期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 12, 期 6, 页码 948-957出版社
WILEY
DOI: 10.1111/jth.12581
关键词
angiogenic factor; endothelial cells; interleukin-33; human; protein degradation; urokinase
资金
- Austrian Science Fund (FWF) [T445-B11]
- Association for the Promotion of Research in Arteriosclerosis, Thrombosis and Vascular Biology
Background Urokinase-type plasminogen activator (u-PA) plays a pivotal role in extracellular proteolysis and is thought to be critically involved in the modulation of angiogenesis. Interleukin (IL)-33 is a member of the IL-1 cytokine family, which is thought to act as danger signal that is released from cells after injury. IL-33 is involved in the pathogenesis of various inflammatory diseases and previously was shown to induce angiogenesis and inflammatory activation of endothelial cells. Objective We investigated the impact of IL-33 on u-PA in endothelial cells as a new possible function for IL-33. Methods and results We could demonstrate that IL-33 upregulated u-PA mRNA expression and protein production in human coronary artery and human umbilical vein endothelial cells in a time- and concentration-dependent manner via interaction with its receptor ST2 and activation of the nuclear factor-B pathway but independent of autocrine IL-1-induced effects. The hydroxymethylglutaryl-coenzyme A reductase inhibitor simvastatin abrogated the IL-33-induced increase in u-PA, thus providing further evidence for pleiotropic effects of statins. IL-33 induced u-PA-dependent capillary-like tube formation and vessel sprouting. In human carotid atherosclerotic plaques (n=16), u-PA mRNA positively correlated with IL-33 mRNA expression (r=0.780, P<0.001). Furthermore, IL-33 and u-PA protein were detected in endothelial cells in these samples using fluorescence immunohistochemistry. Conclusions We hypothesize that IL-33, representing a danger signal that is released after tissue damage, in addition to its role in the inflammatory activation of endothelial cells, is involved in u-PA-driven angiogenesis, a process that has been shown before to be linked to inflammation in various pathologies.
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