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J. Biol. Chem., Vol. 283, Issue 45, 31030-31037, November 7, 2008

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Cyclic AMP-induced Chromatin Changes Support the NFATc-mediated Recruitment of GATA-3 to the Interleukin 5 Promoter^*

Stefan Klein-Hessling¹, Tobias Bopp, Mithilesh K. Jha, Arthur Schmidt, Shoichiro Miyatake^¶, Edgar Schmitt, and Edgar Serfling²

From the Department of Molecular Pathology, Institute of Pathology, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany, the Institute for Immunology, University of Mainz, Hochhaus am Augustusplatz, D-55131 Mainz, Germany, and the ^¶Department of Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan

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 Zn²⁺-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.

Received for publication, July 31, 2008

^* This work was supported by the Deutsche Forschungsgemeinschaft, the Wilhelm-Sander-Stiftung, and the Mildred-Scheel-Stiftung/Deutsche Krebshilfe. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Tel.: 49-931-201-47431 or 95; Fax: 49-931-201-47131; E-mail: stefan.klein-hessling{at}mail.uni-wuerzburg.de.

² To whom correspondence may be addressed: Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Tel.: 49-931-201-47431 or 95; Fax: 49-931-201-47131; E-mail: serfling.e{at}mail.uni-wuerzburg.de.

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