Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis.
The role of astrocytes in the production of the neurotoxin quinolinic acid (QUIN) and other products of the kynurenine pathway (KP) is controversial. Using cytokine-stimulated human astrocytes, we assayed key enzymes and products of the KP. We found that astrocytes lack kynurenine-hydroxylase so that large amounts of kynurenine (KYN) and kynurenic acid (KYNA) were produced, while minor amounts of QUIN were synthesised that were completely degraded. We then showed that kynurenine added to macrophages led to significant production of QUIN. These results suggest that astrocytes alone are neuroprotective by minimising QUIN production and maximising synthesis of KYNA. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes are neurotoxic by producing large concentrations of KYN that can be metabolised by neighbouring monocytic cells to QUIN.
Centre for Immunology of Neurology and HIV Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia. g.guillemin@cfi.unsw.edu.au
G J
GJ
Guillemin
D G
DG
Smith
S J
SJ
Kerr
G A
GA
Smythe
V
V
Kapoor
P J
PJ
Armati
B J
BJ
Brew
D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005333:Fetus; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008954:Models, Biological; D009498:Neurotoxins; D017378:Quinolinic Acid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D007737:Kynurenine; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017378:Quinolinic Acid; D007736:Kynurenic Acid