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Oxidative stress induces anti‐hepatitis C virus status via the activation of extracellular signal‐regulated kinase

Recently, we reported that β‐carotene, vitamin D2, and linoleic acid inhibited hepatitis C virus (HCV) RNA replication in hepatoma cells. Interestingly, in the course of the study, we found that the antioxidant vitamin E negated the anti‐HCV activities of these nutrients. These results suggest that the oxidative stress caused by the three nutrients is involved in their anti‐HCV activities. However, the molecular mechanism by which oxidative stress induces anti‐HCV status remains unknown. Oxidative stress is also known to activate extracellular signal‐regulated kinase (ERK). Therefore, we hypothesized that oxidative stress induces anti‐HCV status via the mitogen activated protein kinase (MAPK)/ERK kinase (MEK)–ERK1/2 signaling pathway. In this study, we found that the MEK1/2‐specific inhibitor U0126 abolished the anti‐HCV activities of the three nutrients in a dose‐dependent manner. Moreover, U0126 significantly attenuated the anti‐HCV activities of polyunsaturated fatty acids, interferon‐γ, and cyclosporine A, but not statins. We further demonstrated that, with the exception of the statins, all of these anti‐HCV nutrients and reagents actually induced activation of the MEK–ERK1/2 signaling pathway, which was inhibited or reduced by treatment not only with U0126 but also with vitamin E. We also demonstrated that phosphorylation of ERK1/2 by cyclosporine A was attenuated with N‐acetylcysteine treatment and led to the negation of inhibition of HCV RNA replication. We propose that a cellular process that follows ERK1/2 phosphorylation and is specific to oxidative stimulation might lead to down‐regulation of HCV RNA replication. Conclusion: Our results demonstrate the involvement of the MEK–ERK1/2 signaling pathway in the anti‐HCV status induced by oxidative stress in a broad range of anti‐HCV reagents. This intracellular modulation is expected to be a therapeutic target for the suppression of HCV RNA replication. (HEPATOLOGY 2009.)