A MECHANISM FOR INCREASED QUINOLINIC ACID FORMATION FOLLOWING ACUTE SYSTEMIC IMMUNE STIMULATION

Mechanisms for increased levels of quinolinic acid (QUIN) following sy stemic immune stimulation were investigated. In gerbils, systemic admi nistration of pokeweed mitogen (PWM) increased plasma and cerebrospina l fluid QUIN levels, while plasma kynurenic acid levels were decreased and cerebrospinal fluid kynurenic acid levels were unchanged. PWM als o increased the QUIN concentrations of brain and systemic tissues. In slices of spleen, lung, liver, duodenum, and kidney, PWM caused marked increases in [C-13(6)]QUIN formation from L-[C-13(6)]tryptophan (but not from [C-13(6)anthranilic acid). PWM also increased QUIN excretion in the urine and enhanced the formation and excretion of [C-13(6)]QUIN following an intraperitoneal injection Of L-[C-13(6)]tryptophan. Indo leamine-2,3-dioxygenase activity was increased in the brain, kidney, l ung, spleen, and duodenum while hepatic L-tryptophan-2,3-dioxygenase a ctivity was reduced, data consistent with in vitro L-kynurenine format ion from L-tryptophan. Kynurenine-3-hydroxylase activity was increased in the duodenum, lung, and spleen, but not in the brain, kidney, or l iver. Kynureninase activity was increased in the brain, lung, and duod enum, but not in the spleen, kidney, or liver. 3-Hydroxyanthranilate-3 ,4-dioxygenase activity was unchanged in the brain, lung, and liver. N o change in kynurenine aminotransferase activity was observed in the b rain or lung, while liver kynurenine aminotransferase activity was red uced. We conclude that increased activities of kynurenine pathway enzy mes in various tissues following systemic immune stimulation, in conju nction with macrophage infiltration of the affected tissue, provide a mechanism to account for increased concentrations of QUIN.