title: Interference with ERK and STAT signaling pathways and inhibition of hepatitis C virus replication by ribavirin.
abstract: Ribavirin in combination with interferon (IFN)-α is the approved treatment for hepatitis C virus (HCV) infection. Interference of ribavirin with signaling events is involved in its biological activities. However, little is known of signaling pathways induced by ribavirin following HCV infection. In human hepatoma cells, effects of ribavirin on ERK and signal transducers and activators of transcription (STAT) pathways, HCV replication, and antiviral gene expression were evaluated before and after cell culture-derived HCV infection. Ribavirin reduced phosphorylation of Raf, MEK, ERK, Tyk2, and STAT1, but selectively increased STAT3 phosphorylation. IFN-α synergistically regulated ERK and STAT3 phosphorylation with ribavirin, and up-regulated expression and phosphorylation of STAT1. Ribavirin dose-dependently decreased HCV RNA replication and HCV protein expression, with slight induction of IFN regulatory factor 9 and IFN-stimulated gene 15. Ribavirin and IFN-α exerted a synergetic inhibitory effect on HCV. ERK and STAT pathways were down-regulated by ribavirin following HCV infection. These results suggest that ribavirin may mediate anti-HCV activity through interference with ERK and STAT pathways.
authors.affiliation: Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lan-Juan
authors.initials: LJ
authors.lastname: Zhao
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D012367:RNA, Viral / Q000096:biosynthesis; D012254:Ribavirin / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D050791:STAT Transcription Factors; D014764:Viral Proteins; D012254:Ribavirin