摘要
Mice with a dominant-negative transforming growth factor beta receptor restricted to T cells (dnTGF beta RII 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(-/-) dnTGF beta RII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGF beta RII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGF beta RII mice, resulting in an IL-12p35(-/-) dnTGF beta RII 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 2/2 mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGF beta RII 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(-/-) dnTGF beta RII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC. (HEPATOLOGY 2013;57:806-816)
- 出版日期2013-2
- 单位中国科学技术大学; NIH