HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF-α in human umbilical vein endothelial cells
HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF-α in human umbilical vein endothelial cells
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DOI：
10.1016/j.imbio.2009.11.001
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发表时间：
2010-12-01
期刊：
影响因子：
2.8
通讯作者：
Guo, Ren-Xuan
中科院分区：
文献类型：
--
作者：
Luan, Zheng-Gang;Zhang, Hao;Guo, Ren-Xuan
目的：高迁移率族盒染色体蛋白 1 (HMGB1) 是最近发现的候选分子，被确定为全身炎症中重要的细胞外介质。全身炎症导致内皮细胞活化和微血管损伤。在本研究中，我们研究了HMGB1对人脐静脉内皮细胞（HUVEC）激活的影响，并明确了HMGB1激活的途径。方法：用HMGB1在体外刺激通过胶原酶处理脐带静脉获得的HUVEC。研究了 HUVEC 的激活：(i) HUVEC 中肿瘤坏死因子-α (TNF-α) 产生的动力学，(ii) HMGB1 诱导的晚期糖基化终末产物受体 (RAGE) 的上调，(iii) HMGB1 诱导的 HUVEC 中核因子 kappa B (NF-kappa B) 的核转位，(iv) 信号转导途径的激活。 结果：HUVEC 激活是HMGB1 以 RAGE 依赖性方式部分刺激。此外，HMGB1 诱导的 HUVEC 激活可被抗 RAGE 单克隆抗体和丙酮酸乙酯 (EP) 显着抑制，EP 已被证明是一种有效的抗炎剂。用 HMGB1 短期预刺激 HUVEC 导致 TNF-α 分泌和 RAGE 表达呈时间依赖性增加。此外，HMGB1 刺激导致转录因子 NF-κ B 的核转位。最重要的是，用抗 RAGE 单克隆抗体预处理显着降低 TNF-α 的量并抑制 NF-κ B 的核转位。此外，在 HUVEC 培养物中，EP 特异性抑制对 TNF-α 释放至关重要的 NF-κ B 信号通路的激活。结论：总而言之，我们的数据表明 HMGB 与 RAGE 功能之间存在联系。内皮细胞并展示了 HMGB1 激活的途径。这些发现可能为改善内皮细胞功能提供新的治疗策略。 (C) 2009 爱思唯尔有限公司。版权所有。
Objective: High mobility group box chromosomal protein 1 (HMGB1) is a lately discovered candidate molecule identified as an important extracellular mediator in systemic inflammation. Systemic inflammation results in endothelial cell activation and microvascular injury. In the present study, we investigated the effects of HMGB1 on the activation of human umbilical vein endothelial cells (HUVECs) and defined pathways activated by HMGB1.Methods: HUVECs obtained by collagenase treatment of umbilical cord veins were stimulated in vitro with HMGB1. The activation of HUVECs was studied regarding (i) the kinetics of tumor necrosis factor-alpha (TNF-alpha) production in HUVECs, (ii) HMGB1-induced up-regulation of receptor for advanced glycation end products (RAGE), (iii) HMGB1-induced nuclear translocation of nuclear factor kappa B (NF-kappa B) in HUVECs, (iv) the activation of signalling transduction pathways.Results: HUVECs activation was stimulated by HMGB1 partially in a RAGE-dependent manner. Additionally, the HMGB1-induced activation of HUVECs was significantly inhibited by anti-RAGE monoclonal antibody and Ethyl pyruvate (EP) that had been shown to be an effective anti-inflammatory agent. Short-term prestimulation of HUVECs with HMGB1 caused a time-dependent increase in the secretion of TNF-alpha and expression of RAGE. Furthermore, HMGB1 stimulation resulted in nuclear translocation of transcription factor NF-kappa B. Most importantly, pretreatment with anti-RAGE monoclonal antibody significantly decreased the amounts of TNF-alpha and inhibited the nuclear translocation of NF-kappa B. Additionally in HUVECs cultures, EP specifically inhibited activation of NF-kappa B signaling pathway that are critical for TNF-alpha release.Conclusions: In conclusion, Our data present a link between HMGBland RAGE function of endothelial cells and demonstrate the pathway activated by HMGB1. These findings may provide a novel therapeutic strategy to improve the endothelial cells function. (C) 2009 Elsevier GmbH. All rights reserved.