Prostaglandin E2 inhibits the nuclear transcription of the human interleukin 2, but not the Il-4, gene in human T cells by targeting transcription factors AP-1 and NF-AT.
Prostaglandin E2 (PGE2) release from activated macrophages and/or stimulation of T cells is associated with cAMP formation and activation of protein kinase A (PKA). cAMP inhibits Th1- but not Th2-cytokine production and may influence the nature of the immune response to a given antigen. Using DNA transfection and electrophoretic mobility shift assays (EMSA), we have examined the mechanisms for the transcriptional regulation of human IL-2 and IL-4 genes by PGE2. Stimulation of Jurkat cells with ionomycin and PMA in the presence of PGE2 inhibited the IL-2- but not the IL-4-promoter activity. In EMSAs, nuclear extracts from primary human T cells stimulated with ionomycin and phorbol esters in the presence of PGE2 demonstrated decreased binding at the AP-1 and NF-AT sites of the human IL-2 promoter; binding to the OCT-1 and NF-kappa B sites was not affected. These results suggest that cAMP regulates IL-2 production in human T cells by a transcriptional mechanism which involves discrete transactivating pathways for IL-2-promoter activation.
Paliogianni
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Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892-1268, USA.
Boumpas
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D002118:Calcium / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D051863:Host Cell Factor C1; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015847:Interleukin-4; D011493:Protein Kinase C; D002118:Calcium