title: Ribavirin enhances the action of interferon-α against hepatitis C virus by promoting the p53 activity through the ERK1/2 pathway.
abstract: OBJECTIVE
  Ribavirin significantly enhances the antiviral response of interferon-α (IFN-α) against Hepatitis C virus (HCV), but the underlying mechanisms remain poorly understood. Recently, p53 has been identified as an important factor involving the suppression of HCV replication in hepatocytes. We, therefore, decided to investigate whether and how ribavirin inhibits the replication of HCV by promoting the activity of p53.
  
  
  METHODS
  HepG2 and HCV replicons (JFH1/HepG2) were utilized to study the relationship between ribavirin and p53. The effect of ribavirin on cell cycles was analyzed by flow cytometry. The activation of p53 and the signaling pathways were determined using immunoblotting. By knocking down ERK1/ERK2 and p53 utilizing RNA interference strategy, we further assessed the role of ERK1/2 and p53 in the suppression of HCV replication by ribavirin in a HCV replicon system.
  
  
  RESULTS
  Using HepG2 and HCV replicons, we demonstrated that ribavirin caused the cell cycle arrest at G1 phase and stabilized and activated p53, which was associated with the antiviral activity of ribavirin. Compared to either ribavirin or IFN-α alone, ribavirin plus IFN-α resulted in greater p53 activation and HCV suppression. We further identified ERK1/2 that linked ribavirin signals to p53 activation. More importantly, knockdown of ERK1/2 and p53 partially mitigated the inhibitory effects of ribavirin on the HCV replication, indicating that ERK1/2-p53 pathway was involved in the anti-HCV effects of ribavirin.
  
  
  CONCLUSIONS
  Ribavirin stimulates ERK1/2 and subsequently promotes p53 activity which at least partly contributes to the enhanced antiviral response of IFN-α plus ribavirin against HCV.
authors.affiliation: Graduate Institute of Clinical Medicine, and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Liu
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Su
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Wang
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Hurng-Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Huang
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lai
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000037:antagonists & inhibitors*; D012093:Replicon / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D016159:Tumor Suppressor Protein p53; D012254:Ribavirin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3