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The immunobiology of colitis and cholangitis in interleukin‐23p19 and interleukin‐17a deleted dominant negative form of transforming growth factor beta receptor type ii mice
Author(s) -
Ando Yugo,
Yang GuoXiang,
Tsuda Masanobu,
Kawata Kazuhito,
Zhang Weici,
Nakajima Takahiko,
Tsuneyama Koichi,
Leung Patrick,
Lian ZheXiong,
Okazaki Kazuichi,
Ridgway William M.,
Norman Gary L.,
Ansari Aftab A.,
He XiaoSong,
Coppel Ross L.,
Gershwin M. Eric
Publication year - 2012
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.25803
Subject(s) - colitis , interleukin 17 , cytokine , immunology , interleukin 23 , inflammatory bowel disease , interleukin , receptor , medicine , disease
Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)‐12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL‐12p40 mediates protection by the IL‐12 or IL‐23 pathways, we generated an IL‐23p19 −/− dnTGFβRII strain deficient in IL‐23, but not in IL‐12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL‐23p19 −/− mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T‐helper (Th)17 cell populations and unchanged IFN‐γ levels. We submit that the IL‐12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL‐23/Th17 pathway mediates colitis. To further assess the mechanism of the IL‐23‐mediated protection from colitis, we generated an IL‐17A −/− dnTGFβRII strain deficient in IL‐17, a major effector cytokine produced by IL‐23‐dependent Th17 cells. Deletion of the IL‐17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL‐23/Th17 pathway contributes to colon disease in an IL‐17‐independent manner. These results affirm that the IL‐12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL‐23. (H EPATOLOGY 2012)