Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products
Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products
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DOI：
10.1186/1475-2840-5-6
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发表时间：
2006-01-01
影响因子：
9.3
通讯作者：
Remppis, Andrew
中科院分区：
文献类型：
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作者：
Ehlermann, Philipp;Eggers, Kai;Remppis, Andrew
背景：动脉粥样硬化是一种炎症性疾病，在该疾病中，通过晚期糖基化终产物受体（RAGE） - 丝裂原活化蛋白激酶（MAPK）信号通路持续激活核因子κB（NFκB）可能在发病机制中起重要作用。由于最近S100蛋白已被确定为RAGE的配体，我们试图确定S100A8/S100A9促炎异二聚体对RAGE - NFκB介导的促炎基因表达诱导的影响。
方法：人脐静脉内皮细胞（HUVEC）用晚期糖基化终产物 - 白蛋白预孵育72小时，用未修饰的白蛋白作为对照，而晚期糖基化终产物 - 白蛋白诱导导致RAGE上调。在此预激活之后，用异二聚体人重组S100A8/S100A9刺激细胞48小时。
结果：异二聚体S100A8/S100A9以剂量依赖的方式增强晚期糖基化终产物 - 白蛋白预处理的人脐静脉内皮细胞中白细胞介素 - 6（IL - 6）、细胞间黏附分子 - 1（ICAM - 1）、血管细胞黏附分子 - 1（VCAM - 1）和单核细胞趋化蛋白1（MCP1）的分泌。用同二聚体蛋白S100A8、S100A9、S100A1和S100B刺激后未检测到这些效应。分别用PD 98059和SB 203580抑制MAP激酶通路ERK1/2和p38可降低异二聚体S100A8/S100A9的作用。
结论：因此，异二聚体S100A8/S100A9可能在触发糖尿病和肾衰竭（与晚期糖基化终产物负担高相关的病理生理实体）中的动脉粥样硬化方面发挥迄今未知的作用。因此，阻断异二聚体S100A8/S100A9可能代表一种治疗动脉粥样硬化的新型治疗方式。
Background: Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression.Methods: Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9.Results: Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively.Conclusion: The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis.