高迁移率族蛋白 B1 通过晚期糖基化终末产物受体激活核因子-κB 信号通路，增加人脐静脉内皮细胞肿瘤坏死因子-α的产生。

HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF-α in human umbilical vein endothelial cells.

机构信息

Department of Intensive Care Unit, The First Hospital, China Medical University, Bei-er Road 92, Shenyang 110001, Liaoning Province, China.

出版信息

Immunobiology. 2010 Dec;215(12):956-62. doi: 10.1016/j.imbio.2009.11.001. Epub 2010 Feb 18.

DOI:10.1016/j.imbio.2009.11.001

PMID:20163887

Abstract

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-α (TNF-α) 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-κB) 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-α and expression of RAGE. Furthermore, HMGB1 stimulation resulted in nuclear translocation of transcription factor NF-κB. Most importantly, pretreatment with anti-RAGE monoclonal antibody significantly decreased the amounts of TNF-α and inhibited the nuclear translocation of NF-κB. Additionally in HUVECs cultures, EP specifically inhibited activation of NF-κB signaling pathway that are critical for TNF-α release.

CONCLUSIONS

In conclusion, Our data present a link between HMGB1and 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.

摘要

目的

高迁移率族蛋白 B1（HMGB1）是最近发现的候选分子，被认为是全身炎症反应中重要的细胞外介质。全身炎症反应导致内皮细胞激活和微血管损伤。本研究旨在探讨 HMGB1 对人脐静脉内皮细胞（HUVEC）激活的影响，并确定 HMGB1 激活的途径。

方法

采用胶原酶处理脐带静脉获得 HUVEC，体外用 HMGB1 刺激 HUVEC。研究 HUVEC 的激活情况：（i）HMGB1 诱导 HUVEC 产生肿瘤坏死因子-α（TNF-α）的动力学，（ii）HMGB1 诱导的晚期糖基化终产物受体（RAGE）上调，（iii）HMGB1 诱导 HUVEC 核转录因子 NF-κB（NF-κB）的核转位，（iv）信号转导途径的激活。

结果

HMGB1 部分通过 RAGE 依赖性方式刺激 HUVEC 激活。此外，抗 RAGE 单克隆抗体和 Ethyl pyruvate（EP）显著抑制 HMGB1 诱导的 HUVEC 激活，EP 已被证明是一种有效的抗炎剂。HMGB1 短期预刺激 HUVEC 可导致 TNF-α分泌和 RAGE 表达的时间依赖性增加。此外，HMGB1 刺激导致转录因子 NF-κB 的核转位。最重要的是，抗 RAGE 单克隆抗体预处理可显著减少 TNF-α的量并抑制 NF-κB 的核转位。此外，在 HUVEC 培养物中，EP 特异性抑制了 NF-κB 信号通路的激活，该通路对于 TNF-α的释放至关重要。