title: Prostaglandin E(2) inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells.
abstract: Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE(2) on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE(2) to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE(2) receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE(2) on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1-259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE(2), while ONO-AE1-329 (EP4R agonist) was much less potent than PGE(2). The EP2/EP4R agonist 11-deoxy-PGE(1) mimicked the effect of PGE(2) with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE(2). Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE(2) down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE(2) may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Hideo K
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwagaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Morichika
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Itoh
authors.forename: Minori
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kubo
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Akagi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D001769:Blood / Q000276:immunology; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D020382:Interleukin-18; D008562:Membrane Glycoproteins; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018799:Intercellular Adhesion Molecule-1; D005576:Colforsin; D003994:Bucladesine; D015232:Dinoprostone