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

Masanobu Tsuda, Weici Zhang, Guo Xiang Yang, Koichi Tsuneyama, Yugo Ando, Kazuhito Kawata, Ogyi Park, Patrick S Leung, Ross L. Coppel, Aftab A. Ansari, William M. Ridgway, Bin Gao, Zhe Xiong Lian, Richard Flavell, Xiaosong He, M. Eric Gershwin

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64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)806-816
Number of pages11
JournalHepatology
Volume57
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Hepatology

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    Tsuda, M., Zhang, W., Yang, G. X., Tsuneyama, K., Ando, Y., Kawata, K., Park, O., Leung, P. S., Coppel, R. L., Ansari, A. A., Ridgway, W. M., Gao, B., Lian, Z. X., Flavell, R., He, X., & Gershwin, M. E. (2013). Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology, 57(2), 806-816. https://doi.org/10.1002/hep.25829