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The Journal of Immunology, 2002, 169: 3600-3605.
Copyright © 2002 by The American Association of Immunologists

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response1

Mari Strengell2,*, Timo Sareneva*, Don Foster{dagger}, Ilkka Julkunen* and Sampsa Matikainen*

* Department of Microbiology, National Public Health Institute, Helsinki, Finland; and {dagger} Department of Functional Cloning, ZymoGenetics, Seattle, WA 98102

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-2R{alpha}, IL-12R{beta}2, 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-2R{alpha} IFN-{gamma}-activated sequence (GAS), MyD88 GAS, and c-sis-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-2R{alpha} GAS. The induction of IFN-{gamma}, T-bet, IL-12R{beta}2, 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.




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