Abstract
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.
Highlights
The antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by the occurrence of thrombosis and/or recurrent miscarriages
Taking into account these circumstances, we investigated the effects of nuclear factor-κB (NF-κB) and c-Jun/ activator protein-1 (AP-1) on aPL/anti-β2GPI-induced expression of prothrombotic and proinflammation molecules by using a specific NF-κB antagonist pyrrolidinedithiocarbamate acid (PDTC) and an AP-1 inhibitor Curcumin in BALB/c mice
We show for the first time that NF-κB and c-Jun/AP-1 are involved in antiβ2GPI-induced expression of prothrombotic and proinflammatory molecules in vivo, and that these effects can be attenuated by Pyrrolidinedithiocarbamic acid (PDTC) [31] and Curcumin [32]
Summary
The antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by the occurrence of thrombosis and/or recurrent miscarriages. The activity of NF-κB and AP-1 can be regulated by several upstream kinases, such as p38-mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and cJun N-terminal kinases (JNKs) [21] Whether both NF-κB and c-Jun/AP-1 are involved in aPL/anti-β2GPI-induced expression of TF, adhesion molecules and inflammatory cytokines in vivo has not yet been clarified. Taking into account these circumstances, we investigated the effects of NF-κB and c-Jun/ AP-1 on aPL/anti-β2GPI-induced expression of prothrombotic and proinflammation molecules by using a specific NF-κB antagonist pyrrolidinedithiocarbamate acid (PDTC) and an AP-1 inhibitor Curcumin in BALB/c mice The alterations in these molecules were assessed by TF activity/expression and the expression of adhesion molecules E-selectin) and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the carotid artery, aorta and peritoneal macrophages in vivo
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