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.

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.