Cyclic AMP-induced chromatin changes support the NFATc-mediated recruitment of GATA-3 to the interleukin 5 promoter.
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.
Klein-Hessling
Stefan
S
Department of Molecular Pathology, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. stefan.klein-hessling@mail.uni-wuerzburg.de
Bopp
Tobias
T
Jha
Mithilesh K
MK
Schmidt
Arthur
A
Miyatake
Shoichiro
S
Schmitt
Edgar
E
Serfling
Edgar
E
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D000242:Cyclic AMP / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D040641:Quantitative Trait Loci / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology
D002843:Chromatin; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D006657:Histones; C508594:IL2 protein, human; C508599:IL5 protein, human; D007376:Interleukin-2; D015848:Interleukin-5; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D000242:Cyclic AMP
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