Up-regulation of lymphocytic cholinergic activity by ONO-4819, a selective prostaglandin EP4 receptor agonist, in MOLT-3 human leukemic T cells.
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.
Suenaga
Aya
A
Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan.
Fujii
Takeshi
T
Ogawa
Hiroshi
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Katsube
Nobuo
N
Obata
Takaaki
T
Kawashima
Koichiro
K
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
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