Lv Ben, Wang Haichao, Tang Yiting, Fan Zhang, Xiao Xianzhong, Chen Fangping
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, People's Republic of China.
Thromb Haemost. 2009 Aug;102(2):352-9. doi: 10.1160/TH08-11-0759.
High-mobility group box 1 protein (HMGB1), an abundant nuclear protein, was recently established as a proinflammatory mediator of experimental sepsis. Although extracellular HMGB1 has been found in atherosclerotic plaques, its potential role in the pathogenesis of atherothrombosis remains elusive. In the present study, we determined whether HMGB1 induces tissue factor (TF) expression in vascular endothelial cells (ECs) and macrophages. Our data showed that HMGB1 stimulated ECs to express TF (but not TF pathway inhibitor) mRNA and protein in a concentration- and time-dependent manner. Blockade of cell surface receptors (including TLR4, TLR2, and RAGE) with specific neutralising antibodies partially reduced HMGB1-induced TF expression. Moreover, HMGB1 increased expression of Egr-1 and nuclear translocation of NF-kappaB (c-Rel/p65) in ECs. Taken together, our data suggest that HMGB1 induces TF expression in vascular endothelial cells via cell surface receptors (TLR4, TLR2, and RAGE), and through activation of transcription factors (NF-kappaB and Egr-1).
高迁移率族蛋白B1（HMGB1）是一种丰富的核蛋白，最近被确定为实验性脓毒症的促炎介质。尽管在动脉粥样硬化斑块中发现了细胞外HMGB1，但其在动脉粥样硬化血栓形成发病机制中的潜在作用仍不清楚。在本研究中，我们确定HMGB1是否诱导血管内皮细胞（ECs）和巨噬细胞中组织因子（TF）的表达。我们的数据显示，HMGB1以浓度和时间依赖性方式刺激ECs表达TF（而非TF途径抑制剂）的mRNA和蛋白。用特异性中和抗体阻断细胞表面受体（包括TLR4、TLR2和RAGE）可部分降低HMGB1诱导的TF表达。此外，HMGB1增加了ECs中Egr-1的表达和NF-κB（c-Rel/p65）的核转位。综上所述，我们的数据表明，HMGB1通过细胞表面受体（TLR4、TLR2和RAGE）并通过激活转录因子（NF-κB和Egr-1）诱导血管内皮细胞中TF的表达。
