title: Prostaglandin E2potentiates interferon-γ-induced nitric oxide production in cultured rat microglia.
abstract: Prostaglandin E2(PGE2) plays crucial roles in managing microglial activation through the prostanoid EP2receptor, a PGE2receptor subtype. In this study, we report that PGE2enhances interferon-γ (IFN-γ)-induced nitric oxide production in microglia. IFN-γ increased the release of nitrite, a metabolite of nitric oxide, which was augmented by PGE2, although PGE2by itself slightly affects nitrite release. The potentiating effect of PGE2was positively associated with increased expression of inducible nitric oxide synthase. In contrast to nitrite release induced by IFN-γ, lipopolysaccharide-induced nitrite release was not affected by PGE2. An EP2agonist, ONO-AE1-259-01 also augmented IFN-γ-induced nitrite release, while an EP1agonist, ONO-DI-004, an EP3agonist, ONO-AE-248, or an EP4agonist, ONO-AE1-329, did not. In addition, the potentiating effect of PGE2was inhibited by an EP2antagonist, PF-04418948, but not by an EP1antagonist, ONO-8713, an EP3antagonist, ONO-AE3-240, or an EP4antagonist, ONO-AE3-208, at 10-6M. Among the EP agonists, ONO-AE1-259-01 alone was able to accumulate cyclic adenosine monophosphate (AMP), and among the EP antagonists, PF-04418948 was the only one able to inhibit PGE2-increased intracellular cyclic AMP accumulation. On the other hand, IFN-γ promoted phosphorylation of signal transducer and activator of transcription 1, which was not affected by PGE2. Furthermore, other prostanoid receptor agonists, PGD2, PGF2α, iloprost, and U-46119, slightly affected IFN-γ-induced nitrite release. These results indicate that PGE2potentiates IFN-γ-induced nitric oxide production in microglia through the EP2receptor, which may shed light on one of the pro-inflammatory aspects of PGE2.
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishiyama
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Sanada
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mutaguchi
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Ioku
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Umeki
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishimoto
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamanaka
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Shinya H
authors.initials: SH
authors.lastname: Kimura
authors.affiliation: Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Takemura
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015232:Dinoprostone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000819:agonists* / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009573:Nitrites; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015232:Dinoprostone
keywords: NOS2; PGE2; PTGER2; STAT1; cAMP; iNOS