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-γ. To test this hypothesis human peripheral-blood macrophages were incubated with L-[¹³C₆] tryptophan in the absence or presence of interferon-γ. [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-γ 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-γ may be an important source of accelerated L-tryptophan conversion into QUIN in inflammatory diseases.