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

Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):769-75. doi: 10.1161/01.ATV.0000258862.61067.14. Epub 2007 Jan 25.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / enzymology
  • Atherosclerosis / etiology
  • Catalysis
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Enzyme Activation
  • Humans
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Monocytes / metabolism
  • NF-kappa B / metabolism
  • Protein Kinase C-alpha / metabolism
  • RNA, Messenger / metabolism
  • Receptor, PAR-2 / metabolism*
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / pharmacology
  • Serine Endopeptidases / blood
  • Serine Endopeptidases / isolation & purification
  • Serine Endopeptidases / metabolism
  • Serine Endopeptidases / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cytokines
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Receptor, PAR-2
  • Recombinant Proteins
  • Protein Kinase C-alpha
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Serine Endopeptidases
  • matriptase