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.
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.
Authors: Barbara Thaler; Nagyung Baik; Philipp J Hohensinner; Johanna Baumgartner; Adelheid Panzenböck; Stefan Stojkovic; Svitlana Demyanets; Ihor Huk; Gersina Rega-Kaun; Christoph Kaun; Manfred Prager; Michael B Fischer; Kurt Huber; Walter S Speidl; Robert J Parmer; Lindsey A Miles; Johann Wojta Journal: Blood Date: 2019-06-20 Impact factor: 22.113
Authors: Suresh Govatati; Prahalathan Pichavaram; Jagadeesh Janjanam; Baolin Zhang; Nikhlesh K Singh; Arul M Mani; James G Traylor; A Wayne Orr; Gadiparthi N Rao Journal: Arterioscler Thromb Vasc Biol Date: 2019-06 Impact factor: 8.311
Authors: Milos Z Milosavljevic; Ivan P Jovanovic; Nada N Pejnovic; Slobodanka L J Mitrovic; Nebojsa N Arsenijevic; Bojana J Simovic Markovic; Miodrag L Lukic Journal: Oncotarget Date: 2016-04-05
Authors: Stefan Stojkovic; Christoph Kaun; Jose Basilio; Sabine Rauscher; Lena Hell; Konstantin A Krychtiuk; Cornelia Bonstingl; Rainer de Martin; Marion Gröger; Cihan Ay; Wolfgang Holnthoner; Wolfgang Eppel; Christoph Neumayer; Ihor Huk; Kurt Huber; Svitlana Demyanets; Johann Wojta Journal: Sci Rep Date: 2016-05-04 Impact factor: 4.379