Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation
Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation
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DOI：
10.1172/jci200113620
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发表时间：
2001-11-01
影响因子：
15.9
通讯作者：
Dimmeler, S
中科院分区：
文献类型：
--
作者：
Urbich, C;Mallat, Z;Dimmeler, S
动脉粥样硬化是大动脉的炎性疾病，其通过促炎介质激活内皮而引发。CD 40受体刺激与动脉粥样硬化的发病机制有关。最重要的动脉粥样硬化保护刺激之一是由流动的血液作用于内皮单层产生的粘性阻力（剪切应力）。在这里，我们证明，剪切力阻止CD 40配体诱导的内皮细胞活化，我们确定上调TNF受体相关因子-3（TRAF-3）作为一种有效的CD 40抑制机制。剪切应力特异性上调培养的内皮细胞中的TRAF-3。此外，在覆盖人动脉粥样硬化斑块的内皮细胞中，TRAF-3表达在高剪切应力区域上调。TRAF-3的过表达抑制促炎细胞因子和组织因子的内皮表达，并阻断转录因子AP-1的DNA结合活性;从而防止CD 40诱导的内皮活化。因此，TRAF-3的上调代表了保护内皮单层功能完整性的新机制。
Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. Shear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpression of TRAF-3 inhibits endothelial expression of proinflammatory cytokines and tissue factor and blocks DNA-binding activity of the transcription factor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer.