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. 
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.  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.  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.