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

Masahiko Yano, Masanori Ikeda, Ken Ichi Abe, Yoshinari Kawai, Misao Kuroki, Kyoko Mori, Hiromichi Dansako, Yasuo Ariumi, Shougo Ohkoshi, Yutaka Aoyagi, Nobuyuki Kato

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 withN-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.

Original languageEnglish
Pages (from-to)678-688
Number of pages11
JournalHepatology
Volume50
Issue number3
DOIs
Publication statusPublished - Nov 27 2009

    Fingerprint

ASJC Scopus subject areas

  • Hepatology

Cite this

Yano, M., Ikeda, M., Abe, K. I., Kawai, Y., Kuroki, M., Mori, K., Dansako, H., Ariumi, Y., Ohkoshi, S., Aoyagi, Y., & Kato, N. (2009). Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase. Hepatology, 50(3), 678-688. https://doi.org/10.1002/hep.23026