Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells.
Several pieces of evidence suggest a major role for brain macrophages in the overproduction of neuroactive kynurenines, including quinolinic acid, in brain inflammatory conditions. In the present work, the regulation of kynurenine pathway enzymes by interferon-gamma (IFN-gamma) was studied in immortalized murine macrophages (MT2) and microglial (N11) cells. In both cell lines, IFN-gamma induced the expression of indoleamine 2,3-dioxygenase (IDO) activity. Whereas tumor necrosis factor-alpha did not affect enzyme induction by IFN-gamma, lipopolysaccharide modulated IDO activity differently in the two IFN-gamma-activated cell lines, causing a reduction of IDO expression in MT2 cells and an enhancement of IDO activity in N11 cells. Kynurenine aminotransferase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilic acid dioxygenase appeared to be constitutively expressed in both cell lines. Kynurenine 3-hydroxylase activity was stimulated by IFN-gamma. It was notable that basal kynureninase activity was much higher in MT2 macrophages than in N11 microglial cells. In addition, IFN-gamma markedly stimulated the activity of this enzyme only in MT2 cells. IFN-gamma-treated MT2 cells, but not N11 cells, were able to produce detectable amounts of radiolabeled 3-hydroxyanthranilic and quinolinic acids from L-[5-3H] tryptophan. These results support the notion that activated invading macrophages may constitute one of the major sources of cerebral quinolinic acid during inflammation.
Alberati-Giani
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Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Ricciardi-Castagnoli
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Köhler
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Cesura
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D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D000818:Animals; D002999:Clone Cells; D049308:Dioxygenases; D004790:Enzyme Induction; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008190:Lyases; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D049308:Dioxygenases; D014366:Tryptophan Oxygenase; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D006867:Hydrolases; C021480:kynureninase; D008190:Lyases