کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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6105792 | 1211153 | 2012 | 9 صفحه PDF | دانلود رایگان |
Background & AimsLiver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXRâ/â) 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 IFNγ is one of the most upregulated pro-inflammatory cytokines in FXRâ/â livers, we generated IFNγâ/âFXRâ/â double knockout mice to determine IFNγ's roles in hepatocarcinogenesis.MethodsIFNγâ/â mice were crossed with an FXRâ/â C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods.ResultsIFNγ deletion accelerated spontaneous hepatocarcinogenesis in FXRâ/â mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFNγ deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNγâ/â livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFNγâ/â and IFNγâ/âFXRâ/â mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNγâ/â and IFNγâ/âFXRâ/â mice. In addition, IFNγ inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression.ConclusionsIncreased IFNγ expression in FXRâ/â livers represents a protective response of the liver against chronic injury and tumorigenesis. IFNγ suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.
Journal: Journal of Hepatology - Volume 57, Issue 5, November 2012, Pages 1004-1012