Quinolinic acid is produced by macrophages stimulated by platelet activating factor, Nef and Tat.
Activated macrophages produce quinolinic acid (QUIN), a neurotoxin, in several inflammatory brain diseases including AIDS dementia complex. We hypothesized that IL1-beta, IL6, transforming growth factor (TGF-beta2 and platelet activating factor could increase macrophage QUIN production. And that the HIV-1 proteins Nef, Tat and gp41 may also increase synthesis of QUIN by macrophages. At 72 h there were significant increases in QUIN production in the cells stimulated with PAF (914 +/- 50 nM) and Nef (2781 +/- 162 nM), with somewhat less production by Tat stimulation (645 +/- 240 nM). The increases in QUIN production approximated in vitro concentrations of QUIN shown to be neurotoxic and correlated closely with indoleamine 2,3-dioxygenase induction. IL1-beta, IL6, TGF-beta2 and gp41 stimulation produced no significant increase in QUIN production. These results suggest that some of the neurotoxicity of PAF, nef and tat may be mediated by QUIN.
Smith
D G
DG
Centre for Immunology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
Guillemin
G J
GJ
Pemberton
L
L
Kerr
S
S
Nath
A
A
Smythe
G A
GA
Brew
B J
BJ
D015526:AIDS Dementia Complex / Q000209:etiology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D015693:Gene Products, nef / Q000494:pharmacology*; D015696:Gene Products, tat / Q000494:pharmacology*; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053781:Transforming Growth Factor beta2; D014366:Tryptophan Oxygenase / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D015696:Gene Products, tat; D015700:HIV Envelope Protein gp41; D007375:Interleukin-1; D015850:Interleukin-6; D010972:Platelet Activating Factor; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid