title: Up-regulation of lymphocytic cholinergic activity by ONO-4819, a selective prostaglandin EP4 receptor agonist, in MOLT-3 human leukemic T cells.
abstract: We used a selective EP4 receptor agonist, ONO-4819, and a human leukemic T cell line MOLT-3 cells, which express all four prostaglandin E2 (PGE2) receptors (EP1-EP4), to investigate whether the EP4 PGE2 receptor subtype is involved in regulating lymphocytic cholinergic activity. Phytohemagglutinin (PHA), a T cell activator, significantly enhanced the expression of EP4 receptor mRNA during the first 3-6 h of exposure, after which, expression gradually declined. Furthermore, PHA stimulation slightly but significantly up-regulated the expression of EP2 mRNA after 12 h and of EP3 mRNA after 6 h. By contrast, expression level of EP1 receptor mRNA was not affected by PHA. ONO-4819 (1 microM), which was added to cultures after 3 h of PHA stimulation, significantly increased cellular ACh content and release, and up-regulated ChAT mRNA expression and activity but inhibited MOLT-3 cell proliferation. These findings suggest that the activation of T lymphocytes up-regulates EP4 receptor mRNA expression and, to a lesser extent, EP2 and EP3 receptors and that PGE2 enhances nonneuronal lymphocytic cholinergic transmission in activated T cells, at least in part, via EP4 receptor-mediated pathways.
authors.affiliation: Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Suenaga
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohuchida
authors.forename: Nobuo
authors.initials: N
authors.lastname: Katsube
authors.forename: Takaaki
authors.initials: T
authors.lastname: Obata
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kawashima
mesh_terms: D000109:Acetylcholine / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D006537:Heptanoates / Q000494:pharmacology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D006537:Heptanoates; C487764:ONO4819; C545650:PTGER4 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine