Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT.
IL-2 gene transcription is affected by several nuclear proteins. We asked whether dexamethasone (Dex) and cyclosporin A (CsA) inhibit IL-2 gene transcription by interfering with the activity of nuclear proteins that bind to the IL-2 promoter. Nuclear extracts from primary human T lymphocytes were analyzed by electrophoretic DNA mobility shift assays. Both Dex and CsA inhibited the binding of transcription factors AP-1 and NF-AT, but not of NF-kB and OCT-1/OAF, to their corresponding sites on the IL-2 gene promoter. To correlate changes in nuclear factor binding in vitro with transcriptional activity in vivo and define the structural requirements for IL-2 promoter repression, we used transient DNA transfections. Jurkat cells were transfected with plasmids containing either the intact IL-2 promoter or its AP-1, NF-AT, and NF-kB motifs. Dex inhibited the IL-2 promoter and the AP-1, but not the NF-AT and NF-kB plasmids. In contrast, CsA inhibited the IL-2 promoter and the NF-AT, but not the AP-1 and NF-kB plasmids. These results suggest that in human T lymphocytes both Dex and CsA inhibited IL-2 gene transcription through interference with transcription factors AP-1 and NF-AT. We propose that, while maximum inhibition may involve interaction with both transcription factors, AP-1 is the primary target of Dex.
Paliogianni
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F
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Raptis
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A
Ahuja
S S
SS
Najjar
S M
SM
Boumpas
D T
DT
D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D003907:Dexamethasone; D016572:Cyclosporine