Calcium-dependent activation of interleukin-21 gene expression in T cells.
Interleukin (IL)-21 is a gamma(c)-dependent cytokine produced by activated T cells with important actions for T, B, and NK cells. The IL-21 gene is adjacent to the IL-2 gene, and like IL-2, IL-21 is strongly induced at the transcriptional level after T cell activation. Interestingly, however, in contrast to the IL-2 gene, a calcium ionophore alone was sufficient to induce IL-21 gene expression in preactivated T cells. Two DNase I hypersensitivity sites were found in the IL-21 gene, corresponding to nucleotide sequences that are conserved in humans and mice. One site is located at the IL-21 promoter region and conferred T cell receptor-mediated IL-21 gene transcription. TCR-induced IL-21 gene expression was inhibited by cyclosporin A and FK506. Correspondingly, the IL-21 5'-regulatory region contains three NFAT binding sites, and induction of IL-21 promoter activity was impaired when these sites were mutated or following treatment with cyclosporin A. Thus, our studies reveal that in contrast to IL-2, a calcium signal alone is sufficient to mediate induction of the IL-21 in preactivated T lymphocytes and that this induction appears to result from specific NFAT binding.
Kim
Hyoung-Pyo
HP
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Korn
Lisa L
LL
Gamero
Ana M
AM
Leonard
Warren J
WJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015704:CD4 Antigens / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis*; D007476:Ionophores / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000098546:Interleukin-21
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007378:Interleukins; D007476:Ionophores; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D012313:RNA; D016572:Cyclosporine; D008156:Luciferases; D003850:Deoxyribonuclease I; D000098546:Interleukin-21; D002118:Calcium; D016559:Tacrolimus