title: Hepatitis C virus infection induces the beta interferon signaling pathway in immortalized human hepatocytes.
abstract: Beta interferon (IFN-beta) expression is triggered by double-stranded RNA, a common intermediate in the replication of many viruses including hepatitis C virus (HCV). The recent development of cell culture-grown HCV allowed us to analyze the IFN signaling pathway following virus infection. In this study, we have examined the IFN-beta signaling pathway following infection of immortalized human hepatocytes (IHH) with HCV genotype 1a (clone H77) or 2a (clone JFH1). We observed that IHH possesses a functional Toll-like receptor 3 pathway. HCV infection in IHH enhanced IFN-beta and IFN-stimulated gene 56 (ISG56) promoter activities; however, poly(I-C)-induced IFN-beta and ISG56 expression levels were modestly inhibited upon HCV infection. IHH infected with HCV (genotype 1a or 2a) exhibited various levels of translocation of IRF-3 into the nucleus. The upregulation of endogenous IFN-beta and 2',5'-oligoadenylate synthetase 1 mRNA expression was also observed in HCV-infected IHH. Subsequent studies suggested that HCV infection in IHH enhanced STAT1 and ISG56 protein expression. A functional antiviral response of HCV-infected IHH was observed by the growth-inhibitory role in vesicular stomatitis virus. Together, our results suggested that HCV infection in IHH induces the IFN signaling pathway, which corroborates observations from natural HCV infection in humans.
authors.affiliation: Department of Pathology, Saint Louis University, St Louis, MO 63104, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Robert
authors.initials: R
authors.lastname: Steele
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
authors.forename: Ratna B
authors.initials: RB
authors.lastname: Ray
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D016174:Hepacivirus / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation