Oxidative stress induces anti‐hepatitis C virus status via the activation of extracellular signal‐regulated kinase
Oxidative stress induces anti‐hepatitis C virus status via the activation of extracellular signal‐regulated kinase
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DOI：
10.1002/hep.23026
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发表时间：
2009-09
期刊：
影响因子：
13.5
通讯作者：
M. Yano;M. Ikeda;K. Abe;Yoshinari Kawai;Misao Kuroki;Kyoko Mori;H. Dansako;Y. Ariumi;S. Ohkoshi;Y. Aoyagi;N. Kato
中科院分区：
文献类型：
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作者：
M. Yano;M. Ikeda;K. Abe;Yoshinari Kawai;Misao Kuroki;Kyoko Mori;H. Dansako;Y. Ariumi;S. Ohkoshi;Y. Aoyagi;N. Kato
最近，我们报道了β-胡萝卜素，维生素D2和亚油酸抑制肝癌细胞中丙型肝炎病毒（HCV）RNA复制。有趣的是，在研究过程中，我们发现抗氧化剂维生素E否定了这些营养素的抗HCV活性。这些结果表明，这三种营养素引起的氧化应激参与了它们的抗HCV活性。然而，氧化应激诱导抗HCV状态的分子机制仍然未知。氧化应激也被称为激活细胞外信号调节激酶（ERK）。因此，我们假设氧化应激通过丝裂原活化蛋白激酶（MAPK）/ERK激酶（MEK）-ERK 1/2信号通路诱导抗HCV状态。在这项研究中，我们发现MEK 1/2特异性抑制剂U 0126以剂量依赖性方式消除了三种营养素的抗HCV活性。此外，U 0126显著减弱了多不饱和脂肪酸、干扰素-γ和环孢素A的抗HCV活性，但对他汀类药物无影响。我们进一步证明，除他汀类药物外，所有这些抗HCV营养素和试剂实际上都诱导了MEK-ERK 1/2信号通路的激活，不仅用U 0126处理，而且用维生素E处理也能抑制或减少MEK-ERK 1/2信号通路的激活。我们还证明，N-乙酰半胱氨酸处理减弱了环孢菌素A对ERK 1/2的磷酸化，并导致对HCV RNA复制的抑制作用消失。我们提出，ERK 1/2磷酸化后的细胞过程，对氧化刺激特异性，可能导致HCV RNA复制下调。结论：我们的研究结果表明，MEK-ERK 1/2信号通路参与了多种抗HCV试剂中氧化应激诱导的抗HCV状态。这种细胞内调节预期是抑制HCV RNA复制的治疗靶点。（肝脏学2009年）
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.)