title: IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12.
abstract: IFN-gamma, a product of NK and T cells, is a key cytokine contributing innate and adaptive immunity. IFN-gamma production is induced via direct cell-cell contacts with APC and IFN-gamma -producing cells or by cytokines. During microbial infections macrophage-derived IFN-alpha, IL-12, and IL-18 enhance IFN-gamma production and Th1 response. Here we show that IFN-alpha in combination with IL-18 very efficiently induces IFN-gamma expression also in primary, nonactivated NK cells and in NK-92 cell line. Comparison of the kinetics of IFN-gamma mRNA expression in nonactivated NK cells, NK-92 cells and activated T cells stimulated with IFN-alpha or IL-12 revealed that, although both of these cytokines directly up-regulate IFN-gamma mRNA expression, its levels remain elevated much longer with IL-12 stimulation. In both NK cells and T cells, Stat4 is known to be critical in IL-12 and IFN-alpha signaling. We show that Stat4 activation is transient in cells stimulated with IFN-alpha, whereas IL-12 induces more long-lasting activation of the transcription factor. This prolonged activation of IFN-gamma gene by IL-12 may result in more efficient IFN-gamma production compared to that of IFN-alpha. Our results demonstrate that IFN-alpha and IL-18 are important innate cytokines in inducing NK cell IFN-gamma production.
authors.affiliation: Department of Microbiology, National Public Health Institute, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Matikainen
authors.forename: A
authors.initials: A
authors.lastname: Paananen
authors.forename: M
authors.initials: M
authors.lastname: Miettinen
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: T
authors.initials: T
authors.lastname: Timonen
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
authors.forename: T
authors.initials: T
authors.lastname: Sareneva
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D050797:STAT4 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D020382:Interleukin-18; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D019000:Phosphotyrosine; D007371:Interferon-gamma; D003513:Cycloheximide