Interferon-gamma-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine

Hepatocarcinogenesis is a complex multifactorial process in which continuous intrahepatic inflammation plays a major role. Although inflammatory cell infiltration is observed in the process of chemical-induced hepatocarcinogenesis, the pathophysiological role of the inflammatory response is not well defined. To approach this question, molecular and cellular responses were monitored during the development of liver tumors in mice exposed to a chemical hepatocarcinogen, diethylnitrosamine (DEN), in drinking water (50 microg/l). Intrahepatic type I and type II interferon (IFN-beta and IFN-gamma, respectively) mRNA expression was found to be induced 2 months before the appearance of hepatocellular carcinomas. The pathogenetic importance of IFNs was determined by monitoring tumor development in mice genetically deficient in the IFN-alpha/beta receptor (IFN-alpha/betaR KO) or the IFN-gamma receptor (IFN-gammaR KO). IFN-gammaR KO mice developed fewer tumors than IFN-alpha/betaR KO and wild-type (wt) mice, although the tumor diameters did not differ significantly among the three lineages. Interestingly, immunohistochemical studies demonstrated that the percentage of monocytes/macrophages in infiltrating mononuclear cells was reduced greatly in the livers of IFN-gammaR KO mice, which is consistent with the facts that intrahepatic cytokine expression was diminished and oxidative DNA damage was induced to a lesser extent. In conclusion, type II IFN, but not type I IFNs, may be involved critically in the initiation stage, but not the promotion stage, of DEN-induced hepatocarcinogenesis by enhancing monocytes/macrophages activation and eventual hepatocyte DNA damage.