Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-κB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway
Article first published online: 29 DEC 2005
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 1, pages 301–311, January 2006
How to Cite
López-Pedrera, C., Buendía, P., José Cuadrado, M., Siendones, E., Angeles Aguirre, M., Barbarroja, N., Montiel-Duarte, C., Torres, A., Khamashta, M. and Velasco, F. (2006), Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-κB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis & Rheumatism, 54: 301–311. doi: 10.1002/art.21549
- Issue published online: 29 DEC 2005
- Article first published online: 29 DEC 2005
- Manuscript Accepted: 6 OCT 2005
- Manuscript Received: 29 APR 2005
- Junta de Andalucía. Grant Number: exp 171/03
- Fondo de Investigación Sanitaria, Spain. Grant Numbers: FIS 01/0715, FIS 03/1033
- Science and Technology postdoctoral fellowship from the Spanish government
Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). In patients with primary APS, expression of tissue factor (TF) on the surface of monocytes is increased, which may contribute to thrombosis in these patients. However, the intracellular mechanisms involved in aPL-mediated up-regulation of TF on monocytic cells are not understood. This study was undertaken to investigate the intracellular signals induced by aPL that mediate TF activation in monocytes from APS patients.
We analyzed, both in vivo and in vitro, aPL interactions with proteins that have signaling functions, including mitogen-activated protein kinases (MAP kinases) and NF-κB/Rel proteins.
In vivo studies demonstrated significantly higher levels of both TF messenger RNA and TF protein in monocytes from APS patients compared with controls. At the molecular level, increased proteolysis of IκBα and activation of NF-κB were observed. Constitutive activation of both p38 and ERK-1 MAP kinases was also found. Treatment of normal monocytes with aPL activated ERK-1 and p38 MAP kinases, as well as the IκB/NF-κB pathway, in a dose-dependent manner. NF-κB activation and IκBα degradation induced by aPL were inhibited by the NF-κB inhibitor SN50 and the p38 MAP kinase inhibitor SB203580, thus suggesting crosstalk between these pathways. However, the MEK-1/ERK inhibitor PD98059 did not affect aPL-induced NF-κB binding activity. TF expression induced by aPL was significantly inhibited by combined treatment with the 3 inhibitors.
Our results suggest that aPL induces TF expression in monocytes from APS patients by activating, simultaneously and independently, the phosphorylation of MEK-1/ERK proteins, and the p38 MAP kinase–dependent nuclear translocation and activation of NF-κB/Rel proteins.