: Chen-Yen Yang, University of California Davis; Xiong Ma, Shanghai Jiao Tong University; Koichi Tsuneyama, University of Toyama; Shanshan Huang, Emory University; Toru Takahashi, JA Niigata Kouseiren Uonuma Hosp; Naga P. Chalasani, Indiana University; Christopher L. Bowlus, University of California Davis; Guo-Xiang Yang, University of California Davis; Patrick S.C. Leung, University of California Davis; Aftab Ansari, Emory University; Linda Wu, Janssen R&D; Ross Coppel, Monash University; M. Eric Gershwin, University of California Davis
• Language: English
• Date: 2014-05-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 by the American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.26979
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 192
• Issue: 5
• Start Page: 1944
• End Page: 1953
• Grant/Funding Information: Funding support provided by a grant from the National Institutes of Health, DK39588.
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

The interleukin (IL)-12/IL-23-mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, interferon-gamma (IFN-γ), IL-12RB2, IL-23p40, IL-23p19, IL-17, and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining was detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most important, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance profibrotic Th17 signaling and proinflammatory IFN-γ production that contribute to PBC pathology. Conclusion: Our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.