Bacterial peptidoglycan-induced tnf-α transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-κB
Bacterial peptidoglycan-induced tnf-α transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-κB
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DOI：
10.4049/jimmunol.167.12.6975
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发表时间：
2001-12-15
影响因子：
4.4
通讯作者：
Gupta, D
中科院分区：
文献类型：
--
作者：
Xu, ZJ;Dziarski, R;Gupta, D
细菌及其普遍存在的细胞壁组分肽聚糖（PGN）激活宿主的先天免疫系统并诱导炎症分子的释放。TNF-α是用PGN刺激的巨噬细胞中最高诱导的细胞因子之一;然而，对PGN活化细胞中TNF-α表达的调节知之甚少。本研究旨在鉴定PGN刺激的巨噬细胞中调节TNF-α基因表达的一些转录因子。我们的研究结果表明，PGN诱导的人nif-ce基因的表达受启动子近端-182 bp序列的调控。cAMP反应元件、早期生长反应（Egr）-1和kappa B3结合位点内的突变显著降低了这种诱导作用。转录因子c-Jun结合cAMP反应元件位点，Egr-1结合Egr-1基序，NF-κ B p50和p65结合TNF-α启动子上的κ B3位点。PGN快速诱导转录的β-1基因，这种诱导显着降低了特异性突变内的血清反应元件-1域的β-1启动子。PGN还诱导Ets家族转录因子Elk-1的磷酸化和活化。Elk-1和血清应答因子蛋白结合血清应答元件-1域上的PGE 1 -1启动子，PGE 1 -1的PGN诱导的表达被显性阴性Elk-1抑制。这些结果表明PGN诱导转录因子Egr-1和Elk-1的活化，并且PGN诱导的tnf-a的表达通过转录因子c-jun、Egr-1和NT-kappaB直接介导，并通过转录因子Elk-1间接介导。
Bacteria and their ubiquitous cell wall component peptidoglycan (PGN) activate the innate immune system of the host and induce the release of inflammatory molecules. TNF-alpha is one of the highest induced cytokines in macrophages stimulated with PGN; however, the regulation of tnf-alpha expression in PGN-activated cells is poorly understood. This study was done to identify some of the transcription factors that regulate the expression of the tnf-a gene in macrophages stimulated with PGN. Our results demonstrated that PGN-induced expression of human nif-ce gene is regulated by sequences proximal to -182 bp of the promoter. Mutations within the binding sites for cAMP response element, early growth response (Egr)-1, and kappa B3 significantly reduced this induction. The transcription factor c-Jun bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and NF-kappaB p50 and p65 bound to the kappa B3 site on the tnf-alpha promoter. PGN rapidly induced transcription of egr-1 gene and this induction was significantly reduced by specific mutations within the serum response element-1 domain of the egr-1 promoter. PGN also induced phosphorylation and activation of Elk-1, a member of the Ets family of transcription factors. Elk-1 and serum response factor proteins bound the serum response element-1 domain on the egr-1 promoter, and PGN-induced expression of the egr-1 was inhibited by dominant-negative Elk-1. These results indicate that PGN induces activation of the transcription factors Egr-1 and Elk-1, and that PGN-induced expression of tnf-a is directly mediated through the transcription factors c-jun, Egr-1, and NT-kappaB, and indirectly through the transcription factor Elk-1.