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Deletion of interleukin (IL)‐12p35 induces liver fibrosis in dominant‐negative TGFβ receptor type II mice
Author(s) -
Tsuda Masanobu,
Zhang Weici,
Yang GuoXiang,
Tsuneyama Koichi,
Ando Yugo,
Kawata Kazuhito,
Park Ogyi,
Leung Patrick S.C.,
Coppel Ross L.,
Ansari Aftab A.,
Ridgway William M.,
Gao Bin,
Lian ZheXiong,
Flavell Richard,
He XiaoSong,
Gershwin M.Eric
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25829
Subject(s) - interleukin 1β , transforming growth factor , liver fibrosis , receptor , interleukin , fibrosis , biology , immunology , medicine , endocrinology , cytokine
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. (H EPATOLOGY 2013;)