Nitric oxide production and neurotoxicity mediated by activated microglia from human versus mouse brain.
Recent studies indicate that human macrophages lack a high-output inducible nitric oxide synthase (NOS) antimicrobial system. In the present study, microglial cells derived from fetal human versus neonatal mouse brain were compared in a coculture assay of human and murine neuronal cell injury. Neurotoxicity (reflected by lactate dehydrogenase release and impaired neuronal uptake of [3H] gamma-amino butyric acid) and nitric oxide (NO) production (assessed by measurement of nitrite) were observed only in cocultures containing interferon (IFN)-gamma-lipopolysaccharide (LPS)-stimulated murine microglia. Cultures of purified human fetal microglia, however, did produce low levels of NO upon stimulation with IFN-gamma-LPS. These findings support the proposal that human macrophages have an inefficient IFN-gamma-inducible NOS and suggest that in tissues, such as brain, this deficiency could be advantageous for neighboring cells.
Dept. of Medicine, Hennepin County Medical Center, Minneapolis, MN 55415.
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Peterson
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Anderson
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Chao
D000368:Aged; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D019323:omega-N-Methylarginine
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D007371:Interferon-gamma; D001120:Arginine; D007770:L-Lactate Dehydrogenase