title: Natural killer cells inhibit hepatitis C virus expression.
abstract: Natural killer (NK) cells are critical in host innate defense against certain viruses. The role of NK cells in controlling hepatitis C virus (HCV) remains obscure. We examined whether NK cells are capable of inhibiting HCV expression in human hepatic cells. When NK cells are cultured with the HCV replicon-containing hepatic cells, they have no direct cytolytic effect but release soluble factor(s) suppressing HCV RNA expression. Media conditioned by NK cell lines (NK-92 and YTS) or primary NK cells isolated from healthy donors contain interferon gamma (IFN-gamma) and potently inhibit HCV RNA expression. Ligation of CD81 on NK cells inhibits IFN-gamma production and results in decreased anti-HCV activity. In addition, the antibodies to IFN-gamma or IFN-gamma receptors abolish the anti-HCV activity of NK cell-conditioned media. The role of IFN-gamma in NK cell-mediated, anti-HCV activity is supported by the observation that NK cell-conditioned media enhanced expression of signal transducer and activator of transcription-1, a nuclear factor that is essential in IFN-gamma-mediated antiviral pathways. NK cell-conditioned media have the ability to stimulate intracellular IFN-alpha expression in the hepatic cells, suggesting a mechanism responsible for NK cell-mediated, anti-HCV activity. Thus, NK cells hold the potential to play a vital role in controlling HCV replication in hepatic cells using an IFN-gamma-dependent mechanism.
authors.affiliation: Division of Allergy & Immunology, Joseph Stokes, Jr. Research Institute at The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 34th Street & Civic Center Blvd., Philadelphia, PA 19104, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Ho
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology; D000998:Antiviral Agents / Q000276:immunology* / Q000378:metabolism; D001681:Biological Assay; D002460:Cell Line; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012367:RNA, Viral / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000187:drug effects / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor; D060225:Tetraspanin 28; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D015703:Antigens, CD; D000998:Antiviral Agents; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007371:Interferon-gamma; D012367:RNA, Viral; D017471:Receptors, Interferon; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D060225:Tetraspanin 28; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C554798:CD81 protein, human; C494079:STAT1 protein, human