抗磷脂综合征患者的抗磷脂抗体通过p38丝裂原活化蛋白激酶途径同时激活NF-κB/Rel蛋白以及MEK-1/ERK途径，诱导单核细胞组织因子表达。

Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway.

作者信息

López-Pedrera Chary, Buendía Paula, Cuadrado Maria José, Siendones Emilio, Aguirre Maria Angeles, Barbarroja Nuria, Montiel-Duarte Cristina, Torres Antonio, Khamashta Munther, Velasco Francisco

机构信息

Unidad de Investigación, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, E-14004 Cordoba, Spain.

出版信息

Arthritis Rheum. 2006 Jan;54(1):301-11. doi: 10.1002/art.21549.

DOI:10.1002/art.21549

PMID:16385547

Abstract

OBJECTIVE

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.

METHODS

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-kappaB/Rel proteins.

RESULTS

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 IkappaBalpha and activation of NF-kappaB 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 IkappaB/NF-kappaB pathway, in a dose-dependent manner. NF-kappaB activation and IkappaBalpha degradation induced by aPL were inhibited by the NF-kappaB 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-kappaB binding activity. TF expression induced by aPL was significantly inhibited by combined treatment with the 3 inhibitors.

CONCLUSION

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-kappaB/Rel proteins.

摘要

目的

抗磷脂综合征（APS）的特征为血栓形成及抗磷脂抗体（aPL）的存在。在原发性APS患者中，单核细胞表面组织因子（TF）的表达增加，这可能促使这些患者发生血栓形成。然而，aPL介导单核细胞上TF上调的细胞内机制尚不清楚。本研究旨在探讨aPL诱导的介导APS患者单核细胞中TF激活的细胞内信号。

方法

我们在体内和体外分析了aPL与具有信号传导功能的蛋白质的相互作用，包括丝裂原活化蛋白激酶（MAP激酶）和NF-κB/Rel蛋白。

结果

体内研究表明，与对照组相比，APS患者单核细胞中TF信使核糖核酸和TF蛋白水平均显著更高。在分子水平上，观察到IκBα的蛋白水解增加以及NF-κB的激活。还发现p38和ERK-1 MAP激酶均呈组成性激活。用aPL处理正常单核细胞以剂量依赖方式激活了ERK-1和p38 MAP激酶以及IκB/NF-κB途径。aPL诱导的NF-κB激活和IκBα降解被NF-κB抑制剂SN50和p38 MAP激酶抑制剂SB203580抑制，从而提示这些途径之间存在相互作用。然而，MEK-1/ERK抑制剂PD98059不影响aPL诱导的NF-κB结合活性。三种抑制剂联合处理可显著抑制aPL诱导的TF表达。