Prostaglandin E-2 receptors of the EP2 and EP4 subtypes downregulate tumornecrosis factor alpha-induced intercellular adhesion molecule-1 expressionin human gingival fibroblasts

Prostaglandin E-2 (PGE(2)) exerts its biological actions via EP receptors, which are divided into 4 subtypes of EP1, EP2, EP3 and EP4. In the present study. we investigated whether PGE(2) regulated intercellular adhesion mole cule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated w ith tumor necrosis factor-alpha (TNF alpha) and if so, which subtype(s) of PGE(2) receptors was involved. Exogenous addition of PGE(2) to HGF inhibite d ICAM-1 expression elicited by TNF alpha in a concentration-dependent mann er. Treatment of HGF with indomethacin, a cyclo-oxygenase inhibitor, had no effect on TNF alpha-elicited ICAM-1 expression. although indomethacin comp letely inhibited PGE(2) production enhanced by TNF alpha. Next, we examined which subtype(s) of the 4 EP receptors modulated the ICAM-1 expression eli cited by TNF alpha, using subtype-specific agonists and antagonists. 11-deo xy-PGE(1), a selective EP2/EP4 agonist, inhibited TNF alpha-elicited ICAM-1 expression as potently as PGE(2), while butaprost, a selective EP2 agonist , was somewhat less effective than PGE(2). AH23848B, an EP4 antagonist, ant agonized the inhibitory effect of TNF alpha-elicited ICAM-1 expression by P GE(2). Sulprostone, an EP1/EP3 agonist, and ONO-AS-324, an EP3 agonist. Her e inert to TNF alpha-elicited ICAM-1 expression. As EP2 and EP4 receptors a re linked to elevation of intracellular cyclic AMP (cAMP), the effect of di butyryl cAMP and 8-bromo-cAMP, cAMP analogs, on TNF alpha-elicited ICAM-1 e xpression was examined. Both the agents downregulated ICAM-1 expression in TNF alpha-stimulated HGF. From these data, we suggest that PGE(2) downregul ates TNF alpha-induced ICAM-1 expression in HGF, via EP2 and EP4 receptors by cAMP-dependent signaling pathways, which may result in control of inflam matory and immunological responses in periodontal disease.