Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2-) regulatory pathways.

N Janabi; S Chabrier; M Tardieu

摘要

Secretion of the eicosanoids, nitric oxide (NO.) and superoxide anion (O2.-) was evaluated in human embryonic astrocytes and microglia. An inducible form of cyclo-oxygenase (COX 2) was demonstrated in astrocytes and microglia after IL-1 beta plus IFN-gamma stimulation; since 1) large amounts of PGF2 alpha were released; 2) PGF2 alpha secretion required protein synthesis and was blocked by indomethacin; and 3) the response was delayed and persistent. Using the same inducers, astrocytes, but not microglial cells, produced NO. and had an inducible form of nitric oxide synthase. Conversely, microglial cells were induced by IL-1 beta and IFN-gamma to generate superoxide anions (O2.-) through an NADPH oxidase-dependent pathway. We then investigated interactions between these different pathways of synthesis by inhibition experiments. The cytokine-induced production of PGF2 alpha in astrocytes was not affected by exposure to N-omega-monomethyl-L-arginine, which inhibits NO. production, whereas it was reduced by 40% in microglia. Since microglia did not secrete any detectable NO. in their supernatant, intracellular production of NO. could occur in these cells that positively regulated PGF2 alpha production. Exposure to indomethacin, which prevented PGF2 alpha production in both astrocytes and microglia, resulted in a 64% increase in cytokine-induced NO. production by astrocytes and a 70% inhibition of O2.- generation by stimulated microglia. Finally, superoxide dismutase depletion of O2.- in astrocytes and microglia had no effect on PGF2 alpha production in these cells. These results demonstrate that there are important interactions between the pathways of synthesis of inflammatory mediators in glial cells that could unveil additional regulatory mechanisms.

机译：评价了人胚星形胶质细胞和小胶质细胞中类花生酸，一氧化氮（NO）和超氧阴离子（O2-）的分泌。 IL-1β加IFN-γ刺激后，星形胶质细胞和小胶质细胞中出现了一种可诱导形式的环氧合酶（COX 2）。因为1）释放了大量的PGF2α; 2）PGF2α分泌需要蛋白质合成，并被消炎痛阻断。 3）响应被延迟且持续。使用相同的诱导剂，星形胶质细胞而非小胶质细胞产生NO。并具有可诱导形式的一氧化氮合酶。相反，IL-1β和IFN-γ诱导小胶质细胞通过NADPH氧化酶依赖性途径生成超氧阴离子（O2-）。然后，我们通过抑制实验研究了这些不同合成途径之间的相互作用。暴露于抑制NO的N-ω-单甲基-L-精氨酸不会影响星形胶质细胞中细胞因子诱导的PGF2α的产生。生产，而在小胶质细胞中减少了40％。由于小胶质细胞不分泌任何可检测的NO。在其上清液中，细胞内产生NO。可能会在这些细胞中积极调节PGF2α的产生。吲哚美辛的暴露会阻止星形胶质细胞和小胶质细胞中PGF2α的产生，导致细胞因子诱导的NO增加64％。星形胶质细胞产生的毒素产生和刺激的小胶质细胞产生的O2。被抑制70％。最后，星形胶质细胞和小胶质细胞中O2.-的超氧化物歧化酶耗竭对这些细胞中PGF2α的产生没有影响。这些结果表明，在神经胶质细胞中炎症介质合成途径之间存在重要的相互作用，这可能揭示其他调节机制。

Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2-) regulatory pathways.

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