Proinflammatory Actions of Glucocorticoids: Glucocorticoids and TNFα Coregulate Gene Expression In Vitro and In Vivo
Proinflammatory Actions of Glucocorticoids: Glucocorticoids and TNFα Coregulate Gene Expression In Vitro and In Vivo
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DOI：
10.1210/en.2012-1020
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发表时间：
2012-08-01
期刊：
影响因子：
4.8
通讯作者：
Cidlowski, John A.
中科院分区：
文献类型：
--
作者：
Lannan, Erica A.;Galliher-Beckley, Amy J.;Cidlowski, John A.
合成糖皮质激素广泛用于治疗许多炎症性疾病。然而，长期糖皮质激素治疗会引起多种副作用。在人肺 A549 细胞中进行全基因组微阵列分析，以确定受抗炎类固醇地塞米松 (Dex) 和促炎细胞因子 TNF α 调节的基因。出乎意料的是，我们发现许多基因受到 Dex 和 TNF α 治疗的共同调节。我们评估了其中一个基因 serpinA3（α-1 抗胰凝乳蛋白酶）的共调节机制，这是一种与多种炎症性疾病密切相关的分泌性急性期蛋白。 serpinA3 的上调需要糖皮质激素受体和 TNF α 可溶性受体 1 的存在。Dex 或 TNF α 治疗导致 serpinA3 mRNA 增加 10 至 25 倍，而 Dex 和 TNF α 共同给药导致 serpinA3 mRNA 协同增加。天然存在的糖皮质激素皮质醇也导致 A549 细胞中 inserpinA3 mRNA 水平协同增加。此外，用 Dex 和 TNF α 体内治疗 C57BL/6 小鼠导致肺和肝组织中 serpinA3 mRNA 水平的共同调节。最后，染色质免疫沉淀分析表明，联合使用 Dex 和 TNF α 处理 A549 细胞可以增强糖皮质激素受体与 serpinA3 转录起始位点的结合。这些研究表明，糖皮质激素和促炎化合物可以共同调节与人类疾病相关的基因。这一发现可能是与长期糖皮质激素治疗相关的一些不良反应的基础。 （内分泌学153：3701-3712，2012）
Synthetic glucocorticoids are widely used for treatment of many inflammatory diseases. However, long-term glucocorticoid treatment can cause a variety of negative side effects. A genome-wide microarray analysis was performed in human lung A549 cells to identify genes regulated by both the antiinflammatory steroid dexamethasone (Dex) and the proinflammatory cytokine TNF alpha. Unexpectedly, we discovered that numerous genes were coregulated by treatment with both Dex and TNF alpha. We evaluated the mechanism of coregulation of one of these genes, serpinA3 (alpha-1 antichymotrypsin), a secreted, acute phase protein strongly associated with numerous inflammatory diseases. Up-regulation of serpinA3 requires the presence of both the glucocorticoid receptor and TNF alpha soluble receptor 1. Treatment with Dex or TNF alpha resulted in a 10- to 25-fold increase of serpinA3 mRNA, whereas coadministration of Dex and TNF alpha led to a synergistic increase in serpinA3 mRNA. The naturally occurring glucocorticoid, cortisol, also resulted in a synergistic increase inserpinA3 mRNA levels in A549 cells. Furthermore, in vivo treatment of C57BL/6 mice with Dex and TNF alpha resulted in coregulation of serpinA3 mRNA levels in both lung and liver tissues. Finally, chromatin immunoprecipitation analyses suggest that glucocorticoid receptor binding to the serpinA3 transcriptional start site can be enhanced by the combination of Dex plus TNF alpha treatment of A549 cells. These studies demonstrate that glucocorticoids and proinflammatory compounds can coregulate genes associated with human disease. This discovery may underlie the basis of some of the adverse effects associated with long-term glucocorticoid therapy. (Endocrinology 153: 3701-3712, 2012)