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.C. Leung, Ross L. Coppel, Aftab A. Ansari, William M. Ridgway, Bin Gao, Zhe Xiong Lian, Richard Flavell, Xiao Song He, M. Eric Gershwin

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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
Issue number2
StatePublished - Feb 2013
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology


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