Activation of MAPKs in the anti-β2GPI/β2GPI-induced tissue factor expression through TLR4/IRAKs pathway in THP-1...

Our previous study has demonstrated that the Toll-like receptor 4 (TLR4) signaling pathways contribute to the induction of tissue factor (TF) expression by anti-β(2)-glycoprotein I/β(2)-glycoprotein I (anti-β(2)GPI/β(2)GPI) in human acute monocytic leukemia cell line THP-1. In this study, we focused on the identification of the downstream targets of the TLR4 pathways. When THP-1 cells were treated with anti-β(2)GPI/β(2)GPI complex, enhanced TF expression was observed, along with induced phosphorylation of p38, ERK1/2 and JNK1/2 MAPKs. When the activity of MAPKs was blocked by their corresponding inhibitors (SB203580: p38; U0126: ERK; SP600125: JNK), the expression of TF was reduced significantly. Furthermore, the anti-β(2)GPI/β(2)GPI-induced phosphorylation of p38, ERK1/2 and JNK1/2 was inhibited significantly by TAK-242, a blocker of the signaling transduction mediated by the intracellular domain of TLR4; sc-204013, a specific inhibitor of IRAKs, was also able to partially inhibit the phosphorylation of the MAPKs. Our results demonstrated that MAPKs (p38, ERK1/2 and JNK1/2) were the crucial downstream targets of the anti-β(2)GPI/β(2)GPI-triggered TLR4 signaling pathways in THP-1 cells. This essential role of MAPKs may also promote better understanding of the pathogenesis of antiphospholipid syndrome (APS).