Ribavirin Enhances the Action of Interferon-α against Hepatitis C Virus by Promoting the p53 Activity through the ERK1/2 Pathway
Journal
PLoS ONE
Journal Volume
7
Journal Issue
9
Pages
e43824
Date Issued
2012
Author(s)
Liu W.-L.
Su W.-C
Wang C.-C
Chen H.-L
Huang W.-H
Lai M.-Y.
Abstract
Background/Aims: 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. Conclusion: 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. ? 2012 Liu et al.
SDGs
Other Subjects
alpha interferon; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein p53; ribavirin; antiviral activity; article; cell cycle G1 phase; cell death; cell proliferation; cell viability; controlled study; cytokine response; drug potentiation; enzyme activation; flow cytometry; G1 phase cell cycle checkpoint; gene expression; gene repression; gene silencing; Hepatitis C virus; human; human cell; immunoblotting; molecular mechanics; protein function; protein stability; replicon; RNA interference; signal transduction; virus replication; Antiviral Agents; Cell Cycle; Cell Survival; Drug Synergism; Gene Expression Regulation; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Interferon-alpha; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Replicon; Ribavirin; RNA, Viral; Tumor Suppressor Protein p53; Virus Replication; Hepatitis C virus
Type
journal article