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Thromb Haemost 2013; 109(03): 525-531
DOI: 10.1160/TH12-06-0421
Platelets and Blood Cells
Schattauer GmbH

Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells

Lessons from the antiphospholipid syndrome
Nadine Prinz
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
,
Natascha Clemens
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
,
Antje Canisius
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
,
Karl J. Lackner
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
› Author Affiliations
Further Information

Publication History

Received: 20 June 2012

Accepted after major revision: 05 January 2012

Publication Date:
29 November 2017 (online)

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Summary

Antiphospholipid antibodies (aPL) have been shown to induce tissue factor (TF) expression in monocytes and endothelial cells. However, the underlying signal transduction has been more or less elusive in the past. We have recently shown that aPL enter the lysosomal route in monocytes and dendritic cells, and subsequently activate endosomal NADPH-oxidase (NOX). The generation of superoxide which is dismutated to hydrogen peroxide upregulates the intracellular toll like receptors (TLR) 7 and 8, and leads to robust production of inflammatory cytokines. Here we show that induction of TF by aPL follows the same signaling pathway. Inhibition of endosomal NOX by the anion channel blocker niflumic acid or capture of superoxide by the radical scavenger N-acetylcysteine blocks TF induction by aPL. Furthermore, monocytes from mice deficient in NOX2 do not increase TF surface expression in response to aPL, while cells from mice deficient in glutathione peroxidase- 1 (GPx-1) show an increased response. Unexpectedly, also induction of TF by tumour necrosis factor (TNF)⍺ and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNF⍺ apparently depends almost fully on endosomal NOX, signalling of LPS is only partially dependent on this pathway. These data provide further insight into the well-known role of reactive oxygen species in the induction of TF expression and suggest that endosomal signalling may represent a central coordinating point in this process.

Keywords

Tissue factor / factor VII - thrombosis - antiphospholipid antibodies - endosome - NADPH oxidase

 

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