Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid.
Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor agonist quinolinic acid (QUIN) occur in human patients and non-human primates with inflammatory diseases. Such increases were postulated to be secondary to induction of indoleamine 2,3-dioxygenase in inflammatory cells, particularly macrophages, by interferon-gamma. To test this hypothesis, human peripheral-blood macrophages were incubated with L-[13C6]tryptophan in the absence or presence of interferon-gamma. [13C6]QUIN was quantified by gas chromatography and electron-capture negative-chemical-ionization mass spectrometry. [13C6]QUIN was detected in the incubation medium of both unstimulated and stimulated cultures. Exposure to interferon-gamma substantially increased the accumulation of [13C6]QUIN in a dose- and time-dependent manner. The QUIN concentrations achieved exceeded those reported in both cerebrospinal fluid and blood of patients and of non-human primates with inflammatory diseases. Macrophages stimulated with interferon-gamma may be an important source of accelerated L-tryptophan conversion into QUIN in inflammatory diseases.
Heyes
M P
MP
Section on Analytical Biochemistry, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892.
Saito
K
K
Markey
S P
SP
D002247:Carbon Isotopes; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000378:metabolism*; D011994:Recombinant Proteins; D014364:Tryptophan / Q000378:metabolism*
D002247:Carbon Isotopes; D011805:Quinolinic Acids; D011994:Recombinant Proteins; D007371:Interferon-gamma; D014364:Tryptophan; D017378:Quinolinic Acid