on January 25, 2007
Published online before print January 25, 2007, doi: 10.1161/01.ATV.0000258862.61067.14
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Submitted on March 26, 2006
Accepted on January 9, 2007
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
Isabell Seitz ;
From the Deutsches Herzzentrum und 1. Medizinische Klinik (I.S., G.B., A.S., I.O.), Technische Universität München, Germany; Morphochem AG München (R.E.), Germany; Morphochem AG Basel (H.S.), Switzerland; the Department of Vascular Surgery (H.P.M., R.B.), Krankenhaus München-Schwabing, Germany; the Institut für Pathologie (S.S.), Technische Universität München, Germany; and Sanofi-Aventis Deutschland GmbH (S.H.), Frankfurt, Germany.
* To whom correspondence should be addressed. E-mail: ott{at}dhm.mhn.de.
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 PKC
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.
Conclusion--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.
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