Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages

We studied the regulation of the kynurenine pathway of tryptophan metabolis m in human monocyte-derived macrophages(MDM) with the aim of evaluating mac rophage involvement in inflammatory neurological disorders. Cultured NDM metabolized tryptophan and released kynurenine metabolites, in cluding the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) o r the pro-inflammatory cytokines INIF gamma and TNF alpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release o f QUIN. The incubation media of INF gamma -exposed MDM caused neuronal death in pri mary cultures of mixed cortical cells. Glutamate receptor antagonists or po ly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuro inflammatory disorders. (C) 2001 Published by Elsevier Science B.V.