Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: Its possible occurrence in cancer patients

Abstract

Human lungs bearing cancer (n = 27) exhibited up to an ~20-fold [on average ~5-fold (P < 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 γ (IFN-γ) induced the de novo synthesis of IDO dose dependently (10-104 units/ml), and at maximum the activity reached nearly 100 times that in the control lungs described above. Human IFN-α also served as an inducer, but it was two to three orders of magnitude less potent that IFN-γ relative to the antiviral titers, suggesting that IFN-γ 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-γ (10-103 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 than 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.