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

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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 - 2009

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Extracellular Signal-Regulated MAP Kinases
Hepacivirus
Oxidative Stress
Virus Replication
MAP Kinase Signaling System
MAP Kinase Kinase 2
RNA
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Food
Vitamin E
Cyclosporine
Phosphorylation
Ergocalciferols
Acetylcysteine
Linoleic Acid
Carotenoids
Mitogen-Activated Protein Kinases
Unsaturated Fatty Acids
Interferons
Hepatocellular Carcinoma

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase. / Yano, Masahiko; Ikeda, Masanori; Abe, Ken Ichi; Kawai, Yoshinari; Kuroki, Misao; Mori, Kyoko; Dansako, Hiromichi; Ariumi, Yasuo; Ohkoshi, Shougo; Aoyagi, Yutaka; Kato, Nobuyuki.

In: Hepatology, Vol. 50, No. 3, 2009, p. 678-688.

Research output: Contribution to journalArticle

Yano, Masahiko ; Ikeda, Masanori ; Abe, Ken Ichi ; Kawai, Yoshinari ; Kuroki, Misao ; Mori, Kyoko ; Dansako, Hiromichi ; Ariumi, Yasuo ; Ohkoshi, Shougo ; Aoyagi, Yutaka ; Kato, Nobuyuki. / Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase. In: Hepatology. 2009 ; Vol. 50, No. 3. pp. 678-688.
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AU - Kuroki, Misao

AU - Mori, Kyoko

AU - Dansako, Hiromichi

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AU - Kato, Nobuyuki

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