Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases

Birgit A. Steppich; Isabell Seitz; Gabi Busch; Andreas Stein; Ilka Ott

doi:10.1160/TH08-05-0293

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(06): 1068-1075
DOI: 10.1160/TH08-05-0293

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases

Authors

Birgit A. Steppich

¹Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
Isabell Seitz

¹Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
Gabi Busch

¹Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
Andreas Stein

¹Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
Ilka Ott

¹Deutsches Herzzentrum der Technischen Universität München, Munich, Germany

Abstract

Summary

During systemic inflammation, neutrophil activation is accompanied by endothelial cell damage and hypercoagulability. Activated neutrophils release serine proteases that participate in tissue injury.We sought to investigate the effects of neutrophil proteases on proinflammatory and procoagulant changes in endothelial cells.The effects of elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3) on expression of tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI) were examined in human umbilical vein endothelial cells. Flow cytometry demonstrated that these proteases proteolytically degraded endothelial cell-bound TFPI. TFPI mRNA expression was reduced by HNE and CG. PR3, but not HNE or CG, increased surface expression of TF and TF mRNA.Yet, increased TF expression did not enhance TF activity suggesting induction of encrypted TF. Using antibodies and siRNA to inhibit and silence PAR-1 and PAR-2, we observed that PR3 upregulation of TF is at least in part mediated by PAR-1.Although CG and HNE cleaved PAR-1, antibody reactivity to the PAR-1 hirudin-like sequence demonstrated inactivating cleavage, accounting for the selective ability of PR3 to induce PAR-1-mediated procoagulant effects.This was supported by induction of p42/44 MAPK by PR3. In conclusion, PR3 degradation of TFPI increases the procoagulant activity of endothelial cells. Release of PR3 after neutrophil activation may represent an important step in neutrophil-mediated vascular injury.

Keywords

Tissue factor (TF) - tissue factor pathway inhibitor (TFPI) - proteinase 3 - cathepsin G - human neutrophil elastase

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Referenzen

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