IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response.
IL-21 is a recently characterized T cell-derived cytokine that regulates NK and T cell function. IL-21R shares the common gamma-chain (gamma(c)) with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Despite the same gamma(c), these cytokines have different effects on diverse cells. In this study, we have studied IL-15- and IL-21-induced gene expression in human primary NK and T cells and the NK-92 cell line. Both IL-15 and IL-21 rapidly induced mRNA synthesis for IFN-gamma, T-bet, IL-2Ralpha, IL-12Rbeta2, IL-18R, and myeloid differentiation factor 88 (MyD88), the genes that are important in activating innate immunity and Th1 response. IL-15 induced STAT5 DNA binding to the IL-2Ralpha IFN-gamma-activated sequence (GAS), MyD88 GAS, and c-cis-inducible elements, whereas IL-21 induced STAT3 DNA binding to MyD88 GAS and c-sis-inducible elements. IL-21-induced STAT3 activation was verified by immunoprecipitation and Western blotting with anti-phosphotyrosine Ab. In addition, pretreatment of NK-92 cells with IL-15 or IL-21 strongly enhanced IL-12-induced STAT4 DNA binding to IL-2Ralpha GAS. The induction of IFN-gamma, T-bet, IL-12Rbeta2, and IL-18R gene expression in NK cells, along with STAT3 activation, suggests that IL-21 is involved in the activation of innate immune responses. Moreover, the enhanced transcription of these genes in T cells establishes a significant role for IL-21 also in the Th1 response.
Strengell
Mari
M
Department of Microbiology, National Public Health Institute, Helsinki, Finland. mari.strengell@ktl.fi
Sareneva
Timo
T
Foster
Don
D
Julkunen
Ilkka
I
Matikainen
Sampsa
S
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050856:Interferon Regulatory Factor-1; D019409:Interleukin-15 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D007694:Killer Cells, Natural / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008894:Milk Proteins; D053594:Myeloid Differentiation Factor 88; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D020218:Response Elements / Q000276:immunology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D019409:Interleukin-15; D007378:Interleukins; C507779:MYD88 protein, human; D008894:Milk Proteins; D053594:Myeloid Differentiation Factor 88; D010750:Phosphoproteins; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D000098546:Interleukin-21