The p38 mitogen-activated protein kinasa (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti β2Glycoprotein I antibodies

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。APL在体外诱导单核细胞产生凝血系统的主要起始物组织因子，部分解释了该综合征的病理生理机制。然而，对于APL诱导的导致TF表达的信号转导途径的性质却知之甚少。本研究利用基因芯片技术和实时定量聚合酶链式反应技术，对外周血单个核细胞(PBMC)中的APL诱导基因进行了研究。结果表明，人抗β_2GPI单抗(β_2GPI依赖于抗心磷脂抗体；β/β_2GPI)处理PBMC时，丝裂原活化蛋白激酶(MAPK)通路与TF的表达有关。用单核细胞系RAW264.7进行的Western blotting研究表明，核因子κB(核因子κB)被单抗acl/β_2GPI激活后，p38MAPK蛋白被磷酸化，而p38 MAPK特异性抑制剂SB203580可降低acl/β_2GPI诱导的TFmRNA表达。无κ_2GPI时，aCL/β_2GPI诱导的p38MAPK磷酸化、NF-βB易位和TFm RNA表达均被抑制。这些结果表明p38MAPK信号通路在APL诱导的单核细胞TF表达中起重要作用，提示p38MAPK可能是改变APS患者血栓前状态的一个可能的治疗靶点。

The antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid 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 peripheral blood mononuclear cell (PBMC) using cDNA array system and real time polymerase chain reaction (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 β_2Glycoprotein I (β_2GPI), with human monoclonal anti-β_2GPI antibodies (β_2GPI dependent anticardiolipin antibodies ; aCL/β_2GPI). Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated with NF-κB (nuclear factor κ B) activation by monoclonal aCL/β_2GPI treatment, and that SB203580, a specific p38 MAPK inihibitor, decreased the aCL/β_2GPI-induced TF mRNA expression. The p38 MAPK phosphorylation, NF-κB translocation and TF mRNA expression triggered by aCL/β_2GPI were abolished in the absence of β_2GPI. 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 prothrombotic state in patients with APS.