In vivo effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of antiphospholipid antibodies

G. Montiel-Manzano, Z. Romay-Penabad, E. Papalardo De Martínez, L. A. Meillon-García, E. García-Latorre, E. Reyes-Maldonado, Silvia S. Pierangeli

Research output: Chapter in Book/Report/Conference proceedingConference contribution

59 Scopus citations

Abstract

It has been shown that endothelial cell (EC) activation and tissue factor (TF) upregulation in EC and monocytes by antiphospholipid antibodies (aPL Abs) leads to a prothrombotic state and involves translocation of nuclear factor-kappa B (NF-κB). Here we examined the effects of an NF-κB inhibitor on aPL-induced thrombosis, TF activity, and EC in vivo. We treated CD1 mice with IgG from a patient with antiphospholipid syndrome (IgG-APS) or with control IgG (IgG-NHS). The adhesion of leukocytes (number of white blood cells) to EC in cremaster muscle (as an indication of EC activation) as well as the size of an induced thrombus in the femoral vein of the mice were examined. Some mice in each group were infused with 10 μM MG132 (an inhibitor of NF-κB). TF activity was determined using a chromogenic assay in homogenates of carotid arteries and in peritoneal cells of mice. In vivo, IgG-APS increased significantly the number of white blood cells adhering to ECs (4.7 ± 2.2) when compared to control mice (1.5 ± 0.8), and these effects were significantly reduced when mice were pretreated with MG132 (0.8 ± 0.2). IgG-APS increased significantly the thrombus size and MG132 inhibited that effect (93%). Treatment of the mice with IgG-APS also induced significantly increased TF function in peritoneal cells and in homogenates of carotid arteries. Pretreatment of the mice with MG132 abrogated those effects significantly. Mice injected with IgG-APS or with IgM-APS with or without the inhibitor had medium-high titers of anticardiolipin antibodies in serum at the time of the surgical procedures. The data show that prothrombotic and proinflammatory properties of IgG-APS and IgM-APS are downregulated in vivo by an NF-κB inhibitor. These findings may be important in designing new modalities of targeted therapies to treat thrombosis in patients with APS.

Original languageEnglish (US)
Title of host publicationAutoimmunity, Part D
Subtitle of host publicationAutoimmune Disease, Annus Mirabilis
Pages540-553
Number of pages14
Volume1108
DOIs
StatePublished - Jun 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1108
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Antiphospholipid antibodies
  • Antiphospholipid syndrome
  • Endothelial cells
  • NF-κB
  • Thrombosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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