Cyclosporin A-resistant transactivation of the IL-2 promoter requires activity of okadaic acid-sensitive serine/threonine phosphatases.
Expression of the IL-2 gene requires activation of T cells through stimulation of the TCR and costimulation through accessory receptors. We have found recently that okadaic acid-sensitive Ser/Thr phosphatases are involved in a cyclosporin A-insensitive pathway that selectively transmits costimulatory signals. In this study, we analyzed whether activities of these phosphatases are necessary for the expression of the IL-2 gene. In both activated peripheral blood T lymphocytes and activated tumorigenic T cell lines, IL-2 gene expression was blocked at the transcriptional level by okadaic acid. The transcription factors active at the IL-2 promoter were differentially influenced: upon down-modulation of okadaic acid-sensitive phosphatases, transactivation by octamer, NF-kappa B, and NF of activated T cells proteins was abrogated, while transactivation by AP-1 proteins was even enhanced.
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Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany. o66@ix.urz.uni-heidelberg.de
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D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D019169:Jurkat Cells; D016328:NF-kappa B / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013945:Thymoma; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019319:Okadaic Acid; D016572:Cyclosporine; D010749:Phosphoprotein Phosphatases