title: WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages.
abstract: OBJECTIVE
  Hydroxamate derivatives have attracted considerable attention because of their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis and infectious diseases. However, the mechanisms of the anti-inflammatory effects of hydroxamate derivatives remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated a novel aliphatic hydroxamate derivative, WMJ-S-001, and explored its anti-inflammatory mechanisms.
  
  
  METHODS
  RAW264.7 macrophages were exposed to LPS in the absence or presence of WMJ-S-001. COX-2 expression and signalling molecules activated by LPS were assessed.
  
  
  RESULTS
  LPS-induced COX-2 expression was suppressed by WMJ-S-001. WMJ-S-001 inhibited p38MAPK, NF-κB subunit p65 and CCAAT/enhancer-binding protein (C/EBP)β phosphorylation in cells exposed to LPS. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced p65 and C/EBPβ phosphorylation and COX-2 expression. LPS-increased p65 and C/EBPβ binding to the COX-2 promoter region was suppressed in the presence of WMJ-S-001. In addition, WMJ-S-001 suppression of p38MAPK, p65 and C/EBPβ phosphorylation, and subsequent COX-2 expression were restored in cells transfected with a dominant-negative (DN) mutant of MAPK phosphatase-1 (MKP-1). WMJ-S-001 also caused an increase in MKP-1 activity in RAW264.7 macrophages.
  
  
  CONCLUSIONS
  WMJ-S-001 may activate MKP-1, which then dephosphorylates p38MAPK, resulting in a decrease in p65 and C/EBPβ binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated RAW264.7 macrophages. The present study suggests that WMJ-S-001 may be a potential drug candidate for alleviating LPS-associated inflammatory diseases.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Chen
authors.forename: Chia-Sheng
authors.initials: CS
authors.lastname: Yen
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009281:Naphthalenes; C000600248:WMJ-S-001; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases