INTERFERON ENHANCES TRYPTOPHAN-METABOLISM BY INDUCING PULMONARY INDOLEAMINE 2,3-DIOXYGENASE - ITS POSSIBLE OCCURRENCE IN CANCER-PATIENTS
INTERFERON ENHANCES TRYPTOPHAN-METABOLISM BY INDUCING PULMONARY INDOLEAMINE 2,3-DIOXYGENASE - ITS POSSIBLE OCCURRENCE IN CANCER-PATIENTS
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DOI：
10.1073/pnas.83.17.6622
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发表时间：
1986-09-01
影响因子：
11.1
通讯作者：
HAYAISHI, O
中科院分区：
文献类型：
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作者：
YASUI, H;TAKAI, K;HAYAISHI, O
携带癌症的人肺（n = 27）表现出高达约100 μ g/ml的细胞毒性。20-倍[平均约5-倍（P < 0.005）]的酶活性增加，所述酶活性降解色氨酸以形成甲酰犬尿氨酸，与作为对照的具有良性病变（水泡）的肺（n = 7）相比。根据分子和动力学性质，该活性归因于吲哚胺2，3-双加氧酶（IDO）[吲哚胺：氧2，3-氧化还原酶（脱环）]。用人肺切片进行的体外研究表明，人干扰素γ（IFN-γ）诱导IDO的剂量依赖性从头合成（10-104单位/ml），并且最大活性达到上述对照肺中的近100倍。人IFN-α也用作诱导剂，但其效力比IFN-γ低2 - 3个数量级。相对于抗病毒滴度，表明IFN-γ。是IDO诱导的主要中介体。因此，在切片中原位诱导IDO强烈代谢色氨酸：在用不同剂量的IFN-γ预处理的肺切片孵育24小时后，（10-103单位/ml）时，切片中高达96%的色氨酸被耗尽，培养基中高达70%的色氨酸被转化，主要转化为甲酰犬尿氨酸、犬尿氨酸或两者。上述结果表明，IFN介导的IDO诱导也作为对癌症的应答在人肺中体内发生，导致代谢后果，如色氨酸的耗尽和（甲酰基）犬尿氨酸的积累，这可以提供独特的宿主防御机制。
Human lungs bearing cancer (n = 27) exhibited up to an .apprxeq. 20-fold [on average .apprxeq. 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 .gamma. (IFN-.gamma.) 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-.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. (10-103 units/ml), up to 96% of the typtophan 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.