Department of Critical Care Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Jing'an, Shanghai, China.
Department of Critical Care Medicine, The Affiliated Hospital of Medical School of Ningbo, Jiangbei District, Ningbo, Zhejiang Province, China.
Aging (Albany NY). 2020 Jul 12;12(13):12740-12749. doi: 10.18632/aging.103173.
Tumor necrosis factor-α (TNF) is a pro-inflammatory cytokine upregulated in many inflammatory diseases, and a potent inducer of endothelial cell-derived microparticle (EMP) formation. In this study, we identified the protein kinase PAK4 as a key regulator of the TNF-induced EMP release from human umbilical vein endothelial cells (HUVECs). TNF induces dose- and time-dependent EMP release and downregulation of PAK4 and upstream cdc42 in HUVECs. PAK4 suppression or inhibition of its kinase activity increases TNF-induced EMP release and apoptosis in HUVECs, while PAK4 overexpression reduces EMP release and apoptosis in TNF-stimulated cells. Collectively, these data indicate that PAK4 suppresses TNF-induced EMP generation occurring during apoptosis, and suggest that modulation of PAK4 activity may represent a novel approach to suppress the TNF-induced EMP levels in pro-inflammatory disorders and other pathological conditions.
肿瘤坏死因子-α（TNF）是一种在许多炎症性疾病中上调的促炎细胞因子，也是内皮细胞衍生的微颗粒（EMP）形成的有效诱导剂。在这项研究中，我们确定了蛋白激酶 PAK4 是人类脐静脉内皮细胞（HUVEC）中 TNF 诱导的 EMP 释放的关键调节因子。TNF 诱导剂量和时间依赖性 EMP 释放以及 PAK4 和上游 cdc42 在 HUVEC 中的下调。PAK4 抑制或抑制其激酶活性增加 TNF 诱导的 EMP 释放和 HUVEC 中的细胞凋亡，而 PAK4 过表达减少 TNF 刺激细胞中的 EMP 释放和细胞凋亡。总的来说，这些数据表明 PAK4 抑制 TNF 诱导的 EMP 生成发生在细胞凋亡过程中，并表明调节 PAK4 活性可能代表一种抑制促炎疾病和其他病理状况中 TNF 诱导的 EMP 水平的新方法。
