Klein-Hessling Stefan, Bopp Tobias, Jha Mithilesh K, Schmidt Arthur, Miyatake Shoichiro, Schmitt Edgar, Serfling Edgar
Department of Molecular Pathology, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
J Biol Chem. 2008 Nov 7;283(45):31030-7. doi: 10.1074/jbc.M805929200. Epub 2008 Sep 4.
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.
细胞内环状AMP水平升高会抑制初始T细胞和1型辅助性T细胞（Th1）的增殖，这是2型辅助性T细胞（Th2）和调节性T细胞的特性。虽然环状AMP信号会干扰白细胞介素-2（IL-2）启动子的诱导，但它们会支持Th2型基因的诱导，特别是il-5基因。我们在此表明，环状AMP信号会支持在il-5基因座上产生三个可诱导的脱氧核糖核酸酶I超敏染色质位点，包括其启动子区域。此外，环状AMP信号会增强IL-5启动子处组蛋白H3的乙酰化以及GATA-3和活化T细胞核因子c（NFATc）与启动子的协同结合。这是通过涉及GATA-3的C末端锌指和NFATc1 DNA结合结构域的C末端区域的直接蛋白质-蛋白质相互作用来实现的。由于体内抑制NFATc与IL-5启动子的结合也会影响GATA-3的结合，因此可以得出结论，在诱导Th2效应细胞时，NFATc会将GATA-3招募到Th2型基因。这些数据证明了环状AMP信号对于Th2效应细胞中淋巴因子表达转录控制中GATA-3和NFATc因子之间相互作用的功能重要性。
