Prostaglandin E2 receptors of the EP2 and EP4 subtypes downregulate tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human gingival fibroblasts.
Prostaglandin E2 (PGE2) 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 PGE2 regulated intercellular adhesion molecule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated with tumor necrosis factor-alpha (TNF alpha) and if so, which subtype(s) of PGE2 receptors was involved. Exogenous addition of PGE2 to HGF inhibited ICAM-1 expression elicited by TNF alpha in a concentration-dependent manner. Treatment of HGF with indomethacin, a cyclo-oxygenase inhibitor, had no effect on TNF alpha-elicited ICAM-1 expression, although indomethacin completely inhibited PGE2 production enhanced by TNF alpha. Next, we examined which subtype(s) of the 4 EP receptors modulated the ICAM-1 expression elicited by TNF alpha, using subtype-specific agonists and antagonists. 11-deoxy-PGE1, a selective EP2/EP4 agonist, inhibited TNF alpha-elicited ICAM-1 expression as potently as PGE2, while butaprost, a selective EP2 agonist, was somewhat less effective than PGE2. AH23848B, an EP4 antagonist, antagonized the inhibitory effect of TNF alpha-elicited ICAM-1 expression by PGE2. Sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, were inert to TNF alpha-elicited ICAM-1 expression. As EP2 and EP4 receptors are linked to elevation of intracellular cyclic AMP (cAMP), the effect of dibutyryl cAMP and 8-bromo-cAMP, cAMP analogs, on TNF alpha-elicited ICAM-1 expression was examined. Both the agents downregulated ICAM-1 expression in TNF alpha-stimulated HGF. From these data, we suggest that PGE2 downregulates TNF alpha-induced ICAM-1 expression in HGF, via EP2 and EP4 receptors by cAMP-dependent signaling pathways, which may result in control of inflammatory and immunological responses in periodontal disease.
Noguchi
K
K
Department of Periodontology, Faculty of Dentistry, Tokyo Medical and Dental University, Japan. kazuyuki-noguchi.peri@dent.tmd.ac.jp
Iwasaki
K
K
Shitashige
M
M
Ishikawa
I
I
D000704:Analysis of Variance; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013268:Stimulation, Chemical; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015232:Dinoprostone