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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.AT

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.

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.

Authors+Show Affiliations

Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, 80636 München, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17255532

Citation

Seitz, Isabell, et al. "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." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 4, 2007, pp. 769-75.
Seitz I, Hess S, Schulz H, et al. 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;27(4):769-75.
Seitz, I., Hess, S., Schulz, H., Eckl, R., Busch, G., Montens, H. P., Brandl, R., Seidl, S., Schömig, A., & Ott, I. (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. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(4), 769-75.
Seitz I, et al. 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;27(4):769-75. PubMed PMID: 17255532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Seitz,Isabell, AU - Hess,Sibylle, AU - Schulz,Henk, AU - Eckl,Robert, AU - Busch,Gabriele, AU - Montens,Hans Peter, AU - Brandl,Richard, AU - Seidl,Stefan, AU - Schömig,Albert, AU - Ott,Ilka, Y1 - 2007/01/25/ PY - 2007/1/27/pubmed PY - 2007/4/26/medline PY - 2007/1/27/entrez SP - 769 EP - 75 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 27 IS - 4 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/17255532/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_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000258862.61067.14?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -