Prostaglandin E-2 downregulates interferon-gamma-induced intercellular adhesion molecule-1 expression via EP2 receptors in human gingival fibroblasts

In the present study, the effect of prostaglandin E-2 (PGE(2)) on intercell ular adhesion molecule-1 (ICAM-1) expression in interferon-gamma (IFN-gamma )-stimulated human gingival fibroblasts (HGF) was investigated. Addition of PGE(2) to HGF inhibited ICAM-1 expression elicited by IFN-gamma. As PGE(2) elevated intercellular cyclic AMP (cAMP) levels in HGF in a dose-dependent fashion, the effect of dibutyryl cAMP and 8-bromo-cAMP, cAMP analogues, on IFN-gamma-elicited ICAM-1 expression was examined. Both the agents downreg ulated ICAM-1 expression in IFN-gamma-stimulated HGF. Next, we examined whi ch subtype(s) of the four PGE(2) receptor subtypes (EP1, EP2, EP3 and EP4) modulated the ICAM-1 expression elicited by IFN-gamma, using subtype-specif ic agonists or antagonists. An EP2/EP4 agonist, 11-deoxy-PGE(1), attenuated IFN-gamma-elicited ICAM-1 expression in a concentration-dependent manner. A specific EP4 antagonist, AH-23848B, showed no effect on inhibition of IFN -gamma-elicited ICAM-1 expression by PGE(2) and 11-deoxy-PGE(1). Butaprost, an EP2-selective agonist, mimicked inhibition of IFN-gamma-elicited ICAM-1 expression by 11-deoxy-PGE(1). An EP3 agonist, ONO-AP-324, was inert with respect to IFN-gamma-elicited ICAM-1 expression. Sulprostone, an EP1/EP3 ag onist, showed stimulatory effect on ICAM-1 expression elicited by IFN-gamma . From these results, we suggest that PGE(2) downregulates IFN-gamma-induce d ICAM-1 expression in HGF, primarily via EP2 receptors by cAMP-dependent s ignaling pathways.