Expression of the kynurenine pathway enzymes in human microglia and macrophages.
There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN) play a role in the pathogenesis of neurological diseases. Monocytic cells are known to be the major producers of QUIN. However, macrophages have the ability to produce approximately 20 to 30-fold more QUIN than microglia. The molecular origin of this difference has not been clarified yet. Using unstimulated and IFN-gamma-stimulated cultures of human fcetal microglia and adult macrophages, we assayed mRNA expression of 8 key enzymes of the KP using RT-PCR and QUIN production using GC-MS. We found that after stimulation with IFN-gamma microglia produced de novo 20-fold less QUIN than macrophages. This quantitative difference in the ability to produce QUIN appears to be associated with a lower expression of 3 important enzymes of the KP in microglia: indoleamine 2,3-dioxygenase (IDO), kynureninase (KYNase) and kynurenine hydroxylase (KYN(OH)ase). These results suggest that activated infiltrating macrophages are the most potent QUIN producers during brain inflammatory diseases with playing a lesser role.
Guillemin
Gilles J
GJ
Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
Smith
Danielle G
DG
Smythe
George A
GA
Armati
Patricia J
PJ
Brew
Bruce J
BJ
D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007737:Kynurenine / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017378:Quinolinic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D000637:Transaminases / Q000235:genetics
D012333:RNA, Messenger; D011994:Recombinant Proteins; D007737:Kynurenine; D007371:Interferon-gamma; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D017378:Quinolinic Acid