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.
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.
Janabi
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Laboratory of Virus, Neuron, and Immunity, UFR Kremlin, University of Paris-South, France.
Chabrier
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S
Tardieu
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M
D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D015237:Dinoprost / Q000096:biosynthesis* / Q000494:pharmacology; D004347:Drug Interactions; D015777:Eicosanoids / Q000494:pharmacology*; D004622:Embryo, Mammalian; D006801:Humans; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D013481:Superoxides / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000494:pharmacology
D015777:Eicosanoids; D013481:Superoxides; D009569:Nitric Oxide; D013929:Thromboxane B2; D015237:Dinoprost