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

Birgit A. Steppich
1   Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
,
Isabell Seitz
1   Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
,
Gabi Busch
1   Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
,
Andreas Stein
1   Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
,
Ilka Ott
1   Deutsches Herzzentrum der Technischen Universität München, Munich, Germany
› Author Affiliations
Further Information

Publication History

Received: 07 May 2008

Accepted after major revision: 05 September 2008

Publication Date:
23 November 2017 (online)

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.

 
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