Glucocorticoids and tumor necrosis factor alpha cooperatively regulate Toll-like receptor 2 gene expression
Glucocorticoids and tumor necrosis factor alpha cooperatively regulate Toll-like receptor 2 gene expression
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DOI：
10.1128/mcb.24.11.4743-4756.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Cidlowski, JA
中科院分区：
文献类型：
--
作者：
Hermoso, MA;Matsuguchi, T;Cidlowski, JA
肿瘤坏死因子α（TNF-α）和糖皮质激素被广泛认为是适应性免疫和炎症的相互拮抗的调节剂。令人惊讶的是，我们在这里表明，它们合作调节先天免疫的组成部分。Toll样受体2（TLR 2）基因编码一种触发先天免疫的跨膜受体。尽管TLR 2 mRNA和蛋白质由TNF-α等炎症分子诱导，但我们表明TLR 2也由细胞中的抗炎糖皮质激素诱导，它们也调节MKP-1 mRNA和蛋白质水平。TNF-α和糖皮质激素通过3'NF-κ B位点、STAT结合元件和3'糖皮质激素反应元件（GRE）的参与协同调节TLR 2启动子。分子研究表明，IkappaB α超阻遏物或STAT显性负性元件阻止TNF-α和地塞米松刺激TLR 2启动子。类似地，糖皮质激素受体的AF-1缺失突变体或假定GRE的消融显著降低了TLR 2的协同调节。使用染色质免疫沉淀试验，我们证明，所有三个转录因子相互作用的内源性和转染的TLR 2启动子刺激后，TNF-α和地塞米松。总之，这些研究为这三种转录因子定义了新的信号传导机制，对先天性和适应性免疫反应的区分产生了深远的影响。
Tumor necrosis factor alpha (TNF-alpha) and glucocorticoids are widely recognized as mutually antagonistic regulators of adaptive immunity and inflammation. Surprisingly, we show here that they cooperatively regulate components of innate immunity. The Toll-like receptor 2 (TLR2) gene encodes a transmembrane receptor critical for triggering innate immunity. Although TLR2 mRNA and protein are induced by inflammatory molecules such as TNF-alpha, we show that TLR2 is also induced by the anti-inflammatory glucocorticoids in cells where they also regulate MKP-1 mRNA and protein levels. TNF-alpha and glucocorticoids cooperate to regulate the TLR2 promoter, through the involvement of a 3' NF-kappaB site, a STAT-binding element, and a 3' glucocorticoid response element (GRE). Molecular studies show that the IkappaBalpha superrepressor or a STAT dominant negative element prevented TNF-alpha and dexamethasone stimulation of TLR2 promoter. Similarly, an AF-1 deletion mutant of glucocorticoid receptor or ablation of a putative GRE notably reduced the cooperative regulation of TLR2. Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-alpha and dexamethasone. Together, these studies define novel signaling mechanism for these three transcription factors, with a profound impact on discrimination of innate and adaptive immune responses.