Deletion of IL-12p35 induces liver fibrosis in dominant negative transforming growth factor β receptor type II mice

• Authors: Masanobu Tsuda, Kansai Medical University; Weici Zhang, University of California; Guo-Xiang Yang, University of California; Koichi Tsuneyama, University of California; Yugo Ando, University of California; Kazuhito Kawata, University of California; Ogyi Park, National Institutes of Health; Patrick S.C. Leung, University of California; Ross L. Coppel, Monash University; Aftab A Ansari, Emory University; William M. Ridgway, University of Cincinnati; Bin Gao, National Institutes of Health; Zhe-Xiong Lian, University of California; Richard Flavell, Yale University; Xiao-Song He, University of California; M. Eric Gershwin, University of California
• Journal Title: Hepatology
• Volume: Volume 57, Number 2
• Publisher: Wiley | 2013-02, Pages 806-816
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/hep.25829
• Subjects: Health Sciences, Immunology
• Keywords: Primary biliary cirrhosis; murine models; autoimmunity; cholangitis

Abstract

We have previously reported that mice with a dominant negative transforming growth factor β receptor restricted to T cells (dnTGFβRII mice) develop an inflammatory biliary ductular disease that strongly resembles human primary biliary cirrhosis (PBC). Furthermore, deletion of the gene encoding interleukin (IL)-12p40 resulted in a strain (IL-12p40−/−dnTGFβRII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGFβRII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGFβRII mice, resulting in an IL-12p35−/− dnTGFβRII strain which is deficient in two members of the IL-12 family, IL-12 and IL-35. In contrast to IL-12p40−/− mice, the IL-12p35−/− mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGFβRII mice. The p35−/− mice also demonstrated a distinct cytokine profile characterized by a shift from a Th1 to a Th17 response. Strikingly, liver fibrosis was frequently observed in IL-12p35−/− mice. In conclusion, IL-12p35−/− dnTGFβRII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC.