QUINOLINIC ACID PRODUCTION BY MACROPHAGES STIMULATED WITH IFN-GAMMA, TNF-ALPHA, AND IFN-ALPHA

Quinolinic acid (QUIN) has been associated with several inflammatory n eurologic disorders, including AIDS dementia complex (ADC), Recent stu dies suggest that activation of macrophages with either HIV-1 or inter feron-gamma (IFN-gamma) can lead to QUIN production, However, the impo rtance of other cytokines, especially those related to the macrophage and that are especially important in ADC pathogenesis, remains unclear , We, therefore, sought to determine the role of tumor necrosis factor -alpha (TNF-alpha) and IFN-alpha in the production of QUIN, Primary hu man macrophages were stimulated with two different concentrations of t hese cytokines alone, in combination with each other, and with IFN-gam ma. QUIN concentrations in the supernatants were then measured by mass spectrometry at 24, 48, and 72 hs, Results at 72 h showed significant increases in QUIN production in the cells stimulated with IFN-gamma ( 10297 +/- 170 nmol/L) and also in those stimulated with IFN-alpha (360 0 +/- 113 nmol/L), whereas TNF-alpha-stimulated macrophages produced l ow levels of QUIN (1108 +/- 23 nmol/L), Macrophages stimulated with th e cytokine combinations TNF-alpha and IFN-gamma, IFN-alpha, and IFN-ga mma, and TNF-alpha and IFN-alpha also resulted in increases in QUIN pr oduction (11471 +/- 77.6 nmol/L, 16656 +/- 184 nmol/L, and 3369 +/- 12 0.5 nmol/L, respectively), The increases in QUIN production in all of the cytokine treatments approached or exceeded in vivo concentrations of QUIN that have been shown to be neurotoxic, These data further supp ort a role for QUIN in cytokine-mediated neuronal death in inflammator y disorders of the brain, especially ADC.