Involvement of reactive oxygen species on the apoptotic mechanism induced by IFN-alpha2b in rat preneoplastic liver.

Interferon-alpha2b (IFN-alpha2b) is an important component in the preventive treatment of patients who have severe hepatic illness such as hepatitis B or C and hepatocarcinomas. In a previous work, using a rat liver preneoplastic model, we have demonstrated that IFN-alpha2b reduces the number and volume of altered hepatic foci (AHF) inducing apoptosis through a mechanism mediated by TGF-beta(1). In this study, the implication of hepatocytes redox status of IFN-alpha2b-treated preneoplastic liver in the TGF-beta(1)-induced apoptotic death was analyzed. Results indicate that IFN-alpha2b induces hepatocytic TGF-beta(1) production and secretion by induction of reactive oxygen species (ROS) formation through the activation of a membrane bound NADPH oxidase complex. TGF-beta(1), in turn, reduces hepatocytes antioxidant defenses and induces programmed cell death. On the other hand, it was also demonstrated that treatment of rats with IFN-alpha2b plus a ROS scavenger such as ascorbic acid, abolishes the apoptotic effect of IFN-alpha2b in rat preneoplastic livers, leading to an increase of the foci volume. In conclusion, these findings strongly suggest that ROS have a fundamental role as signaling and/or regulator molecules in the IFN-alpha2b-induced apoptosis in hepatic preneoplastic cells.