Flow-dependent regulation of endothelial toll-like receptor 2 expression through inhibition of SP1 activity
Flow-dependent regulation of endothelial toll-like receptor 2 expression through inhibition of SP1 activity
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DOI：
10.1161/01.res.0000143900.19798.47
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发表时间：
2004-10-01
影响因子：
20.1
通讯作者：
Tobias, PS
中科院分区：
文献类型：
--
作者：
Dunzendorfer, S;Lee, HK;Tobias, PS
先天性免疫系统激活与动脉粥样硬化病变发展相关。病变发展的特定部位被认为是由血流的剪切应力定义的。因此，我们研究了人冠状动脉内皮细胞（HCAECs）的Toll样受体（TLR）2和4激动剂在体外模型的慢性层流的反应。慢性层流下的HCAEC在E-选择素表达方面对脂多糖（和肿瘤坏死因子）正常应答，但对特异性TLR 2配体巨噬细胞活化脂肽-2，PAM（2）-Cys和Lip 19的刺激应答低下;观察到这可归因于TLR 2转录和蛋白表达的下调。我们发现，层流诱导SP1丝氨酸磷酸化的蛋白激酶CK 2，从而阻止SP1结合到TLR 2启动子，这是TLR 2表达所需的。这种调节机制也阻断了脂多糖和肿瘤坏死因子诱导的HCAECs中TLR 2的上调，并且对于抑制其他流动敏感性内皮蛋白可能是重要的。这些结果扩展了血流在控制内皮反应性中的作用。鉴于目前的证据表明TLR是致动脉粥样硬化的，TLR 2表达的血流抑制可能是动脉粥样硬化保护的。
Innate immune system activation is associated with atherosclerotic lesion development. The specific sites of lesion development are believed to be defined by the shear stress of blood flow. Consequently, we investigated the responsiveness of human coronary artery endothelial cells (HCAECs) to Toll-like receptor (TLR) 2 and 4 agonists in an in vitro model of chronic laminar flow. HCAECs under chronic laminar flow were found to be normally responsive to lipopolysaccharide (and tumor necrosis factor) in terms of E-selectin expression but were found to be hyporesponsive to stimulation with the specific TLR2 ligands macrophage activating lipopeptide-2, PAM(2)-Cys, and Lip19; this was observed to be attributable to downregulation of TLR2 transcription and protein expression. We found that laminar flow induced SP1 serine phosphorylation by protein kinase CK2 and thereby blocked SP1 binding to the TLR2 promoter, which is required for TLR2 expression. This regulatory mechanism also blocked lipopolysaccharide- and tumor necrosis factor-induced TLR2 upregulation in HCAECs and could be important for suppression of other flow-sensitive endothelial proteins. These results extend the role of flow in controlling endothelial responsiveness. Given the current evidence that TLRs are proatherogenic, flow suppression of TLR2 expression may be atheroprotective.