Interferon-α2b (IFN-α2b)-induced apoptosis is mediated by p38 MAPK in hepatocytes from rat preneoplastic liver via activation of NADPH oxidase

Abstract

It is still unclear how Interferon-alfa (IFN-α) acts on preventing the appearance of hepatocarcinogenesis. We have demonstrated that IFN-α2b induces hepatocytic transforming growth factor-beta1 (TGF-β1) production and secretion by inducing reactive oxygen species (ROS) formation through the activation of NADPH oxidase. This TGF-β1, alters antioxidant defences and induces programmed cell death. Since it was demonstrated that IFN-α induces apoptosis through the activation of p38 mitogen-activated protein kinase (p38 MAPK), this study was aimed to assess the role of this kinase in the IFN-α2b-induced apoptosis in rat liver preneoplasia; and to further evaluate the participation of NADPH oxidase. p38 MAPK pathway was activated during the IFN-α2b-induced apoptosis in rat liver preneoplasia. This activation was accompanied with phosphorylation of different transcription factors, depending on the time of IFN-α2b stimulus. Our data suggest that NADPH oxidase is activated by IFN-α2b through p38 MAPK. p38 MAPK-induced activation of NADPH oxidase is accomplished by a two-step pathway: first, ROS-independent and second ROS- and TGF-β1-dependent.