Activation of gene expression in human neutrophils by high mobility group box 1 protein
Activation of gene expression in human neutrophils by high mobility group box 1 protein
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DOI：
10.1152/ajpcell.00322.2002
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发表时间：
2003-04-01
影响因子：
5.5
通讯作者：
Abraham, E
中科院分区：
文献类型：
--
作者：
Park, JS;Arcaroli, J;Abraham, E
高迁移率组框1 （HMGB1）蛋白是一种稳定核小体和促进转录的DNA结合蛋白，最近被确定为内毒素致死性的晚期介质。败血症患者的高血清HMGB1水平与死亡率增加有关，在肺损伤和内毒素血症动物模型中，HMGB1的使用会产生急性炎症。中性粒细胞在介导内毒素血症相关急性肺损伤的发展中起着关键作用，但以前不知道HMGB1是否会影响中性粒细胞的激活。在本实验中，我们证明HMGB1增加了NF-kappaB的核易位，并增强了人中性粒细胞中促炎细胞因子的表达。HMGB1在中性粒细胞中的这些促炎作用似乎涉及p38 MAPK、磷脂酰肌醇3-激酶/Akt和ERK1/2途径。HMGB1诱导中性粒细胞激活的机制与内毒素诱导的信号不同，因为与LPS相比，HMGB1导致不同的基因表达谱、细胞因子表达模式和p38激活动力学。这些发现表明，HMGB1是中性粒细胞激活的有效刺激，可以促进以HMGB1水平过高为特征的疾病的促炎表型的发展。
High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.