Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients.
Human lungs bearing cancer (n = 27) exhibited up to an approximately 20-fold [on average approximately 5-fold (P less than 0.005)] increase in the enzyme activity that degrades tryptophan to form formylkynurenine, in comparison with lungs with benign lesions (blebs) (n = 7) taken as controls. On the basis of molecular and kinetic properties, this activity was ascribed to indoleamine 2,3-dioxygenase (IDO) [indoleamine:oxygen 2,3-oxidoreductase (decyclizing)]. In vitro studies with human lung slices revealed that human interferon gamma (IFN-gamma) induced the de novo synthesis of IDO dose dependently (10-10(4) units/ml), and at maximum the activity reached nearly 100 times that in the control lungs described above. Human IFN-alpha also served as an inducer, but it was two to three orders of magnitude less potent than IFN-gamma relative to the antiviral titers, suggesting that IFN-gamma is the main mediator of the IDO induction. IDO thus induced in slices avidly metabolized tryptophan in situ: Upon a 24-hr incubation of lung slices pretreated with varied doses of IFN-gamma (10-10(3) units/ml), up to 96% of the tryptophan in the slices was depleted and up to 70% of the tryptophan in the medium was converted, mainly to formylkynurenine, kynurenine, or both. The foregoing results suggest that an IFN-mediated induction of IDO also takes place in vivo in human lungs as a response to cancer, leading to metabolic consequences such as depletion of tryptophan and accumulation of (formyl)kynurenine, which may provide a unique host defense mechanism.
D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007372:Interferons / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000201:enzymology; D010105:Oxygenases / Q000096:biosynthesis*; D011030:Pneumothorax / Q000201:enzymology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D003609:Dactinomycin; D014364:Tryptophan; D007372:Interferons; D003513:Cycloheximide; D010105:Oxygenases; D014366:Tryptophan Oxygenase