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 EP 4 receptor agonist, ONO-4819, and a human leukemic T cell line MOLT-3 cells, which express all four prostaglandin E 2 (PGE 2 ) receptors (EP 1 –EP 4 ), to investigate whether the EP 4 PGE 2 receptor subtype is involved in regulating lymphocytic cholinergic activity. Phytohemagglutinin (PHA), a T cell activator, significantly enhanced the expression of EP 4 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 EP 2 mRNA after 12 h and of EP 3 mRNA after 6 h. By contrast, expression level of EP 1 receptor mRNA was not affected by PHA. ONO-4819 (1 μM), 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 EP 4 receptor mRNA expression and, to a lesser extent, EP 2 and EP 3 receptors and that PGE 2 enhances nonneuronal lymphocytic cholinergic transmission in activated T cells, at least in part, via EP 4 receptor-mediated pathways.