Interleukin‐33 induces urokinase in human endothelial cells―possible impact on angiogenesis

Summary 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 r...

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Bibliographic Details
Published in:	Journal of thrombosis and haemostasis Vol. 12; no. 6; pp. 948 - 957
Main Authors:	Stojkovic, S., Kaun, C., Heinz, M., Krychtiuk, K. A., Rauscher, S., Lemberger, C. E., Martin, R., Gröger, M., Petzelbauer, P., Huk, I., Huber, K., Wojta, J., Demyanets, S.
Format:	Journal Article
Language:	English
Published:	England Elsevier Limited 01-06-2014
Subjects:	Angiogenesis Inducing Agents - pharmacology angiogenic factor Carotid Arteries - metabolism Carotid Arteries - pathology Carotid Artery Diseases - genetics Carotid Artery Diseases - metabolism Carotid Artery Diseases - pathology Cells, Cultured Dose-Response Relationship, Drug endothelial cells Endothelial Cells - drug effects Endothelial Cells - enzymology Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - enzymology Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Interleukin-1 Receptor-Like 1 Protein Interleukin-33 Interleukins - genetics Interleukins - metabolism Interleukins - pharmacology interleukin‐33, human Neovascularization, Physiologic - drug effects NF-kappa B - metabolism Plaque, Atherosclerotic protein degradation Receptors, Cell Surface - agonists Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Recombinant Proteins - pharmacology RNA Interference RNA, Messenger - metabolism Signal Transduction - drug effects Simvastatin - pharmacology Time Factors Transfection Up-Regulation urokinase Urokinase-Type Plasminogen Activator - genetics Urokinase-Type Plasminogen Activator - metabolism angiogenic factor endothelial cells interleukin-33, human protein degradation urokinase
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Summary:	Summary 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–κB 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.
ISSN:	1538-7933 1538-7836 1538-7836
DOI:	10.1111/jth.12581