title: MAPK phosphatase-1 contributes to trichostatin A inhibition of cyclooxygenase-2 expression in human umbilical vascular endothelial cells exposed to lipopolysaccharide.
abstract: BACKGROUND
  Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agents because they were demonstrated to induce cell cycle arrest, promote cell apoptosis, and inhibit metastasis. Recently, HDAC inhibitors were also shown to exhibit pronounced anti-inflammatory properties. However, the underlying mechanism contributing to the suppression of inflammatory responses by HDAC inhibitors remains to be fully defined. In the present study, we explored the actions of trichostatin A (TSA), a potent HDAC inhibitor, on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 expression in human umbilical vascular endothelial cells (HUVECs).
  
  
  METHODS
  HUVECs were exposed to LPS in the absence or presence of TSA. COX-2 expression and signaling molecules (JNK, p38MAPK and c-jun) activated by LPS were assessed.
  
  
  RESULTS
  The LPS-induced cox-2 messenger RNA and protein were markedly suppressed by TSA. TSA inhibited JNK and p38MAPK phosphorylation in cells exposed to LPS. Treatment of cells with a JNK signaling inhibitor (JNK inhibitor II) or a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced COX-2 expression. TSA suppression of JNK and p38MAPK phosphorylation and subsequent COX-2 expression were restored by selective inhibition of MKP-1 using MKP-1 siRNA. In addition, TSA caused an increase in MKP-1 phosphatase activity in HUVECs. In conclusion, TSA may cause MKP-1 activation to dephosphorylate JNK and p38MAPK, leading to the downregulation of COX-2 in HUVECs stimulated by LPS, a proinflammatory stimulus.
  
  
  CONCLUSIONS
  MKP-1 contributes to TSA's protective actions in HUVECs exposed to LPS. The present study also supports the therapeutic value of TSA in treating inflammatory vascular diseases.
authors.affiliation: Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Chen
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.forename: Pei-Ting
authors.initials: PT
authors.lastname: Chiu
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D017931:DNA Primers; D006877:Hydroxamic Acids; C012589:trichostatin A; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1