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 ()DO) [indoleamine:oxygen 2,3-oxidoreductase (decyclizing)]. In vitro studies with human lung slices revealed that human interferon y (IFN-y) induced the de novo synthesis of I1DO dose dependently (10-104 units/ml), and at maximum the activity reached nearly 100 times that in the control lungs described above. Human IFN-a also served as an inducer, but it was two to three orders of magnitude less potent than IFN-yrelative to the antiviral titers, suggesting that IFN-y is the main mediator of the 1DO induction. 1DO thus induced in slices avidly metabolized tryptophan in situ: Upon a 24-hr incubation of lung slices pretreated with varied doses of IFN-y (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 that an IFN-mediated induction of 1DO 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.Increased urinary excretion of tryptophan metabolites of the kynurenine pathway has been described for patients with various diseases, including malignant neoplasms and infectious diseases (reviewed in ref. 1). This observation was accounted for by the depressed catabolism of these metabolites (1) and later explained by the glucocorticoid-mediated induction of hepatic tryptophan 2,3-dioxygenase [TDO; Ltryptophan:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.11], known at that time as the sole enzyme that catalyzes the first step of the kynurenine pathway (2). Subsequently another enzyme capable of converting tryptophan to formylkynurenine, indoleamine 2,3-dioxygenase [IDO; indoleamine:oxygen 2,3-oxidoreductase (decyclizing)] was identified (3). In contrast with TDO, which is found exclusively in liver, IDO was ubiquitously distributed in extrahepatic organs of mammals (4,5). In mice IDO in many organs, but not TDO in the liver, was markedly induced in vivo upon influenza virus infection (6) or administration of bacterial endotoxin (7). An in vitro system with mouse lung slices was then established in which bacterial endotoxin induced IDO, and murine interferon-a/,3 (IFN-a/,8) was found to replace the endotoxin (8). Human IFN-y reportedly induced an activity similar to that of IDO in cultured human fibroblasts (9). Thus the induction of IDO, rather than TDO, appeared to be closely related to pathological conditions and host defense mechanisms. In this context, it was of interest to assess the IDO activity in patients. with cancer...

Impairment of Lipid Metabolism Due to Deficiency of Pyridoxal-5-phosphate and/or Activated Immune system: its Interpretation

“…IllNo. 4 induced by viruses, bacterial exotoxins and interferona (24,54). It is mentioned, that IDO takes part in the elevated kynurenine formation in pathological as well as in host defence mechanisms (54).…”

Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer

“…Essentially, IDO has been associated to peripheral tolerance and maternal tolerance towards the fetus. 2 Initial work of Musajo and Benassi 3 demonstrating increased urinary excretion of tryptophan metabolites of the kynurenine pathway in cancer patients followed by seminal work of Yasui et al 4 showing interferon γ (IFNγ)-mediated induction of IDO in lung cancer, paved the way for the more recent identification of increased expression of IDO by tumor cells 5 as well as for the attempts to clarify its possible role in tumor immune escape. 6 Mounting evidence indicates that, within the tumor microenvironment, not only tumor cells but also some subsets of tumor infiltrating cells, such as lymphocytes, dendritic cells and monocytes, can be sources of IDO.…”

Interaction Between Inflammatory State and Neurochemical Changes in Major Psychiatric Disorders

“…However, KYNA is the NMDA-R antagonist (Perkins and Stone, 1982) and is protective against excitotoxicity of QUIN ( Kim and Choi, 1987). Therefore, the pro-inflammatory status in major depression would activate not only IDO (Carlin et al, 1987;Yasui et al, 1986) but also KMO enzyme activities (Mellor and Munn, 1999) and this might in turn shift the KYN metabolism to the 3HK and QUIN arm with possible reduction in KYNA (Figure-2). The changes in NMDA-R agonist and antagonist, QUIN and KYNA might have impact on glutamatergic neurotransmission.…”

“…The investigators reported the increased tryptophan and kynurenine in the brain of schizophrenia without evidence of generalized deficit in serotonin (Jospeh et al, 1979). After the discovery of the effect of pro-inflammatory cytokines on IDO enzyme activity (Carlin et al, 1987;Yasui et al, 1986) and the interaction between glucocorticoids and TDO activity (Knox, 1951;Nakamura et al, 1987;Salter and Pogson, 1985), the link between inflammatory state, tryptophan metabolism and serotonergic neurotransmission became of interest in the field of psychoneuroimmunology. Somehow, the report of a study on QUIN and kynurenine pathway metabolism in different inflammatory and non-inflammatory neurological diseases brought this field forward although it failed to show the significant association between metabolites in the CSF and psychiatric disorder such as depression (Heyes et al, 1992).…”

“…In this case, tryptophan breakdown through KYN pathway occurs mainly in the blood and lymphoid tissues (Moffett and Namboodiri, 2003). The IDO activity is enhanced by pro-inflammatory cytokines such as interferon- (IFN) (Carlin et al, 1987;Yasui et al, 1986), and inhibited by the anti-inflammatory cytokine IL4 (Musso et al, 1994). As discussed above, in case of stress or related conditions, such as inflammation, HPA axis activity will be enhanced and glococorticoid secretion is increased.…”