Pathogen recognition by toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells
Pathogen recognition by toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells
复制标题
DOI：
10.1074/jbc.m609962200
复制
发表时间：
2007-03-16
影响因子：
4.8
通讯作者：
Matsushita, Kenji
中科院分区：
文献类型：
--
作者：
Into, Takeshi;Kanno, Yosuke;Matsushita, Kenji
内皮细胞特异性颗粒 Weibel-Palade 小体释放能够调节血管炎症的血管活性物质。尽管Toll样受体（TLR）对病原体的先天识别被认为在促进炎症反应中发挥着至关重要的作用，但内皮细胞对细菌病原体早期反应的分子基础尚未完全了解。我们在此报道，人主动脉内皮细胞对细菌脂磷壁酸（LTA）和合成细菌脂肽（而不是脂多糖或肽聚糖）做出反应，诱导Weibel-Palade小体胞吐作用，并伴随着储存成分冯维勒布兰德因子和P-选择素的释放或外化。 LTA 可以通过 TLR2 和 MyD88 依赖性机制激活快速 Weibel-Palade 体胞吐作用，而无需从头合成蛋白质。这一过程至少是通过 MyD88 依赖性磷酸化和磷脂酶 C γ 激活介导的。此外，LTA 通过从头蛋白质合成和磷脂酶 C γ 依赖性激活 NF-κ B 途径，激活白细胞介素 1 受体相关激酶 1 依赖性延迟胞吐作用。通过转染或干扰素-γ处理增加TLR2表达会增加TLR2介导的Weibel-Palade小体胞吐作用，而层流下TLR2表达减少会降低反应。因此，我们提出TLR2在通过Weibel-Palade体胞吐作用诱导主动脉内皮细胞初级促炎症事件中的新作用，这可能是将细菌病原体的先天识别与血管炎症联系起来的重要步骤。
The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation. Although innate recognition of pathogens,by Toll-like receptors (TLRs) is thought to play a crucial role in promotion of inflammatory responses, the molecular basis for early-phase responses of endothelial cells to bacterial pathogens has not fully been understood. We here report that human aortic endothelial cells respond to bacterial lipoteichoic acid (LTA) and synthetic bacterial lipopeptides, but not lipopolysaccharide or peptidoglycan, to induce Weibel-Palade body exocytosis, accompanied by release or externalization of the storage components von Willebrand factor and P-selectin. LTA could activate rapid Weibel-Palade body exocytosis through a TLR2- and MyD88-dependent mechanism without de novo protein synthesis. This process was at least mediated through MyD88-dependent phosphorylation and activation of phospholipase C gamma. Moreover, LTA activated interleukin-1 receptor-associated kinase-1-dependent delayed exocytosis with de novo protein synthesis and phospholipase C gamma-dependent activation of the NF-kappa B pathway. Increased TLR2 expression by transfection or interferon-gamma treatment increased TLR2-mediated Weibel-Palade body exocytosis, whereas reduced TLR2 expression under laminar flow decreased the response. Thus, we propose a novel role for TLR2 in induction of a primary proinflammatory event in aortic endothelial cells through Weibel-Palade body exocytosis, which may be an important step for linking innate recognition of bacterial pathogens to vascular inflammation.