Abstract
Elevated intracellular cyclic AMP levels, which suppress the proliferation of naive T cells and type 1 T helper (Th1) cells are a property of T helper 2 (Th2) cells and regulatory T cells. While cyclic AMP signals interfere with the IL-2 promoter induction, they support the induction of Th2-type genes, in particular of il-5 gene. We show here that cyclic AMP signals support the generation of three inducible DNase I hypersensitive chromatin sites over the il-5 locus, including its promoter region. In addition, cyclic AMP signals enhance histone H3 acetylation at the IL-5 promoter and the concerted binding of GATA-3 and NFATc to the promoter. This is facilitated by direct protein-protein interactions involving the C-terminal Zn(2+)-finger of GATA-3 and the C-terminal region of the NFATc1 DNA binding domain. Because inhibition of NFATc binding to the IL-5 promoter in vivo also affects the binding of GATA-3, one may conclude that upon induction of Th2 effector cells NFATc recruits GATA-3 to Th2-type genes. These data demonstrate the functional importance of cyclic AMP signals for the interplay between GATA-3 and NFATc factors in the transcriptional control of lymphokine expression in Th2 effector cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Cell Line
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Cell Proliferation
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Chromatin / genetics
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Chromatin / immunology
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Chromatin / metabolism
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Chromatin Assembly and Disassembly / physiology*
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Cyclic AMP / genetics
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Cyclic AMP / immunology
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Cyclic AMP / metabolism*
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / immunology
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GATA3 Transcription Factor / metabolism*
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Gene Expression Regulation / physiology
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Histones / genetics
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Histones / immunology
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Histones / metabolism
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Humans
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Interleukin-2 / genetics
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Interleukin-2 / immunology
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Interleukin-2 / metabolism
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Interleukin-5 / biosynthesis*
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Interleukin-5 / genetics
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Interleukin-5 / immunology
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Mice
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Mice, Inbred BALB C
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / immunology
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NFATC Transcription Factors / metabolism*
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Promoter Regions, Genetic / physiology*
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Protein Structure, Tertiary / physiology
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Quantitative Trait Loci / physiology
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Signal Transduction / physiology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / immunology
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Th2 Cells / metabolism*
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Zinc Fingers / physiology
Substances
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Chromatin
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GATA3 Transcription Factor
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GATA3 protein, human
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Gata3 protein, mouse
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Histones
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IL2 protein, human
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IL5 protein, human
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Interleukin-2
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Interleukin-5
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NFATC Transcription Factors
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NFATC1 protein, human
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Nfatc1 protein, mouse
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Cyclic AMP