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 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