Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice§

Authors

  • Masanobu Tsuda,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    2. Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan
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  • Weici Zhang,

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    • Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
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    • These authors contributed equally to this work.

  • Guo-Xiang Yang,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Koichi Tsuneyama,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    2. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
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  • Yugo Ando,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Kazuhito Kawata,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Ogyi Park,

    1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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  • Patrick S.C. Leung,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Ross L. Coppel,

    1. Department of Microbiology, Monash University, Victoria, Australia
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  • Aftab A. Ansari,

    1. Department of Pathology, Emory University School of Medicine, Atlanta, GA
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  • William M. Ridgway,

    1. Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH
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  • Bin Gao,

    1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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  • Zhe-Xiong Lian,

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    2. Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei China
    • Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
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  • Richard Flavell,

    1. Section of Immunobiology, Yale University School of Medicine, New Haven, CT
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  • Xiao-Song He,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • M.Eric Gershwin

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    • Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Dr., Ste. 6510, Davis, CA 95616
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    • Fax: 530-752-4669


  • Potential conflict of interest: Nothing to report.

  • Financial support provided by National Institutes of Health grant DK090019.

Abstract

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 T-helper 1 (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. (HEPATOLOGY 2013;)

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