Prostaglandin E₂ potentiates interferon-γ-induced nitric oxide production in cultured rat microglia

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• 作者：Takayuki Nagano ; Ryo Nishiyama ; Ayaka Sanada ; Yukiko Mutaguchi ; Anna Ioku ; Hirohisa Umeki ; Satoshi Kishimoto ; Daisuke Yamanaka ; Shinya H. Kimura and Motohiko Takemura
• 刊名：Journal of Neurochemistry
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：140
• 期：4
• 页码：605-612
• 全文大小：472K
• ISSN：1471-4159

文摘

Prostaglandin E₂ (PGE₂) plays crucial roles in managing microglial activation through the prostanoid EP₂ receptor, a PGE₂ receptor subtype. In this study, we report that PGE₂ enhances 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 PGE₂ by itself slightly affects nitrite release. The potentiating effect of PGE₂ was 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 EP₂ agonist, ONO-AE1-259-01 also augmented IFN-γ-induced nitrite release, while an EP₁ agonist, ONO-DI-004, an EP₃ agonist, ONO-AE-248, or an EP₄ agonist, ONO-AE1-329, did not. In addition, the potentiating effect of PGE₂ was inhibited by an EP₂ antagonist, PF-04418948, but not by an EP₁ antagonist, ONO-8713, an EP₃ antagonist, ONO-AE3-240, or an EP₄ antagonist, ONO-AE3-208, at 10⁻⁶ M. 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, PGF_2α, iloprost, and U-46119, slightly affected IFN-γ-induced nitrite release. These results indicate that PGE₂ potentiates IFN-γ-induced nitric oxide production in microglia through the EP₂ receptor, which may shed light on one of the pro-inflammatory aspects of PGE₂.