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

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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.