title: Transcriptional regulation of IFN-λ genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-κB complex.
abstract: Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-λ), including IL-28A, IL-28B, and IL-29. However, the molecular mechanism(s) regulating the expression of IFN-λ genes in HCV-infected hepatocytes remains undefined. In this study, we examined regulatory elements involved in the induction of IFN-λ genes following HCV infection in hepatocytes and further determined the binding of specific transcription factor(s) to promoter regions of IFN-λ genes. Our studies reveal that the regulatory portion for IL-28A, IL-28B, and IL-29 genes is localized to a 1-kb region in their respective promoters. Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28B genes, whereas NF-κB is an additional requirement for the induction of the IL-29 gene. Ligation of Toll-like receptors (TLR) 3, 7, 8, and 9, which also activate IRFs and NF-κB, resulted in more robust production of IFN-λ than that observed with HCV infection, verifying the importance of TLR pathways in IFN-λ production. Furthermore, the addition of IFN-λ to HCV-infected hepatocytes decreased viral replication and produced a concurrent reduction in microRNA-122 (miR-122). The decrease in viral replication was enhanced by the co-administration of IFN-λ and miR-122 inhibitor (miRIDIAN), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.
authors.affiliation: From the Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Hai-Chon
authors.initials: HC
authors.lastname: Lee
authors.forename: Sowmya
authors.initials: S
authors.lastname: Narayanan
authors.forename: Sung-Jae
authors.initials: SJ
authors.lastname: Park
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seong
authors.forename: Young S
authors.initials: YS
authors.lastname: Hahn
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000095022:Interferon Lambda
chemical_list: D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007372:Interferons; D007378:Interleukins; D008024:Ligands; D035683:MicroRNAs; D016328:NF-kappa B; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C548375:MIRN22 microRNA, human
keywords: Cytokines induction; Hepatitis c virus; Interferon; Interferon regulatory factor; NF-κB; Transcription factors; Transcription promoter