Oxidative stress inhibits IFN-α-induced antiviral gene expression by blocking the JAK-STAT pathway

Background/Aims: Unresponsiveness to IFN-alpha is common in chronic hepatitis C. Since conditions associated with an increased oxidative stress (advanced age, steatosis, fibrosis, iron overload, and alcohol consumption) reduce the likelihood of response, we hypothesized that oxidative stress may affect the antiviral actions of IFN-alpha. Methods: We examined in a human hepatocellular carcinoma cell line (Huh-7) the effect of hydrogen peroxide (H2O2), as a generator of oxidative stress, on the IFN-alpha signaling pathway. Results: Pretreatment of Huh-7 cells with 0.5-1 MM H2O2 resulted in the suppression of the WN-a-induced antiviral protein MxA and of IRF-9 mRNA expression. The reduced expression of these genes was associated to H2O2-mediated suppression of the IFN-alpha-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFN-alpha-inducible genes. This was accomplished by preventing the IFN-alpha-induced tyrosine phosphorylation of STAT-1 and STAT-2 through the inactivation of the upstream receptor associated tyrosine kinases, JAK-1 and Tyk-2. The suppression was fast, occurring within 5 mins of pretreatment with H2O2, and did not require protein synthesis. Conclusions: In conclusion, oxidative stress impairs IFN-alpha signaling and might cause resistance to the antiviral action of IFN-a in chronically HCV infected patients with high level of oxidative stress in the liver. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.