Strasser Barbara, Becker Kathrin, Fuchs Dietmar, Gostner Johanna M
Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Austria.
Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Austria.
Neuropharmacology. 2017 Jan;112(Pt B):286-296. doi: 10.1016/j.neuropharm.2016.02.030. Epub 2016 Feb 26.
Immune activation is inextricably linked with dysregulation of the tryptophan metabolism, shifting catabolic routes towards oxidative breakdown along the kynurenine axis. Several enzymes are able to metabolize tryptophan, but activity of inducible indoleamine 2,3-dioxygenase (IDO-1) plays a major role under pro-inflammatory, interferon-γ (IFN-γ) dominated settings. Accelerated breakdown of tryptophan into kynurenine, dysregulation of further downstream metabolism and impaired enzymatic activities due to the absence of oxidation sensitive cofactors are associated with a broad variety of primary disorders and co-morbidities. Deprivation of the essential amino acid tryptophan suppresses growth of pathogens or tumor cells but also restricts T cell proliferation, which favors immunosuppression. In addition, diminished levels of tryptophan lead to lower synthesis of neurotransmitter serotonin, this being probably the most important biochemical cause of psychiatric co-morbidities associated with a broad variety of chronic inflammatory disorders. Also other frequent co-occurring symptoms and conditions such as anemia or cachexia may be at least partially caused by the lowered levels of the essential growth factor tryptophan. Tissue and cell specific expression of kynurenine downstream processing enzymes and their defective regulation may contribute to symptom diversification. Several kynurenine downstream metabolites show potent bioactivities, thus leading to the defects in a variety of affected target pathways. Measuring peripheral tryptophan breakdown, which is usually done by estimating the kynurenine to tryptophan ratio, in parallel to determination of other immune activation markers to confirm the involvement of IDO-1 activity in deregulated breakdown, is a reliable tool to monitor status and progression of a variety of disorders and has great potential to be applied to monitor treatments and to predict e.g. the necessity of psychiatric interventions before aggravation of symptoms, thus in helping to personalize therapeutic strategies. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
免疫激活与色氨酸代谢失调密切相关，导致分解代谢途径沿犬尿氨酸轴转向氧化分解。几种酶能够代谢色氨酸，但在促炎、以干扰素-γ（IFN-γ）为主导的环境中，诱导型吲哚胺2,3-双加氧酶（IDO-1）的活性起主要作用。色氨酸加速分解为犬尿氨酸、下游进一步代谢的失调以及由于缺乏氧化敏感辅因子导致的酶活性受损与多种原发性疾病和合并症相关。必需氨基酸色氨酸的缺乏会抑制病原体或肿瘤细胞的生长，但也会限制T细胞增殖，这有利于免疫抑制。此外，色氨酸水平降低会导致神经递质血清素的合成减少，这可能是与多种慢性炎症性疾病相关的精神合并症的最重要生化原因。其他常见的并发症状和病症，如贫血或恶病质，可能至少部分是由必需生长因子色氨酸水平降低引起的。犬尿氨酸下游加工酶的组织和细胞特异性表达及其调节缺陷可能导致症状多样化。几种犬尿氨酸下游代谢产物具有强大的生物活性，从而导致多种受影响的靶途径出现缺陷。测量外周色氨酸分解（通常通过估计犬尿氨酸与色氨酸的比率来进行），同时测定其他免疫激活标志物以确认IDO-1活性参与失调的分解，是监测多种疾病状态和进展的可靠工具，并且在监测治疗以及预测例如症状加重前精神干预的必要性方面具有巨大潜力，从而有助于实现治疗策略的个性化。本文是名为“健康与疾病中的犬尿氨酸途径”特刊的一部分。
