4-CHLORO-3-HYDROXYANTHRANILATE, 6-CHLOROTRYPTOPHAN AND NORHARMANE ATTENUATE QUINOLINIC ACID FORMATION BY INTERFERON-GAMMA-STIMULATED MONOCYTES (THP-1 CELLS)

Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined reponded to interferon-gamma by increased conversion of L-[C-13(6)]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [C-13(6)]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 muM, 58 muM and 0.11 muM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 muM and 51 muM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.