Abstract
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.
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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CD4 Antigens / biosynthesis
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Calcium / metabolism*
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Cyclosporine / metabolism
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Cyclosporine / pharmacology
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DNA-Binding Proteins / metabolism
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Deoxyribonuclease I / metabolism
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Gene Expression Regulation
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-2 / metabolism
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Interleukin-21
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Interleukins / biosynthesis*
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Ionophores / metabolism
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Luciferases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Genetic
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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Protein Binding
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RNA / metabolism
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Receptors, Antigen, T-Cell / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Nucleic Acid
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Species Specificity
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T-Lymphocytes / metabolism*
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Tacrolimus / pharmacology
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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CD4 Antigens
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DNA-Binding Proteins
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Immunosuppressive Agents
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Interleukin-2
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Interleukins
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Ionophores
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NFATC Transcription Factors
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Nuclear Proteins
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Receptors, Antigen, T-Cell
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Transcription Factors
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RNA
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Cyclosporine
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Luciferases
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Deoxyribonuclease I
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Interleukin-21
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Calcium
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Tacrolimus