The Effects of NF-κB and c-Jun/AP-1 on the Expression of Prothrombotic and Proinflammatory Molecules Induced by Anti-β2GPI in Mouse.
The Effects of NF-κB and c-Jun/AP-1 on the Expression of Prothrombotic and Proinflammatory Molecules Induced by Anti-β2GPI in Mouse.
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DOI：
10.1371/journal.pone.0147958
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Xia L;Xie H;Yu Y;Zhou H;Wang T;Yan J
我们的前期研究表明，核因子-κB（NF-κB）和激活蛋白-1（AP-1）参与了抗β 2 GPI/β 2 GPI诱导单核细胞表达组织因子（TF）的过程。然而，NF-κB和AP-1在体内抗磷脂综合征（APS）发病机制中的作用研究很少。本研究旨在探讨NF-κB和c-Jun/AP-1是否参与抗β 2 GPI诱导的小鼠血栓前和炎症前分子的表达。在有或无PDTC（NF-κB的特异性抑制剂）和Curcumin（AP-1的有效抑制剂）处理的情况下，将IgG-APS或抗β2GPI抗体注射到BALB/c小鼠中。结果表明，IgG-APS和anti-β2GPI均可诱导小鼠腹腔巨噬细胞NF-κB和c-Jun/AP-1的活化。PDTC和/或Curcumin均能显著降低抗β 2GPI诱导的小鼠颈动脉匀浆和腹腔巨噬细胞TF活性，其中以PDTC的抑制作用最强，但两种抑制剂联合应用无协同作用。PDTC和/或Curcumin均能显著抑制抗β 2GPI诱导的小鼠主动脉TF、VCAM-1、ICAM-1和E-选择素的表达以及腹腔巨噬细胞TF、IL-1β、IL-6和TNF-α的表达。这些结果表明，NF-κB和c-Jun/AP-1参与调节抗β 2 GPI诱导的血栓前和炎症前分子的表达。抑制NF-κB和c-Jun/AP-1通路可能有利于预防和治疗APS患者的血栓形成和炎症。
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.