These authors contributed equally to this work.
Article first published online: 5 FEB 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 806–816, February 2013
How to Cite
Tsuda, M., Zhang, W., Yang, G.-X., Tsuneyama, K., Ando, Y., Kawata, K., Park, O., Leung, P. S.C., Coppel, R. L., Ansari, A. A., Ridgway, W. M., Gao, B., Lian, Z.-X., Flavell, R., He, X.-S. and Gershwin, M.Eric. (2013), Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology, 57: 806–816. doi: 10.1002/hep.25829
Potential conflict of interest: Nothing to report.
Financial support provided by National Institutes of Health grant DK090019.
- Issue published online: 5 FEB 2013
- Article first published online: 5 FEB 2013
- Accepted manuscript online: 10 MAY 2012 06:45AM EST
- Manuscript Accepted: 1 MAY 2012
- Manuscript Received: 28 NOV 2011
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. (HEPATOLOGY 2013;)