Transcriptional regulation of the human Toll-like receptor 2 gene in monocytes and macrophages
Transcriptional regulation of the human Toll-like receptor 2 gene in monocytes and macrophages
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DOI：
10.4049/jimmunol.168.11.5629
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发表时间：
2002-06-01
影响因子：
4.4
通讯作者：
Rehli, M
中科院分区：
文献类型：
--
作者：
Haehnel, V;Schwarzfischer, L;Rehli, M
本报告研究了人类单核细胞和巨噬细胞中模式识别受体Toll样受体（TLR）2的组织限制性和调节性表达的分子基础。为了确定近端启动子，确定TLR 2 mRNA的完整5 '序列和转录起始位点。发现人TLR 2基因由两个5'非编码外显子和第三个编码外显子组成。外显子II的选择性剪接主要在人血单核细胞中检测到。发现近端启动子、外显子I和部分内含子I位于CpG岛上。尽管细胞系中近端人TLR 2启动子的CpG甲基化与TLR 2抑制相关，但该启动子在原代细胞中未甲基化，表明CpG甲基化对正常组织中人TLR 2的细胞类型特异性表达没有贡献。启动子序列含有几个转录因子的假定结合位点，包括Sp1和Ets家族成员。报告基因分析揭示了一个最小的启动子220被发现是由Sp1，温泉，并可能PU.1。有趣的是，在人和鼠TLR 2启动子区之间没有检测到序列同源性。与鼠TLR 2相反，人TLR 2在单核细胞/巨噬细胞中的表达不由促炎刺激LPS或巨噬细胞活化脂肽-2诱导，并且启动子的报告活性不由刺激诱导的NF-κ B在THP-1或MonoMac-6细胞中的活化增强。我们的研究结果提供了人类TLR 2启动子的初步定义，并揭示了人类和小鼠中重要模式识别分子调控的深刻差异。
This report investigates the molecular basis for tissue-restricted and regulated expression of the pattern recognition receptor Toll-like receptor (TLR)2 in human monocytes and macrophages. To define the proximal promoter, the full 5'-sequence and transcriptional start sites of TLR2 mRNA were determined. The human TLR2 gene was found to consist of two 5' noncoding exons followed by a third coding exon. Alternative splicing of exon II was detected primarily in human blood monocytes. The proximal promoter, exon I, and part of intron I were found to be located in a CpG island. Although CpG methylation of the proximal human TLR2 promoter in cell lines correlated with TLR2 repression, the promoter was unmethylated in primary cells, indicating that CpG methylation does not contribute to the cell-type specific expression of human TLR2 in normal tissues. The promoter sequence contains putative binding sites for several transcription factors, including Sp1 and Ets family members. Reporter gene analysis revealed a minimal promoter of 220 by that was found to be regulated by Sp1, Spa, and possibly PU.1. Interestingly, no sequence homology was detected between human and murine TLR2 promoter regions. In contrast to murine TLR2, expression of human TLR2 in monocytes/macrophages is not induced by the proinflammatory stimuli LPS or macrophage-activating lipopeptide-2, and reporter activity of the promoter was not enhanced by stimuli-induced NF-kappaB activation in THP-1 or MonoMac-6 cells. Our findings provide an initial definition of the human TLR2 promoter and reveal profound differences in the regulation of an important pattern recognition molecule in humans and mice.