Anti-β2GPI/β2GPI stimulates activation of THP-1 cells through TLR4/MD-2/MyD88 and NF-κB signaling pathways

Abstract

Our previous study demonstrated that Toll-like receptor 4 (TLR4) could act as a co-receptor with annexin A2 (ANX2) mediating anti-β2-glycoprotein I/β2- glycoprotein I (anti-β2GPI/β2GPI) -induced tissue factor (TF) expression in human acute monocytic leukaemia cell line THP-1. In the current study, we further explored the roles of TLR4 and its adaptors, MD-2 and MyD88, as well as nuclear factor kappa B (NF-κB), in anti-β2GPI/β2GPI-induced the activation of THP-1 cells, especially on the expression of some proinflammatory molecules. The results showed that treatment of THP-1 cells with anti-β2GPI (10μg/ml)/β2GPI (100μg/ml) complex could increase IL-6 (interleukin-6), IL-8 (interleukin-8) as well as TNF-α (tumor necrosis factor alpha) expression (both mRNA and protein levels). These effects could be blocked by addition of TAK-242 (5μM), a blocker of signaling transduction mediated by the intracellular domain of TLR4, and also by NF-κB inhibitor PDTC (20μM). Overall, our results indicate that anti-β2GPI/β2GPI complex induced IL-6, IL-8 and TNF-α expression involving TLR4/MD-2/MyD88 and NF-κB signaling pathways and this might be associated with pathological mechanisms of antiphospholipid syndrome (APS).

Keywords: Anti-β(2)-glycoprotein I antibodies; NF-κB; THP-1 cells; TLR4/MD-2/MyD88; proinflammatory molecules; β(2)-glycoprotein I.