Glucocorticoid inhibition of granulocyte macrophage-colony-stimulating factor from T cells is independent of control by nuclear factor-κB and conserved lymphokine element 0
Glucocorticoid inhibition of granulocyte macrophage-colony-stimulating factor from T cells is independent of control by nuclear factor-κB and conserved lymphokine element 0
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DOI：
10.1165/rcmb.2003-0295oc
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发表时间：
2004-04-01
影响因子：
6.4
通讯作者：
Newton, R
中科院分区：
文献类型：
--
作者：
Bergmann, MW;Staples, KJ;Newton, R
T 细胞释放粒细胞巨噬细胞集落刺激因子 (GM-CSF) 对于炎症细胞的分化、成熟和存活很重要。其中，T 细胞 GMCSF 表达的诱导依赖于转录和翻译，并且被地塞米松阻止。在原代人 CD3+ T 细胞中，高达 3.3 kb 的人 GM-CSF 启动子被 PMA + PHA 强烈激活。 -85/-76 核因子 (NF)-kappaB 位点或 -54/-31 保守淋巴因子元件 0 (CLEO) 位点激活蛋白 1 区域的突变显着降低了启动子活性。 GM-CSF启动子和NF-κB依赖性构建体均对地塞米松无反应，而GM-CSF的释放被有效抑制。对不同时间点 GM-CSF mRNA 和蛋白表达的分析以及刺激后添加地塞米松的效果揭示了在翻译水平上存在有效的抑制机制。 tristetraproline 和 HuR（与 GM-CSF 3'-非翻译区中富含 AU 的元件结合的蛋白质）的表达不受地塞米松的影响，并且总体上富含 AU 的元件结合活性未改变。综上所述，我们的数据支持 NF-kappaB 和 CLEO 位点在原代人 T 细胞 GM-CSF 表达的转录控制中发挥重要作用，并表明转录后/转化机制是糖皮质激素依赖性抑制的关键介质。
Release of granulocyte macrophage-colony-stimulating factor (GM-CSF) from T cells is important in the differentiation, maturation, and survival of inflammatory cells. Here the induction of GMCSF expression from T cells was dependent on transcription and translation and was prevented by dexamethasone. In primary human CD3+ T cells, up to 3.3 kb of human GM-CSF promoter was strongly activated by PMA + PHA. Mutations in either the -85/-76 nuclear factor (NF)-kappaB site or the activator protein-1 region in the -54/-31 conserved lymphokine element 0 (CLEO) site substantially reduced promoter activity. Both GM-CSF promoter and NF-kappaB-dependent constructs were unresponsive to dexamethasone whereas the release of GM-CSF was potently repressed. Analysis of GM-CSF mRNA and protein expression at various time points and the effect of adding dexamethasone after the stimulus revealed the existence of potent mechanisms of inhibition acting at a translational level. The expression of tristetraproline and HuR, proteins that bind the AU-rich element in the GM-CSF 3'-untranslated region was unaffected by dexamethasone and overall AU-rich element binding activity was unaltered. Taken together our data support an important role for the NF-kappaB and CLEO sites in the transcriptional control of GM-CSF expression in primary human T cells and suggest that post-transcriptional/transiational mechanisms are key mediators of glucocorticoid-dependent repression.