Activation of mTOR is involved in anti-β2GPI/β2GPI-induced expression of tissue factor and IL-8 in monocytes

Abstract

Previous study has demonstrated that activation of the mammalian target of rapamycin (mTOR) pathway in endothelial cells (ECs) results in the formation of chronic vascular lesions associated with antiphospholipid syndrome (APS). In addition, it has been shown that stimulation of monocytes and ECs by antiphospholipid antibodies (aPL) leads to a prothrombotic and proinflammatory state and up-regulated expression of tissue factor (TF) and inflammatory cytokines. However, the role of mTOR in pathogenic mechanisms of APS remains largely unexplored. In the present study, we aimed to investigate whether mTOR was involved in anti-β₂GPI/β₂GPI complex-induced expression of TF and interleukin-8 (IL-8/CXCL8) in monocytes and explore the relationship among TLR4, mTOR, MAPKs and NF-κB in such a process. The results showed that treatment of anti-β₂GPI/β₂GPI or APS-IgG/β₂GPI complex could markedly induce mTOR activation as well as expression of TF and IL-8 in THP-1 cells or primary monocytes. The mTOR inhibitor rapamycin (100nM) could attenuate the elevated expression of TF and IL-8. In addition, rapamycin could also decrease the phosphorylation of p38, ERK1/2 and NF-κB p65 stimulated by anti-β₂GPI/β₂GPI or APS-IgG/β₂GPI complex, but it had no effect on JNK. Moreover, the anti-β₂GPI/β₂GPI or APS-IgG/β₂GPI complex-induced phosphorylation of mTOR in THP-1 cells was down-regulated through inhibition of p38 (10μM, SB203580) or ERK (5μM, U0126) rather than inhibition of JNK (90nM, SP600125) or NF-κB (20μM, PDTC). Finally, the mTOR activation could also be affected by exposure to TLR4 inhibitor TAK-242 (5μM). Taken together, our results indicated that mTOR was involved in regulating anti-β₂GPI/β₂GPI-induced expression of TF and IL-8 in monocytes. In addition, the inhibition of mTOR pathway might be beneficial for the prevention and treatment of aPL-mediated thrombosis and inflammation in APS patients.

Keywords: Anti-β(2)-glycoprotein I antibodies; Interleukin-8; Tissue factor; mTOR; β(2)-glycoprotein I.