Cyclooxygenase‐2‐Dependent Prostaglandin (PG) E 2 Downregulates Matrix Metalloproteinase‐3 Production via EP 2 /EP 4 Subtypes of PGE 2 Receptors in Human Periodontal Ligament Cells Stimulated With Interleukin‐1α

Background: Prostaglandin E 2 (PGE 2 ), which exerts its actions via EP receptors (EP 1 , EP 2 , EP 3 , and EP 4 ), 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 PGE 2 regulated matrix metalloproteinase (MMP)‐3 production in human periodontal ligament (PDL) cells stimulated with interleukin (IL)‐1α and which EP receptors were involved in PGE 2 regulation of IL‐1α‐induced MMP‐3 production. Methods: Human PDL cells obtained from periodontally healthy subjects were stimulated with vehicle or IL‐1α in the presence or absence of indomethacin (a COX‐1/COX‐2 inhibitor), NS‐398 (a specific COX‐ 2 inhibitor), PGE 2 , EP receptor agonists, dibutyryl cAMP, and forskolin. PGE 2 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‐1α enhanced both MMP‐3 and PGE 2 production. Indomethacin and NS‐398 enhanced IL‐1α‐induced MMP‐3 production in PDL cells, to the same extent, although both the agents completely inhibited IL‐1α‐induced PGE 2 production. Exogenous PGE 2 reduced IL‐1α‐induced MMP‐3 production in a dose‐dependent manner. Butaprost, a selective EP 2 agonist, and ONO‐AE1‐329, a selective EP 4 agonist, significantly inhibited IL‐1α‐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‐1α‐stimulated MMP‐3 production in PDL cells. Conclusions: These data suggest that COX‐2‐dependent PGE 2 downregulates IL‐1α‐elicited MMP‐3 production by cAMP‐dependent pathways via EP 2 /EP 4 receptors in human PDL cells. cAMP‐elevating agents such as EP 2 /EP 4 receptor activators may regulate the destruction of extracellular matrix components in periodontal tissue. J Periodontol 2005;76:929‐935 .