Hepatitis C virus infection induces the beta interferon signaling pathway in immortalized human hepatocytes.
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.
Kanda
Tatsuo
T
Department of Pathology, Saint Louis University, St Louis, MO 63104, USA.
Steele
Robert
R
Ray
Ranjit
R
Ray
Ratna B
RB
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