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)-1α and which EP receptors were involved in PGE2 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), 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-1α enhanced both MMP-3 and PGE2 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 PGE2 production. Exogenous PGE2 reduced IL-1α-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-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 PGE2 downregulates IL-1α-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. J Periodontol 2005;76:929-935.