Anti-VCAM1 Anticorps (A28245)

Our previous data demonstrated that nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) are involved in the process of anti-β2GPI/β2GPI-induced tissue factor (TF) expression in monocytes. However, the role of NF-κB and AP-1 in pathogenic mechanisms of antiphospholipid syndrome (APS) in vivo has been rarely studied. This study aimed to investigate whether NF-κB and c-Jun/AP-1 are involved in anti-β2GPI-induced expression of prothrombotic and proinflammatory molecules in mouse. IgG-APS or anti-β2GPI antibodies were injected into BALB/c mice in the presence or absence of PDTC (a specific inhibitor of NF-κB) and Curcumin (a potent inhibitor of AP-1) treatment. Our data showed that both IgG-APS and anti-β2GPI could induce the activation of NF-κB and c-Jun/AP-1 in mouse peritoneal macrophages. The anti-β2GPI-induced TF activity in homogenates of carotid arteries and peritoneal macrophages from mice could significantly decrease after PDTC and/or Curcumin treatment, in which PDTC showed the strongest inhibitory effect, but combination of two inhibitors had no synergistic effect. Furthermore, anti-β2GPI-induced expression of TF, VCAM-1, ICAM-1 and E-selectin in the aorta and expression of TF, IL-1β, IL-6 and TNF-α in peritoneal macrophages of mice were also significantly attenuated by PDTC and/or Curcumin treatment. These results indicate that both NF-κB and c-Jun/AP-1 are involved in regulating anti-β2GPI-induced expression of prothrombotic and proinflammatory molecules in vivo. Inhibition of NF-κB and c-Jun/AP-1 pathways may be beneficial for the prevention and treatment of thrombosis and inflammation in patients with APS.

Antiphospholipid (aPL)/anti-β2-glycoprotein I (β2GPI) antibodies are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing an intracellular signaling and procoagulant/proinflammatory phenotype that leads to thrombosis. There is increasing evidence that Toll-like receptor 4 (TLR4) could serve as an important molecule for anti-β2GPI recognition on target cells. However, few studies have focused on the effects of TLR4 in in vivo models. Here, we investigated the role of TLR4 in the pathogenic effects of aPL/anti-β2GPI more precisely using TLR4-intact (C3H/HeN) and TLR4-defective (C3H/HeJ) mice. C3H/HeN and C3H/HeJ mice were injected with either IgG isolated from patient with APS (IgG-APS) or epitope-specific anti-β2GPI purified from β2GPI peptide-immunized rabbits. We found that, following anti-β2GPI injections and vascular injury, thrombus formation in both the carotid artery and femoral vein was markedly reduced in C3H/HeJ mice when compared with C3H/HeN mice. IgG-APS or anti-β2GPI-induced carotid artery and peritoneal macrophage tissue factor activity/expression was significantly lesser in C3H/HeJ than in C3H/HeN mice. Furthermore, the IgG-APS or anti-β2GPI induced expression of VCAM-1, ICAM-1, and E-selectin in the aorta and of IL-1β, IL-6, and TNF-α in peritoneal macrophages of C3H/HeJ mice was also significantly reduced compared to C3H/HeN mice. Together, these data suggest that TLR4 is involved in the pathogenic effects of aPL/anti-β2GPI antibodies in vivo.