Nagano Takayuki, Nishiyama Ryo, Sanada Ayaka, Mutaguchi Yukiko, Ioku Anna, Umeki Hirohisa, Kishimoto Satoshi, Yamanaka Daisuke, Kimura Shinya H, Takemura Motohiko
Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
J Neurochem. 2017 Feb;140(4):605-612. doi: 10.1111/jnc.13926. Epub 2017 Feb 2.
Prostaglandin E (PGE ) plays crucial roles in managing microglial activation through the prostanoid EP receptor, a PGE receptor subtype. In this study, we report that PGE 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 PGE , although PGE by itself slightly affects nitrite release. The potentiating effect of PGE 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 PGE . An EP agonist, ONO-AE1-259-01 also augmented IFN-γ-induced nitrite release, while an EP agonist, ONO-DI-004, an EP agonist, ONO-AE-248, or an EP agonist, ONO-AE1-329, did not. In addition, the potentiating effect of PGE was inhibited by an EP antagonist, PF-04418948, but not by an EP antagonist, ONO-8713, an EP antagonist, ONO-AE3-240, or an EP antagonist, ONO-AE3-208, at 10 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 PGE -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 PGE . Furthermore, other prostanoid receptor agonists, PGD , PGF , iloprost, and U-46119, slightly affected IFN-γ-induced nitrite release. These results indicate that PGE potentiates IFN-γ-induced nitric oxide production in microglia through the EP receptor, which may shed light on one of the pro-inflammatory aspects of PGE .
前列腺素E（PGE）通过前列腺素EP受体（一种PGE受体亚型）在调控小胶质细胞激活中发挥关键作用。在本研究中，我们报告PGE增强了小胶质细胞中干扰素-γ（IFN-γ）诱导的一氧化氮生成。IFN-γ增加了一氧化氮的代谢产物亚硝酸盐的释放，PGE可增强这种释放，尽管PGE本身对亚硝酸盐释放的影响较小。PGE的增强作用与诱导型一氧化氮合酶表达增加呈正相关。与IFN-γ诱导的亚硝酸盐释放不同，脂多糖诱导的亚硝酸盐释放不受PGE影响。EP激动剂ONO-AE1-259-01也增强了IFN-γ诱导的亚硝酸盐释放，而EP激动剂ONO-DI-004、EP激动剂ONO-AE-248或EP激动剂ONO-AE1-329则没有。此外，在10 μM浓度下，EP拮抗剂PF-04418948可抑制PGE的增强作用，但EP拮抗剂ONO-8713、EP拮抗剂ONO-AE3-240或EP拮抗剂ONO-AE3-208则不能。在EP激动剂中，仅ONO-AE1-259-01能够积累环磷酸腺苷（cAMP），在EP拮抗剂中，PF-04418948是唯一能够抑制PGE增加的细胞内cAMP积累的药物。另一方面，IFN-γ促进信号转导和转录激活因子1的磷酸化，这不受PGE影响。此外，其他前列腺素受体激动剂，PGD、PGF、伊洛前列素和U-46119，对IFN-γ诱导的亚硝酸盐释放影响较小。这些结果表明，PGE通过EP受体增强小胶质细胞中IFN-γ诱导的一氧化氮生成，这可能揭示了PGE促炎方面的一个机制。
