Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes

Area of Science:

• Immunology
• Molecular Biology
• Pathophysiology

Background:

• Previous studies linked Toll-like receptor 4 (TLR4) signaling to anti-β2-glycoprotein I/β2-glycoprotein I (anti-β2GPI/β2GPI)-induced tissue factor (TF) expression in monocytes.
• The downstream nuclear transcription factors involved in this process remained largely unexplored.

Purpose of the Study:

• To investigate the activation and roles of nuclear factor kappa B (NF-κB) and activator protein (AP-1) in anti-β2GPI/β2GPI complex-induced TF expression.
• To elucidate the signaling pathways connecting TLR4, transcription factors, and TF expression in monocytes.

Main Methods:

• Human blood monocytes and THP-1 cells were treated with anti-β2GPI/β2GPI complexes.
• Levels of phosphorylated NF-κB (p-NF-κB p65) and c-Jun/AP-1 (p-c-Jun) were measured.
• Inhibitors of NF-κB (PDTC), AP-1 (curcumin), and MAPKs (SB203580, U0126, SP600125) were used to assess their effects on TF expression and transcription factor activation.
• The role of TLR4 was assessed using the TLR4 inhibitor TAK-242.

Main Results:

• Anti-β2GPI/β2GPI complex treatment significantly increased p-NF-κB p65, p-c-Jun, and TF expression.
• Inhibition of NF-κB and AP-1 attenuated TF expression induced by anti-β2GPI/β2GPI or APS-IgG/β2GPI.
• Combinations of MAPK inhibitors reduced NF-κB activation, and specific combinations also reduced c-Jun/AP-1 phosphorylation.
• Neither NF-κB nor c-Jun/AP-1 activation was affected by the TLR4 inhibitor TAK-242.

Conclusions:

• NF-κB and c-Jun/AP-1 are activated by anti-β2GPI/β2GPI complexes and play critical roles in inducing TF expression in monocytes.
• These findings highlight a signaling pathway independent of TLR4 that contributes to the pathophysiology of antiphospholipid syndrome.