Platelet factor 4/CXCL4‐stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals
Platelet factor 4/CXCL4‐stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals
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DOI：
10.1189/jlb.0907592
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发表时间：
2008-04
影响因子：
5.5
通讯作者：
G. Woller;E. Brandt;J. Mittelstädt;C. Rybakowski;F. Petersen
中科院分区：
文献类型：
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作者：
G. Woller;E. Brandt;J. Mittelstädt;C. Rybakowski;F. Petersen
活性氧（ROS）的产生是吞噬细胞防御微生物入侵的关键因素。然而，氧化应激也参与血管损伤的病理生理过程，导致内皮细胞（EC）的细胞死亡。目前，参与这一过程的ROS产生细胞以及其激活所需的相应细胞外信号尚不明确。在这项研究中，我们研究了血小板衍生的CXC趋化因子血小板因子4（PF 4/CXCL 4）对人单核细胞和EC相互作用的影响。我们可以首次证明PF 4激活的单核细胞对EC而不是上皮细胞具有细胞毒性。细胞毒性具有时间和剂量依赖性，在培养15 h后和0.125 μM PF 4以上浓度下观察到最早效应。通过进行transwell实验和使用特异性抑制性抗体，我们可以证明，效应细胞和靶细胞之间的直接细胞接触，由β 2整合素及其相应的配体ICAM-1介导，是细胞毒性作用所必需的。细胞毒性的细胞机制研究表明，在EC存在下，PF 4活化的单核细胞能够在刺激后释放大量ROS超过2小时。这导致EC中的程序性细胞死亡，因为NADPH氧化酶的抑制剂（diphenyleneiodonium和夹竹桃苷）有效地阻断了PF 4诱导的单核细胞氧化爆发并保护EC免于经历凋亡。总之，我们的数据表明血小板衍生的PF 4在氧化应激介导的血管疾病中的作用，如在动脉粥样硬化或缺血/再灌注损伤期间观察到的。
The generation of reactive oxygen species (ROS) represents a pivotal element of phagocyte defense against microbial invaders. However, oxidative stress also participates in pathophysiological processes of vascular damage leading to cell death of endothelial cells (EC). Currently, ROS‐producing cells involved in this process as well as the corresponding extracellular signals required for their activation are ill‐defined. In this study, we investigate the impact of the platelet‐derived CXC chemokine platelet factor 4 (PF4/CXCL4) on the interaction of human monocytes and EC. We can show for the first time that PF4‐activated monocytes become cytotoxic for EC but not epithelial cells. Cytotoxicity was time‐ and dose‐dependent, and earliest effects were seen after 15 h of culture and at a concentration from 0.125 μM PF4 up. By performing transwell experiments and by using specific inhibitory antibodies, we could show that direct cell contact between effector and target cells, mediated by β2integrins as well as their corresponding ligand ICAM‐1, is essential for the cytotoxic effect. Investigations of the cellular mechanisms of cytotoxicity revealed that in the presence of EC, PF4‐activated monocytes are capable of releasing high amounts of ROS for more than 2 h following stimulation. This causes programmed cell death in EC, as inhibitors of the NADPH oxidase (diphenyleneiodonium and apocynin) effectively blocked PF4‐induced monocyte oxidative burst and protected EC from undergoing apoptosis. Taken together, our data suggest a role for platelet‐derived PF4 in oxidative stress‐mediated vascular disorders, as observed during atherosclerosis or ischemia/reperfusion injury.