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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

 

  • References

  • 1 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
    CrossrefPubMedGoogle Scholar
  • 2 Butenas S. et al. TF in coagulation: Which?. Where? When? Arterioscler Thromb Vasc Biol 2009; 29: 1989-1996.
    PubMedGoogle Scholar
  • 3 Camerer E. et al. Cell biology of TF, the principal initiator of blood coagulation. Thromb Res 1996; 81: 1-41.
    CrossrefPubMedGoogle Scholar
  • 4 Drake TA. et al. Selective cellular expression of TF in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134: 1087-1097.
    PubMedGoogle Scholar
  • 5 Fleck RA. et al. Localization of human TF antigen by immunostaining with monospecific, polyclonal anti-human TF antibody. Thromb Res 1990; 59: 421-437.
    CrossrefPubMedGoogle Scholar
  • 6 Kuczynski J. et al. TF (TF) and TF pathway inhibitor (TFPI) in the placenta and myometrium. Eur J Obst Gynecol Rep Biol 2002; 105: 15-19.
    PubMedGoogle Scholar
  • 7 Siegbahn A. et al. Binding of factor VIIa to TF on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis. Blood 2000; 96: 3452-3458.
    PubMedGoogle Scholar
  • 8 Mandal SK. et al. Cellular localization and trafficking of TF. Blood 2006; 107: 4746-4753.
    CrossrefPubMedGoogle Scholar
  • 9 Erlich J. et al. TF is required for uterine hemostasis and maintenance of the placental labyrinth during gestation. Proc Natl Acad Sci USA 1999; 96: 8138-8143.
    CrossrefPubMedGoogle Scholar
  • 10 Isermann B. et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 9: 331-337.
    CrossrefPubMedGoogle Scholar
  • 11 Pawlinski R. et al. Role of TF and protease-activated receptors in a mouse model of endotoxemia. Blood 2004; 103: 1342-1347.
    PubMedGoogle Scholar
  • 12 Ginsburg KS. et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 997-1002.
    CrossrefPubMedGoogle Scholar
  • 13 Blank M. et al. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA 1991; 88: 3069-3073.
    CrossrefPubMedGoogle Scholar
  • 14 Pierangeli SS. et al. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice. Thromb Haemost 1994; 71: 670-674.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Boles J, Mackman N. Role of TF in thrombosis in antiphospholipid antibody syndrome. Lupus 2010; 19: 370-378.
    CrossrefPubMedGoogle Scholar
  • 16 Meroni PL. et al. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7: 330-339.
    CrossrefPubMedGoogle Scholar
  • 17 Prinz N. et al. Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 2011; 118: 2322-2332.
    CrossrefPubMedGoogle Scholar
  • 18 von Landenberg C. et al. Isolation and characterization of two human monoclonal anti-phospholipid IgG from patients with autoimmune disease. J Autoimmun 1999; 13: 215-223.
    CrossrefPubMedGoogle Scholar
  • 19 Lackner KJ. et al. Analysis of prothrombotic effects of two human monoclonal IgG antiphospholipid antibodies of apparently similar specificity. Thromb Haemost 2000; 83: 583-588.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Doring Y. et al. Human antiphospholipid antibodies induce TNFalpha in monocytes via Toll-like receptor 8. Immunobiology 2010; 215: 230-241.
    CrossrefPubMedGoogle Scholar
  • 21 Prinz N. et al. Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody. Immunobiology 2011; 216: 145-151.
    CrossrefPubMedGoogle Scholar
  • 22 Wilson WA. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-1311.
    CrossrefPubMedGoogle Scholar
  • 23 Farmer-Boatwright MK, Roubey RA. Venous thrombosis in the antiphospholipid syndrome. Arterioscler Thromb Vasc Biol 2009; 29: 321-325.
    CrossrefPubMedGoogle Scholar
  • 24 Meroni PL. et al. Updating on the pathogenic mechanisms 5 of the antiphospholipid antibodies-associated pregnancy loss. Clin Rev Allergy Immunol 2008; 34: 332-337.
    CrossrefPubMedGoogle Scholar
  • 25 Zhou H. et al. Characterization of monocyte TF activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood 2004; 104: 2353-2358.
    CrossrefPubMedGoogle Scholar
  • 26 Crossman DC. et al. The regulation of TF mRNA in human endothelial cells in response to endotoxin or phorbol ester. J Biol Chem 1990; 265: 9782-9787.
    PubMedGoogle Scholar
  • 27 Donovan-Peluso M. et al. Lipopolysaccharide induction of TF expression in THP-1 monocytic cells. Protein-DNA interactions with the promoter. J Biol Chem 1994; 269: 1361-1369.
    PubMedGoogle Scholar
  • 28 Moll T. et al. Regulation of the TF promoter in endothelial cells. Binding of NF kappa B-, AP-1-, and Sp1-like transcription factors. J Biol Chem 1995; 270: 3849-3857.
    CrossrefPubMedGoogle Scholar
  • 29 Simoncini S. et al. Role of reactive oxygen species and p38 MAPK in the induction of the pro-adhesive endothelial state mediated by IgG from patients with anti-phospholipid syndrome. Int Immunol 2005; 17: 489-500.
    CrossrefPubMedGoogle Scholar
  • 30 DeCoursey TE. et al. The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels. Nature 2003; 422: 531-534.
    CrossrefPubMedGoogle Scholar
  • 31 Miller Jr. FJ. , et al. Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC-3. Circ Res 2007; 101: 663-671.
    CrossrefPubMedGoogle Scholar
  • 32 Meister A, Anderson ME. Glutathione. Ann Rev Biochem 1983; 52: 711-760.
    CrossrefPubMedGoogle Scholar
  • 33 Koczor CA. et al. Mitochondrial DNA damage initiates a cell cycle arrest by a Chk2-associated mechanism in mammalian cells. J Biol Chem 2009; 284: 36191-36201.
    CrossrefPubMedGoogle Scholar
  • 34 Babior BM. et al. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 1973; 52: 741-744.
    CrossrefPubMedGoogle Scholar
  • 35 Parchment RE. Programmed cell death (apoptosis) in murine blastocysts: extracellular free-radicals, polyamines, and other cytotoxic agents. In Vivo 1991; 5: 493-500.
    PubMedGoogle Scholar
  • 36 Pierce GB. et al. Hydrogen peroxide as a mediator of programmed cell death in the blastocyst. Differentiation 1991; 46: 181-186.
    CrossrefPubMedGoogle Scholar
  • 37 Ferro D. et al. Enhanced monocyte expression of TF by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment. J Thromb Haemost 2003; 1: 523-531.
    CrossrefPubMedGoogle Scholar
  • 38 Poitevin S. et al. Type I collagen induces TF expression and matrix metalloproteinase 9 production in human primary monocytes through a redox-sensitive pathway. J Thromb Haemost 2008; 6: 1586-1594.
    CrossrefPubMedGoogle Scholar
  • 39 Herkert O, Gorlach A. Redox control of TF expression in smooth muscle cells and other vascular cells. Methods Enzymol 2002; 352: 220-231.
    PubMedGoogle Scholar
  • 40 Schmidt KN. et al. The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-kappa B. Chem Biol 1995; 2: 13-22.
    CrossrefPubMedGoogle Scholar
  • 41 Oeth P. et al. Regulation of the TF gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17: 365-374.
    CrossrefPubMedGoogle Scholar
  • 42 Schreck R. et al. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991; 10: 2247-2258.
    PubMedGoogle Scholar
  • 43 Yeh SH. et al. Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway. Nucleic Acids Res 2011; 39: 5412-5423.
    CrossrefPubMedGoogle Scholar
  • 44 Manea A. et al. AP-1-dependent transcriptional regulation of NADPH oxidase in human aortic smooth muscle cells: role of p22phox subunit. Arterioscler Thromb Vasc Biol 2008; 28: 878-885.
    CrossrefPubMedGoogle Scholar
  • 45 Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 1996; 10: 709-720.
    CrossrefPubMedGoogle Scholar
  • 46 Banfi C. et al. Mitochondrial reactive oxygen species: a common pathway for PAR1- and PAR2-mediated TF induction in human endothelial cells. J Thromb Haemost 2009; 7: 206-216.
    PubMedGoogle Scholar