title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, 80636 München, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Seitz
authors.forename: Sibylle
authors.initials: S
authors.lastname: Hess
authors.forename: Henk
authors.initials: H
authors.lastname: Schulz
authors.forename: Robert
authors.initials: R
authors.lastname: Eckl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Busch
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Montens
authors.forename: Richard
authors.initials: R
authors.lastname: Brandl
authors.forename: Stefan
authors.initials: S
authors.lastname: Seidl
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Ilka
authors.initials: I
authors.lastname: Ott
mesh_terms: D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology; D002384:Catalysis; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D011994:Recombinant Proteins; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases; C485595:matriptase