Primary murine microglia are resistant to nitric oxide inhibition of indoleamine 2,3-dioxygenase.
Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that is activated by proinflammatory cytokines, including interferon-γ (IFNγ), and metabolizes tryptophan along the kynurenine pathway. Activation of murine macrophages induces not only IDO but also nitric oxide synthase (iNOS), and the ensuing production of nitric oxide (NO) inhibits IDO. To determine the sensitivity of primary cultures of murine microglia to NO, microglia were stimulated with recombinant murine IFNγ (1 ng/ml) and lipopolysaccharide (LPS) (10 ng/ml). This combination of IFNγ+LPS synergized to produce maximal amounts of nitrite as early as 16h. Steady-state mRNAs for both iNOS and IDO were significantly increased by IFNγ+LPS at 4h post-treatment, followed by an increase in IDO enzymatic activity at 24h. Murine microglia (>95% CD11b(+)) were pretreated with the iNOS inhibitor, L-NIL hydrochloride, at a dose (30 μM) that completely abrogated production of nitrite. L-NIL had no effect on IDO mRNA at 4h or IDO enzymatic activity at 24h following stimulation with IFNγ+LPS. These data establish that IDO regulation in murine microglia is not restrained by NO, thereby permitting the accumulation of kynurenine and its downstream metabolites in the central nervous system.
Wang
Yunxia
Y
Integrative Immunology and Behavior Program, Department of Animal Sciences, 227 Edward R Madigan Laboratory, College of ACES, 1201 W Gregory Drive, University of Illinois at Urbana-Champaign, Urbana, IL 61801-3873, USA. crazyfishing08@hotmail.com
Lawson
Marcus A
MA
Kelley
Keith W
KW
Dantzer
Robert
R
D000818:Animals; D002478:Cells, Cultured; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D007737:Kynurenine / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology*; D009569:Nitric Oxide / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D009573:Nitrites; D009569:Nitric Oxide; D007737:Kynurenine; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II
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