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

ABSTRACT

We studied the regulation of the kynurenine pathway of tryptophan metabolism in human monocyte-derived macrophages (MDM) with the aim of evaluating macrophage involvement in inflammatory neurological disorders. Cultured MDM metabolized tryptophan and released kynurenine metabolites, including the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) or the pro-inflammatory cytokines INFgamma and TNFalpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release of QUIN. The incubation media of INFgamma-exposed MDM caused neuronal death in primary cultures of mixed cortical cells. Glutamate receptor antagonists or poly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuroinflammatory disorders.