Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages.
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.
Chiarugi
A
A
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Calvani
M
M
Meli
E
E
Traggiai
E
E
Moroni
F
F
D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured / Q000201:enzymology / Q000276:immunology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004660:Encephalitis / Q000201:enzymology / Q000276:immunology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D009474:Neurons / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D009498:Neurotoxins / Q000276:immunology / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D009498:Neurotoxins; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006867:Hydrolases; C021480:kynureninase; D017378:Quinolinic Acid