Prostaglandin E2 (PGE2), which exerts its actions via EP receptors (EP,, EP2, EP 3, and EP4), is a bioactive metabolite of arachidonic acid produced by cyclooxygenase (COX)-l and/or COX-2. We have previously demonstrated that PGE, downregulates intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1β (IL-1β)-stimulated human gingival fibroblasts (HGF). In the present study, we investigated which COX was involved in down-regulation of ICAM-1 expression by PGE2 in IL-1β-stimulated HGF and which subtypes of EP receptors modulated the ICAM-1 expression. NS-398, a specific COX-2 inhibitor, completely inhibited PGE2 production by IL-1β-stimulated HGF, as did indomethacin, a COX-1/COX-2 inhibitor. Northern blot analysis and immunocytochemical staining showed that mRNA and protein of COX-2 were expressed in IL-1β-challenged HGF, but not in unstimulated HGF, and that the expression of mRNA and protein of COX-1 was similar both in unstimulated and in stimulated cells. NS-398 and indomethacin enhanced ICAM-1 expression in IL-1β-challenged HGF. EP1, EP 2, and EP4 receptor mRNA was expressed in HGF according to reverse-transcription/polymerase chain-reaction. PGE2, 11-deoxy-PGE 1 (a selective EP2/EP4 agonist), and Butaprost (a selective EP2 agonist) attenuated IL-1β-elicited ICAM-1 expression, although Butaprost was less potent than PGE2 and 11-deoxy-PGE1. AH-23848B, an EP4 antagonist, antagonized the inhibitory effect of IL-1β-elicited ICAM-1 expression by PGE2. Sulprostone, an EP1/EP3 agonist, had no effect on IL-1β-elicited ICAM-1 expression. Analysis of these data suggests that COX-2-derived PGE 2 downregulates ICAM-1 expression via EP2/EP 4 receptors in IL-1β-stimulated HGF.
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