HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway
HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway
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HMGB1 通过 RAGE 依赖性内质网应激途径诱导内皮细胞炎症反应
DOI：
10.1016/j.bbrc.2013.07.098
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发表时间：
2013-09-06
影响因子：
3.1
通讯作者：
Chen, Fang-Ping
中科院分区：
文献类型：
--
作者：
Luo, Ying;Li, Shu-Jun;Chen, Fang-Ping
高迁移率族1B蛋白（HMGB 1）介导内皮细胞的慢性炎症反应，在动脉粥样硬化中起关键作用。然而，其潜在机制尚不清楚。本研究的目的是确定HMGB 1对RAGE诱导的内皮细胞炎症反应的影响，并测试内质网应激途径的可能参与。我们的研究结果表明，孵育的内皮细胞与HMGB 1（0.01-1 μ g/ml）24小时诱导内质网应激传感器的剂量依赖性激活，评估PERK和IRE 1蛋白表达。此外，HMGB 1还促进了ATF 6的核转位。HMGB 1介导的ICAM-1和P-选择素的产生被PERK siRNA或IRE 1 siRNA显著抑制。然而，非靶向siRNA没有这样的效果。HMGB 1诱导的ICAM-1和P-选择素表达的增加也被特异性eIF 2 α抑制剂（salubrinal）和特异性JNK抑制剂（SP 600125）抑制。重要的是，特异性靶向ICAM-1的阻断抗体（抗ICAM-1抗体）降低了ICAM-1、P-选择素和内质网应激分子（PERK、eIF 2 α、IRE 1和JNK）蛋白的表达水平。总的来说，这些新的发现表明，HMGB 1促进炎症反应诱导ICAM-1和P-选择素的表达，通过RAGE介导的刺激内质网应激途径。皇冠版权所有（C）2013由Elsevier Inc.发布。All rights reserved.
The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01-1 mu g/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2 alpha inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2 alpha, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.