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
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
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DOI：
10.1002/art.21549
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Velasco, F
中科院分区：
文献类型：
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作者：
López-Pedrera, C;Buendía, P;Velasco, F
objective.抗磷脂综合征（APS）的特征是血栓形成和抗磷脂抗体（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，这可能导致这些患者的血栓形成。然而，涉及APL介导的单核细胞TF上调的细胞内机制尚不清楚。本研究旨在研究APS患者单核细胞中aPL诱导的介导TF活化的细胞内信号。方法.我们在体内和体外分析了aPL与具有信号功能的蛋白质（包括有丝分裂原活化蛋白激酶（MAP激酶）和NF-KB/Rel蛋白）的相互作用。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RNA和TF蛋白的水平显着升高。在分子水平上，观察到I κ B α蛋白水解增加和NF-κ B活化。p38和ERK-1 MAP激酶也被激活，aPL处理正常单核细胞后，ERK-1和p38 MAP激酶以及IKB/NF-κ B通路被激活，并呈剂量依赖性。NF-κ B抑制剂SN 50和p38 MAP激酶抑制剂SB 203580抑制aPL诱导的NF-κ B活化和I κ B α降解，从而表明这些途径之间的串扰。然而，MEK-1/ERK抑制剂PD98059不影响aPL诱导的NF-κ B结合活性。3种物质联合应用可显著抑制aPL诱导的TF表达。我们的研究结果表明，aPL诱导TF表达的单核细胞从APS患者激活，同时和独立的，磷酸化的MEK-1/ERK蛋白，和p38 MAP激酶依赖的核转位和激活NF-κ B/Rel蛋白。
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 upregulation 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-KB/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 I kappa B alpha and activation of NF-kappa B 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 IKB/NF-icB pathway, in a dose-dependent manner. NF-kappa B activation and I kappa B alpha degradation induced by aPL were inhibited by the NF-KB 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-KB 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-KB/Rel proteins.