Regulation of the Kynurenine Metabolic Pathway by Interferon‐γ in Murine Cloned Macrophages and Microglial Cells

Abstract

Abstract: 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‐γ (IFN‐γ) was studied in immortalized murine macrophages (MT2) and microglial (N11) cells. In both cell lines, IFN‐γ induced the expression of indoleamine 2,3‐dioxygenase (IDO) activity. Whereas tumor necrosis factor‐α did not affect enzyme induction by IFN‐γ, lipopolysaccharide modulated IDO activity differently in the two IFN‐γ‐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‐γ. It was notable that basal kynureninase activity was much higher in MT2 macrophages than in N11 microglial cells. In addition, IFN‐γ markedly stimulated the activity of this enzyme only in MT2 cells. IFN‐γ‐treated MT2 cells, but not N11 cells, were able to produce detectable amounts of radiolabeled 3‐hydroxyanthranilic acid quinolinic acids from l‐[5‐3 H]tryptophan. These results support the notion that activated invading macrophages may constitute one of the major sources of cerebral quinolinic acid during inflammation.