title: IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.
abstract: NK and T cell-derived IFN-gamma is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-gamma, T-bet, IL-12R beta 2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-gamma gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-gamma mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-gamma gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-gamma gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-gamma production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-gamma gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-gamma gene regulatory sites. IL-18, however, activated the binding of NF-kappa B to the IFN-gamma promoter NF-kappa B site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response.
authors.affiliation: Department of Microbiology, National Public Health Institute, Helsinki, Finland. mari.strengell@ktl.fi
authors.forename: Mari
authors.initials: M
authors.lastname: Strengell
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.forename: Jukka
authors.initials: J
authors.lastname: Sirén
authors.forename: Anne
authors.initials: A
authors.lastname: Lehtonen
authors.forename: Don
authors.initials: D
authors.lastname: Foster
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.forename: Timo
authors.initials: T
authors.lastname: Sareneva
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D000098546:Interleukin-21; D000099185:Interferon Regulatory Factor-8
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D019409:Interleukin-15; D020382:Interleukin-18; D007378:Interleukins; D016328:NF-kappa B; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D000098546:Interleukin-21; D000099185:Interferon Regulatory Factor-8; C494079:STAT1 protein, human; C494090:STAT4 protein, human