Arterioscler Thromb Vasc Biol. 2007 Jan 25; [Epub ahead of print]
Membrane-Type Serine Protease-1/Matriptase Induces Interleukin-6 and -8 in Endothelial Cells by Activation of Protease-Activated Receptor-2. Potential Implications in Atherosclerosis.
Seitz I, Hess S, Schulz H, Eckl R, Busch G, Montens HP, Brandl R, Seidl S, Schomig A, Ott I.
Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universitat Munchen, Germany; Morphochem AG Munchen, Germany; Morphochem AG Basel, Switzerland; the Department of Vascular Surgery, Krankenhaus Munchen-Schwabing, Germany; the Institut fur Pathologie, Technische Universitat Munchen, Germany; and Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
OBJECTIVE: The serine protease MT-SP1/matriptase plays an important role in cell migration and matrix degradation. Hepatocyte growth factor (HGF), urokinase-type plasminogen activator (uPA), and protease-activated receptor 2 (PAR-2) have been identified as in vitro substrates of MT-SP1/matriptase. Because PAR-2 is expressed in endothelial cells and contributes to inflammatory processes, we sought to investigate the effects of MT-SP1/matriptase on endothelial cytokine expression and analyzed MT-SP1/matriptase expression in vascular cells and atherosclerotic lesions. METHODS AND RESULTS: In endothelial cells, recombinant MT-SP1/matriptase dose-dependently induced interleukin (IL)-8 and IL-6 mRNA and protein expression dependent on its proteolytic activity. MT-SP1/matriptase time-dependently induced phosphorylation of p38 MAPK and p42/44 MAPK. Inhibitor experiments revealed that p38 MAPK and PKCalpha were necessary for IL-8 induction. PAR-2 downregulation abolished and PAR-2 overexpression augmented MT-SP1/matriptase-induced IL-8 expression as evidence for PAR-2 signaling. In human atherectomies, MT-SP1/matriptase was expressed in blood cells adherent to the endothelium. Concordantly, basal MT-SP1/matriptase expression was detected in isolated monocytes. Coincubation of monocytes and endothelial cells resulted in an increased IL-8 release, which was reduced after downregulation of endothelial PAR-2 and monocytic MT-SP1/matriptase. CONCLUSIONS: MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2. MT-SP1/matriptase is expressed in monocytes, thus, interaction of monocytic MT-SP1/matriptase with endothelial PAR-2 may contribute to atherosclerosis. |
