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Platelet factor 4/CXCL4‐stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals
Author(s) -
Woller Geske,
Brandt Ernst,
Mittelstädt Jessica,
Rybakowski Christian,
Petersen Frank
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0907592
Subject(s) - nadph oxidase , microbiology and biotechnology , apocynin , biology , reactive oxygen species , oxidative stress , monocyte , chemokine , endothelial stem cell , apoptosis , platelet activation , platelet factor 4 , platelet , immunology , biochemistry , inflammation , in vitro
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 β 2 integrins 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.