DNA demethylation-dependent enhancement of toll-like receptor-2 gene expression in cystic fibrosis epithelial cells involves SP1-activated transcription.
DNA demethylation-dependent enhancement of toll-like receptor-2 gene expression in cystic fibrosis epithelial cells involves SP1-activated transcription.
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囊性纤维化上皮细胞中 Toll 样受体 2 基因表达的 DNA 去甲基化依赖性增强涉及 SP1 激活的转录。
DOI：
10.1186/1471-2199-9-39
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发表时间：
2008-04-21
影响因子：
--
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
--
作者：
Furuta, Takashi;Shuto, Tsuyoshi;Shimasaki, Shogo;Ohira, Yuko;Suico, Mary Ann;Gruenert, Dieter C.;Kai, Hirofumi
囊性纤维化（CF）的临床过程以反复肺部感染和慢性炎症为特征。我们最近发现toll样受体-2 （TLR2）启动子甲基化降低导致TLR2明显的cf相关上调。这种上调在一定程度上可能是上皮细胞对各种细菌产物的cf相关的促炎反应增强的原因。然而，CF细胞中DNA低甲基化依赖性TLR2表达增强的分子机制尚不清楚。本研究表明，在一些CF上皮细胞系中，在SP1结合位点附近存在一个特异性CpG区域（cpg# 18-20），该区域显著低甲基化。这些CpGs包含基础TLR2表达所需的最小启动子区域，表明cpg# 18-20甲基化调节上皮细胞中TLR2的表达。此外，报告基因分析表明SP1结合位点参与TLR2启动子的甲基化依赖性调控。用米霉素A抑制SP1可降低CF和5-氮胞苷处理的非CF上皮细胞中TLR2的表达。此外，即使SP1结合不受CpG甲基化的影响，SP1依赖性转录也会被CpG甲基化所消除。该报告暗示SP1是CF上皮细胞中DNA去甲基化依赖性TLR2表达上调的关键组成部分。
The clinical course of cystic fibrosis (CF) is characterized by recurrent pulmonary infections and chronic inflammation. We have recently shown that decreased methylation of the toll-like receptor-2 (TLR2) promoter leads to an apparent CF-related up-regulation of TLR2. This up-regulation could be responsible, in part, for the CF-associated enhanced proinflammatory responses to various bacterial products in epithelial cells. However, the molecular mechanisms underlying DNA hypomethylation-dependent enhancement of TLR2 expression in CF cells remain unknown. The present study indicates that there is a specific CpG region (CpG#18-20), adjacent to the SP1 binding site that is significantly hypomethylated in several CF epithelial cell lines. These CpGs encompass a minimal promoter region required for basal TLR2 expression, and suggests that CpG#18-20 methylation regulates TLR2 expression in epithelial cells. Furthermore, reporter gene analysis indicated that the SP1 binding site is involved in the methylation-dependent regulation of the TLR2 promoter. Inhibition of SP1 with mithramycin A decreased TLR2 expression in both CF and 5-azacytidine-treated non-CF epithelial cells. Moreover, even though SP1 binding was not affected by CpG methylation, SP1-dependent transcription was abolished by CpG methylation. This report implicates SP1 as a critical component of DNA demethylation-dependent up-regulation of TLR2 expression in CF epithelial cells.
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