title: Involvement of ERK pathway in interferon alpha-mediated antiviral activity against hepatitis C virus.
abstract: Interferon alpha (IFN-α) is the key component of the therapy for hepatitis C virus (HCV) infection. IFN-α exerts anti-HCV activity by targeting certain signaling pathways. Using infectious HCV culture system in human hepatoma Huh7.5.1 cells, we analyzed functional relevance of extracellular signal-regulated kinase (ERK) pathway for IFN-α-mediated anti-HCV activity. IFN-α treatment resulted in activation of ERK pathway by increasing phosphorylation of c-Raf, MEK, and ERK1/2 in Huh7.5.1 cells, whereas HCV impaired such activation. IFN-α-dependent ERK1/2 phosphorylation was blocked by MEK inhibitor U0126. Pharmacological inhibition of ERK1/2 by U0126 or siRNA-mediated knockdown of ERK1/2 resulted in suppressive effects on HCV RNA levels and expression of HCV nonstructural protein 3 and envelope protein 2, establishing an important role for ERK pathway in HCV replication. Moreover, induction of a set of antiviral genes by IFN-α was enhanced in HCV-infected Huh7.5.1 cells due to the ERK1/2 knockdown, suggesting that impairment of ERK signaling may potentiate HCV inhibition by IFN-α. These results demonstrate that ERK pathway is involved in IFN-α-mediated antiviral activity against HCV.
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lan-Juan
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China. Electronic address: hren2013@139.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefence, Second Military Medical University, Shanghai 200433, China. Electronic address: qizt@smmu.edu.cn.
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002070:Butadienes; D016898:Interferon-alpha; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases
keywords: ERK; HCV; IFN-α