The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-β2Glycoprotein I antibodies
The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-β2Glycoprotein I antibodies
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DOI：
10.1093/intimm/dxh166
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Koike, T
中科院分区：
文献类型：
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作者：
Bohgaki, M;Atsumi, T;Koike, T
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。组织因子（TF），凝血系统的主要启动子，诱导单核细胞在体外的aPL，解释，部分，在这种综合征的病理生理。然而，关于APL诱导的信号转导途径导致TF表达的性质知之甚少。在本研究中，我们使用cDNA阵列系统和实时荧光定量PCR研究PBMC中aPL诱导基因。我们的研究结果表明，在β 2糖蛋白I（β 2 GPI）存在的情况下，用人单克隆抗β 2 GPI抗体[β 2 GPI依赖性抗心磷脂抗体（aCL/β 2 GPI）]处理PBMC时，丝裂原活化蛋白激酶（MAPK）途径与TF表达相关。采用单核细胞系RAW264.7进行的蛋白质印迹研究表明，p38 MAPK蛋白被核因子κ B（NF-κ B）激活的单克隆aCL/β（2）GPI磷酸化，特异性p38 MAPK抑制剂SB 203580降低aCL/β（2）GPI诱导的TF mRNA表达。在β（2）GPI缺乏的情况下，aCL/β（2）GPI触发的p38 MAPK磷酸化、NF-κ B易位和TF mRNA表达被消除。这些结果表明p38 MAPK信号通路在aPL诱导的单核细胞TF表达中起重要作用，并表明p38 MAPK可能是一个可能的治疗靶点，以改变APS患者的血栓前状态。
The anti-phospholipid syndrome (APS) is characterized by thrombosis and the presence of anti-phospholipid antibodies (aPL). Tissue factor (TF), the major initiator of the coagulation system, is induced on monocytes by aPL in vitro, explaining, in part, the pathophysiology in this syndrome. However, little is known regarding the nature of the aPL-induced signal transduction pathways leading to TF expression. In this study, we investigated aPL-inducible genes in PBMC using cDNA array system and real-time PCR. Our results indicated that the mitogen-activated protein kinase (MAPK) pathway was related to TF expression when PBMCs were treated, in the presence of beta(2)Glycoprotein I (beta(2)GPI), with human monoclonal anti-beta(2)GPI antibodies [beta(2)GPI-dependent anti-cardiolipin antibodies (aCL/beta(2)GPI)]. Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated with nuclear factor kappaB (NF-kappaB) activation by monoclonal aCL/beta(2)GPI treatment, and that SB203580, a specific p38 MAPK inhibitor, decreased the aCL/beta(2)GPI-induced TF mRNA expression. The p38 MAPK phosphorylation, NF-kappaB translocation and TF mRNA expression triggered by aCL/beta(2)GPI were abolished in the absence of beta(2)GPI. These results demonstrated that the p38 MAPK signaling pathway plays an important role in aPL-induced TF expression on monocytes and suggest that the p38 MAPK may be a possible therapeutic target to modify a pro-thrombotic state in patients with APS.