2009年9月
Oxidative Stress Induces Anti-Hepatitis C Virus Status via the Activation of Extracellular Signal-Regulated Kinase
HEPATOLOGY
- 巻
- 50
- 号
- 3
- 開始ページ
- 678
- 終了ページ
- 688
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1002/hep.23026
- 出版者・発行元
- JOHN WILEY & SONS INC
Recently, we reported that beta-carotene, vitamin D(2), 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 m 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-spedfic 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-gamma, 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;50: 678-688.)
- リンク情報
- ID情報
-
- DOI : 10.1002/hep.23026
- ISSN : 0270-9139
- eISSN : 1527-3350
- PubMed ID : 19492433
- Web of Science ID : WOS:000269551100006