INDUCTION OF PTERIN SYNTHESIS IS NOT REQUIRED FOR CYTOKINE-STIMULATEDTRYPTOPHAN-METABOLISM

Activation of the immune system which occurs in inflammatory diseases leads to parallel increases in pterin synthesis and increased producti on of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxy lation reactions, could be required in the oxidative kynurenine pathwa y Of L-tryptophan degradation. Treatment of mice with interferon-gamma increased L-tryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of pterin synthesis. Whe n pterin synthesis de novo was blocked, either by an inhibitor of GTP cyclohydrolase or because of a genetic deficiency of one of the enzyme s of the pathway of pterin biosynthesis, cytokine-stimulated increases in tryptophan metabolism were unaffected. Furthermore, increasing int racellular tetrahydrobiopterin concentrations by treating cells with s epiapterin also had no effect on markers of tryptophan metabolism. The refore, both normal and cytokine-stimulated L-tryptophan metabolism ap pears to be completely independent of pterin biosynthesis.