Brown R R, Ozaki Y, Datta S P, Borden E C, Sondel P M, Malone D G
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Adv Exp Med Biol. 1991;294:425-35. doi: 10.1007/978-1-4684-5952-4_39.
Tryptophan (Trp) is an indispensable amino acid required for biosynthesis of proteins, serotonin and niacin. Indoleamine 2,3-dioxygenase (IDO) is induced by infections, viruses, lipopolysaccharides, or interferons (IFNs) and this results in significant catabolism of Trp along the kynurenine (Kyn) pathway. Intracellular growth of Toxoplasma gondii and Chlamydia psittaci in human fibroblasts in vitro is inhibited by IFN-gamma and this inhibition is negated by extra Trp in the medium. Similarly, growth of a number of human cell lines in vitro is inhibited by IFN-gamma and addition of extra Trp restores growth. Thus, in some in vitro systems, antiproliferative effects of IFN-gamma are mediated by induced depletion of Trp. We find that cancer patients given Type I or Type II IFNs can induce IDO which results in decreased serum Trp levels (20-50% of pretreatment) and increased urinary metabolites of the Kyn pathway (5 to 500 fold of pretreatment). We speculate that in vivo antineoplastic effects of IFNs and clinical side effects are mediated, at least in part, by a general or localized depletion of Trp. In view of reported increases of IFNs in autoimmune diseases and our earlier findings of elevated urinary Trp metabolites in autoimmune diseases, it seems likely that systemic or local depletion of Trp occurs in autoimmune diseases and may relate to degeneration, wasting and other symptoms in such diseases. We find high levels of IDO in cells isolated from synovia of arthritic joints. IFNs are also elevated in human immunodeficiency virus (HIV) patients and increasing IFN levels are associated with a worsening prognosis. We propose that IDO is induced chronically by HIV infection, is further increased by opportunistic infections, and that this chronic loss of Trp initiates mechanisms responsible for the cachexia, dementia, diarrhea and possibly immunosuppression of AIDS patients. In these symptoms, AIDS resembles classical pellagra due to dietary deficiency of Trp and niacin. In preliminary studies, others report low levels of Trp and serotonin, and elevated levels of Kyn and quinolinic acid in AIDS patients. The implications of these data in cancer, autoimmune diseases and AIDS are discussed.
色氨酸（Trp）是蛋白质、血清素和烟酸生物合成所需的必需氨基酸。吲哚胺2,3-双加氧酶（IDO）可由感染、病毒、脂多糖或干扰素（IFN）诱导产生，这会导致色氨酸沿犬尿氨酸（Kyn）途径大量分解代谢。在体外，γ干扰素可抑制人成纤维细胞中弓形虫和鹦鹉热衣原体的细胞内生长，而培养基中额外添加的色氨酸可消除这种抑制作用。同样，γ干扰素可抑制多种人类细胞系在体外的生长，添加额外的色氨酸可恢复其生长。因此，在某些体外系统中，γ干扰素的抗增殖作用是由诱导色氨酸耗竭介导的。我们发现，接受I型或II型干扰素治疗的癌症患者可诱导IDO产生，这会导致血清色氨酸水平降低（降至治疗前的20 - 50%），犬尿氨酸途径的尿代谢产物增加（增至治疗前的5至500倍）。我们推测，干扰素的体内抗肿瘤作用和临床副作用至少部分是由色氨酸的普遍或局部耗竭介导的。鉴于自身免疫性疾病中干扰素水平升高的报道以及我们早期发现自身免疫性疾病中尿色氨酸代谢产物升高，自身免疫性疾病中似乎可能发生色氨酸的全身或局部耗竭，这可能与这类疾病中的退化、消瘦及其他症状有关。我们发现，从关节炎关节滑膜分离的细胞中IDO水平很高。在人类免疫缺陷病毒（HIV）患者中干扰素水平也会升高，且干扰素水平升高与预后恶化相关。我们提出，HIV感染会长期诱导IDO产生，机会性感染会使其进一步升高，而色氨酸的这种长期缺失会引发导致艾滋病患者恶病质、痴呆、腹泻以及可能的免疫抑制的机制。在这些症状方面，艾滋病类似于因饮食中色氨酸和烟酸缺乏导致的典型糙皮病。在初步研究中，其他人报告艾滋病患者色氨酸和血清素水平较低，犬尿氨酸和喹啉酸水平升高。本文讨论了这些数据在癌症、自身免疫性疾病和艾滋病中的意义。
