title: Cyclooxygenase-2-dependent prostaglandin (PG) E2 downregulates matrix metalloproteinase-3 production via EP2/EP4 subtypes of PGE2 receptors in human periodontal ligament cells stimulated with interleukin-1alpha.
abstract: BACKGROUND
  Prostaglandin E2 (PGE2), which exerts its actions via EP receptors (EP1, EP2, EP3, and EP4), is a bioactive metabolite produced by cyclooxygenase (COX)-1 and/or COX-2 from arachidonic acid. In the present study, we investigated whether COX-2-derived PGE2 regulated matrix metalloproteinase (MMP)-3 production in human periodontal ligament (PDL) cells stimulated with interleukin (IL)-1alpha and which EP receptors were involved in PGE2 regulation of IL-1alpha-induced MMP-3 production.
  
  
  METHODS
  Human PDL cells obtained from periodontally healthy subjects were stimulated with vehicle or IL-1alpha in the presence or absence of indomethacin (a COX-1/COX-2 inhibitor), NS-398 (a specific COX- 2 inhibitor), PGE2, EP receptor agonists, dibutyryl cAMP, and forskolin. PGE2 levels were assayed by enzyme-linked immunosorbent assay (ELISA). MMP-3 levels and caseinolytic activities were evaluated by ELISA and casein zymography, respectively.
  
  
  RESULTS
  IL-1alpha enhanced both MMP-3 and PGE2 production. Indomethacin and NS-398 enhanced IL-1alpha-induced MMP-3 production in PDL cells, to the same extent, although both the agents completely inhibited IL-1alpha-induced PGE2 production. Exogenous PGE2 reduced IL-1alpha-induced MMP-3 production in a dose-dependent manner. Butaprost, a selective EP2 agonist, and ONO-AE1-329, a selective EP4 agonist, significantly inhibited IL-1alpha-induced MMP-3 production, although butaprost was less potent than ONO-AE-1-329. Dibutyryl cAMP, a cAMP analog, and forskolin, an adenylate cyclase activator, significantly inhibited IL-1alpha-stimulated MMP-3 production in PDL cells.
  
  
  CONCLUSIONS
  These data suggest that COX-2-dependent PGE2 downregulates IL-1alpha-elicited MMP-3 production by cAMP-dependent pathways via EP2/EP4 receptors in human PDL cells. cAMP-elevating agents such as EP2/EP4 receptor activators may regulate the destruction of extracellular matrix components in periodontal tissue.
authors.affiliation: Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mingming
authors.initials: M
authors.lastname: Yan
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Noguchi
authors.forename: Senarath M P M
authors.initials: SM
authors.lastname: Ruwanpura
authors.forename: Isao
authors.initials: I
authors.lastname: Ishikawa
mesh_terms: D000704:Analysis of Variance; D003994:Bucladesine / Q000494:pharmacology; D018929:Cell Culture Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D010513:Periodontal Ligament / Q000187:drug effects* / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D008565:Membrane Proteins; D009578:Nitrobenzenes; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003994:Bucladesine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019278:Matrix Metalloproteinase 3; D015232:Dinoprostone; D007213:Indomethacin