title: Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells. Lessons from the antiphospholipid syndrome.
abstract: 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)α and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNFα apparently depends alm ost 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.
authors: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors: Nadine
authors: N
authors: Prinz
authors: Natascha
authors: N
authors: Clemens
authors: Antje
authors: A
authors: Canisius
authors: Karl J
authors: KJ
authors: Lackner
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016736:Antiphospholipid Syndrome / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009544:Niflumic Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009544:Niflumic Acid; D013925:Thromboplastin; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000111:Acetylcysteine; D000094765:Glutathione Peroxidase GPX1