Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.
Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.
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DOI：
10.1007/s00702-010-0475-7
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发表时间：
2011-01
影响因子：
3.3
通讯作者：
Oxenkrug, Gregory F.
中科院分区：
文献类型：
--
作者：
Oxenkrug, Gregory F.
关键词：
这篇文献综述和我们的数据表明，外周和大脑中干扰素-γ（IFNG）的上调产生触发色氨酸（TRY）-犬尿氨酸（KYN）和鸟嘌呤-四氢生物蝶呤（BH 4）代谢途径合并为衰老和衰老相关医学和精神疾病（AAPD）（代谢综合征、抑郁症、血管性认知障碍）相关的炎症级联反应。IFNG诱导的KYN/蝶啶类炎症级联反应的特征在于一氧化氮合酶（NOS）活性的上调（由KYN诱导）和NOS辅因子BH 4的形成减少，这导致NOS解偶联，将精氨酸从NO转移到超氧阴离子产生。KYN衍生物中的超氧阴离子和自由基引发与AAPD相关的磷脂酶A2-花生四烯酸级联反应。IFNG诱导的吲哚胺2，3-双加氧酶（IDO）（TRY-KYN途径的限速酶）的上调降低TRY转化为血清素（抗抑郁作用的底物），并增加与糖尿病[黄尿酸（XA）]、焦虑（KYN）、精神病和认知障碍（犬尿烯酸）相关的KYN的产生。IFNG诱导的KYN/蝶啶类炎症级联反应受编码细胞因子产生的IFNG（+874）T/A基因型的影响。除了关于KYN/TRY比率（IDO活性指数）的文献数据之外，我们观察到新蝶呤水平（鸟嘌呤-BH 4途径的限速酶的活性指数）在高（T）生产者等位基因的携带者中高于低（A）生产者等位基因的携带者;并且与AAPD标记（例如，胰岛素抵抗、体重指数、死亡风险），并与丙型肝炎患者IFN-α诱导的抑郁症相关。IFNG诱导型级联受环境因素影响（例如，维生素B6缺乏会增加XA形成）和药理学试剂;并可能提供抗衰老和抗AMPD干预的新方法。
This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)–kynurenine (KYN) and guanine–tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY–KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine–BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.
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DOI：
10.1097/00042192-200107000-00008
发表时间：
2001-07-01
影响因子：
2.7
作者：
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影响因子：
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