Activated protein C inhibits high mobility group box 1 signaling in endothelial cells
Activated protein C inhibits high mobility group box 1 signaling in endothelial cells
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DOI：
10.1182/blood-2011-06-360701
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发表时间：
2011-10-06
期刊：
影响因子：
20.3
通讯作者：
Rezaie, Alireza R.
中科院分区：
文献类型：
--
作者：
Bae, Jong-Sup;Rezaie, Alireza R.
高迁移率族蛋白1（HMGB 1）蛋白在严重脓毒症中的致病作用已被假定。活化蛋白C（APC）是美国食品和药物管理局批准用于严重脓毒症的唯一药物;然而，其对HMGB 1信号传导的影响从未被研究过。在这里，我们监测了APC对脂多糖介导的HMGB 1释放和HMGB 1介导的HUVECs促炎反应调节的影响。APC有效地抑制HMGB 1的释放，并下调单核细胞系THP-1与HMGB 1激活的内皮细胞的粘附。HMGB 1通过与3种病原体相关的模式识别受体TLR 2和TLR 4以及晚期糖基化终产物受体相互作用上调促炎反应。APC不仅能抑制内皮细胞HMGB 1的释放，而且能下调内皮细胞表面HMGB 1 3种受体的表达。APC的保护作用通过内皮细胞蛋白C受体（EPCR）和蛋白酶激活受体1（PAR-1）介导。有趣的是，含有APC的Gla结构域的凝血酶衍生物以20至50倍的高功效再现了APC的所有保护作用。这些结果表明，APC在严重脓毒症中的EPCR和PAR-1依赖性保护作用可能部分是通过抑制HMGB 1信号转导介导的，并且嵌合凝血酶突变体对严重脓毒症具有潜在的治疗效用。（血。2011;118（14）：3952-3959）
A pathogenic role for high-mobility group box 1 (HMGB1) protein has been postulated in severe sepsis. Activated protein C (APC) is the only drug approved by the Food and Drug Administration for severe sepsis; however, its effect on HMGB1 signaling has never been investigated. Here, we monitored the effect of APC on the lipopolysaccharide-mediated release of HMGB1 and the HMGB1-mediated modulation of proinflammatory responses in HUVECs. APC potently inhibited the release of HMGB1 and down-regulated the adhesion of the monocytic cell line, THP-1, to HMGB1-activated endothelial cells. HMGB1 up-regulated proinflammatory responses by interacting with 3 pathogen-related pattern recognition receptors: TLR2 and TLR4 and the receptor for advanced glycation end products. APC not only inhibited HMGB1 release but also down-regulated the cell surface expression of all 3 HMGB1 receptors in endothelial cells. The protective effects of APC were mediated through endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR-1). Interestingly, a thrombin derivative containing the Gla-domain of APC recapitulated all protective effects of APC with a 20- to 50-fold higher efficacy. These results suggest that the EPCR-and PAR-1-dependent protective effects of APC in severe sepsis may partially be mediated through the inhibition of HMGB1 signaling and that the chimeric thrombin mutant has potential therapeutic utility for severe sepsis. (Blood. 2011;118(14):3952-3959)