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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:769.)
© 2007 American Heart Association, Inc.

Vascular Biology

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; Sibylle Hess; Henk Schulz; Robert Eckl; Gabriele Busch; Hans Peter Montens; Richard Brandl; Stefan Seidl; Albert Schömig; Ilka Ott

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.

Correspondence to I. Ott, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany. 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.

In endothelial cells, soluble MT-SP1/matriptase induced IL-8 and IL-6 expression. MT-SP1/matriptase proteolytic activity, activation of p38 MAPK and PKC were required for cytokine release, which was abolished by downregulation of PAR-2. In the interaction of monocytes and endothelial cells MT-SP1/matriptase and PAR-2, respectively, were crucial for IL-8 release.

Key Words: pathophysiology • growth factors • endothelium

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