Xia Longfei, Xie Hongxiang, Yu Yinjing, Zhou Hong, Wang Ting, Yan Jinchuan
Jiangsu Key Laboratory of Medicine Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China.
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China.
PLoS One. 2016 Feb 1;11(2):e0147958. doi: 10.1371/journal.pone.0147958. eCollection 2016.
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.
我们之前的数据表明，核因子-κB（NF-κB）和活化蛋白-1（AP-1）参与了单核细胞中抗β2糖蛋白I/β2糖蛋白I诱导的组织因子（TF）表达过程。然而，NF-κB和AP-1在抗磷脂综合征（APS）体内致病机制中的作用鲜有研究。本研究旨在探讨NF-κB和c-Jun/AP-1是否参与抗β2糖蛋白I诱导的小鼠促血栓形成和促炎分子的表达。在有或没有PDTC（NF-κB的特异性抑制剂）和姜黄素（AP-1的强效抑制剂）处理的情况下，将IgG-APS或抗β2糖蛋白I抗体注射到BALB/c小鼠体内。我们的数据显示，IgG-APS和抗β2糖蛋白I均可诱导小鼠腹腔巨噬细胞中NF-κB和c-Jun/AP-1的活化。PDTC和/或姜黄素处理后，小鼠颈动脉和腹腔巨噬细胞匀浆中抗β2糖蛋白I诱导的TF活性可显著降低，其中PDTC的抑制作用最强，但两种抑制剂联合使用无协同作用。此外，PDTC和/或姜黄素处理还可显著减弱抗β2糖蛋白I诱导的小鼠主动脉中TF、血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）和E-选择素的表达以及腹腔巨噬细胞中TF、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达。这些结果表明，NF-κB和c-Jun/AP-1均参与调节抗β2糖蛋白I诱导的体内促血栓形成和促炎分子的表达。抑制NF-κB和c-Jun/AP-1途径可能有利于APS患者血栓形成和炎症的预防和治疗。
