Valproic acid suppresses lipopolysaccharide-induced cyclooxygenase-2 expression via MKP-1 in murine brain microvascular endothelial cells
Valproic acid suppresses lipopolysaccharide-induced cyclooxygenase-2 expression via MKP-1 in murine brain microvascular endothelial cells
复制标题
DOI：
10.1016/j.bcp.2014.02.004
复制
发表时间：
2014-04-01
影响因子：
5.8
通讯作者：
Hsu, Ming-Jen
中科院分区：
文献类型：
--
作者：
Chuang, Yu-Fan;Yang, Hung-Yu;Hsu, Ming-Jen
炎症和血管扰动越来越多地参与神经退行性疾病的发病机制。现有证据表明，丙戊酸（VPA），抗癫痫药和情绪稳定剂，不仅表现出神经保护作用，而且在神经退行性疾病中具有抗炎作用。然而，VPA抑制炎症反应的潜在机制仍不清楚。在这项研究中，我们探讨了VPA对bEnd. 3小鼠脑微血管内皮细胞暴露于脂多糖（LPS）（一种促炎刺激物）时环氧合酶（考克斯）-2表达的抑制作用。VPA显著抑制LPS诱导的考克斯-2蛋白水平和考克斯-2启动子荧光素酶活性的升高。VPA抑制LPS刺激的bEnd.3细胞中p38 MAPK和JNK磷酸化。用p38 MAPK抑制剂（p38 MAPK抑制剂III）或JNK信号传导抑制剂（JNK抑制剂II）处理细胞显著抑制LPS诱导的考克斯-2表达。VPA抑制LPS诱导的NF-κ B亚基p65磷酸化和κ B-荧光素酶活性。在VPA存在下，LPS增加的p65和C/EBP β与考克斯-2启动子区域的结合减弱。此外，VPA对p38 MAPK、JNK和p65磷酸化以及随后的考克斯-2表达的抑制在转染有丝分裂原活化蛋白激酶磷酸酶-1（MKP-1）显性阴性（DN）突变体的细胞中恢复。VPA还导致bEnd.3细胞中MKP-1乙酰化和MKP-1磷酸酶活性增加。总之，VPA可能导致MKP-1活化，使p38 MAPK和JNK去磷酸化，导致p65和C/EBP β与考克斯-2启动子区域的结合减少，并导致LPS刺激的bEnd.3细胞中考克斯-2下调。因此，本研究支持VPA在缓解脑炎症过程中的治疗价值。(c)2014爱思唯尔公司All rights reserved.
Inflammation and vascular perturbations are increasingly implicated in the pathogenesis of neurodegenerative diseases. Prevailing evidence suggests that valproic acid (VPA), an antiepileptic and mood stabilizer, exhibits not only neuro-protective effects, but also anti-inflammatory effects in neurodegenerative diseases. However, the underlying mechanism contributing to VPA's suppression of inflammatory responses remains unclear. In this study, we explored the inhibitory action of VPA on cyclooxygenase (COX)-2 expression in bEnd.3 mouse brain microvascular endothelial cells exposed to lipopolysaccharide (LPS), a pro-inflammatory stimulus. The LPS-induced increases in COX-2 protein level and COX-2 promoter-luciferase activity were significantly suppressed by VPA. VPA inhibited p38MAPK and JNK phosphorylation in LPS-stimulated bEnd.3 cells. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) or a JNK signaling inhibitor (JNK inhibitor II) significantly inhibited LPS-induced COX-2 expression. VPA inhibited LPS-induced NF-kappa B subunit p65 phosphorylation and kappa B-luciferase activity. LPS-increased p65 and C/EBP beta binding to the COX-2 promoter region was attenuated in the presence of VPA. In addition, VPA suppression of p38MAPK, JNK and p65 phosphorylation, and subsequent COX-2 expression was restored in cells transfected with mitogen-activated protein kinase phosphatase-1 (MKP-1) dominant negative (DN) mutant. VPA also caused increases in MKP-1 acetylation and MKP-1 phosphatase activity in bEnd.3 cells. In conclusion, VPA may cause MKP-1 activation to dephosphorylate p38MAPK and JNK, leading to decrease in p65 and C/EBP beta binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated bEnd.3 cells. The present study therefore supports the therapeutic value of VPA in alleviating brain inflammatory processes. (c) 2014 Elsevier Inc. All rights reserved.