Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice

Background & Aims: Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR-/-) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFN gamma is one of the most upregulated proinflammatory cytokines in FXR-/- livers, we generated IFN gamma-/-FXR-/- double knockout mice to determine IFN gamma's roles in hepatocarcinogenesis. Methods: IFN gamma(-/-) mice were crossed with an FXR-/- C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods. Results: IFN gamma deletion accelerated spontaneous hepatocarcinogenesis in FXR-/- mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFN gamma deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNy(-/-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFN gamma(-/-) and IFN gamma-/-FXR-/- mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNy(-/-) and IFN gamma-/-FXR-/- mice. In addition, IFN gamma inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression. Conclusions: Increased IFN gamma expression in FXR-/- livers represents a protective response of the liver against chronic injury and tumorigenesis. IFN gamma suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.