title: Valproic acid suppresses lipopolysaccharide-induced cyclooxygenase-2 expression via MKP-1 in murine brain microvascular endothelial cells.
abstract: 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-κB subunit p65 phosphorylation and κB-luciferase activity. LPS-increased p65 and C/EBPβ 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/EBPβ 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.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Chuang
authors.affiliation: Division of Cardiology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Hung-Yu
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tsui-Ling
authors.initials: TL
authors.lastname: Ko
authors.affiliation: Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: aspirin@tmu.edu.tw.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D022782:CCAAT-Enhancer-Binding Protein-beta; D008070:Lipopolysaccharides; D051996:Transcription Factor RelA; D014635:Valproic Acid; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: Brain microvascular endothelial cells; Cyclooxygenase-2 (COX-2); Mitogen-activated protein kinase phosphatase-1 (MKP-1); Valproic acid (VPA)