Interferon gamma/STAT1 signalling prevents hepatocarcinogenesis by sensitizing for p53-induced apoptosis in response to DNA-damage

Abstract

Interferon gamma [IFNgamma] has been implicated in acute and chonic inflammation in the liver. Indeed, IFNgamm-transgenic mice exhibit chronic hepatitis, liver injury and regeneration. Such state of chronic regeneration under inflammatory stress is believed to be a major risk factor for the development of liver cancer. However, we previously found that overexpression of IFN gamma in the liver protected IFNgamma-transgenic mice from chemically induced hepatocarinogenesis. despite chronic hepatitis. This tumour-suppressive activity of IFNgamma was independent of a functional T-cell response. Here, we investigated the molecular mechanisms underlying the IFNgamma-induced resistance to liver cancer. In contrast to non-transgenic mice, IFNgamma-transgenic mice exhibited increased expression of CyclinD and PCNA in whole liver extracts, indicating chronic regenerative proliferation of hepatocytes. Moreover, the livers of IFNgamma transgenic mice manifested marked accumulation of p53, compared to non-transgenic mice, and increased p53 activation, indicated by elevated expression of p53-regulated p21 protein. In vivo administration of diethylnitrosamine–a DNA-damage inducing carcinogen–induced a significant increase in hepatocyte apoptosis in the IFNgamma-transgenic, compared to non-transgenic mice, determined by TUNEL-staining of liver tissue sections and by Caspase–3 cleavage in whole liver lysates. In contrast to the p53 pathway, the NFkappaB or JNK pathways, which have been described as important modulators of hepatocarcinogenesis in other models, appeared to be irrelevant, since both the IFNgamma-transgenic and the non-transgenic mice displayed a similar degree of activity of these pathways, determined by Western blot. Our findings indicate that chronic inflammation and regeneration of the liver does not necessarily predispose to hepatocarcinogenesis, provided that inflammation is of a type that is dominated by IFNgamma. Inflammatory IFNgamma may directly activate the intrinsic p53 tumour-suppressor mechanism of aberrant cells, independent of the successful recruitment of tumour-lysing immune cells.