Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease
Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease
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DOI：
10.1177/1756284819881304
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Urbanska, Ewa M.
中科院分区：
文献类型：
--
作者：
Dudzinska, Ewa;Szymona, Kinga;Urbanska, Ewa M.
背景：遗传缺陷与环境因素的复杂相互作用似乎在炎症性肠病(IBD)的发病机制中起着重要作用。越来越多的数据暗示了色氨酸代谢紊乱在IBD中的潜在作用。犬尿酸(KYNA)是色氨酸(Trp)沿着犬尿氨酸(KYN)途径的衍生物，具有细胞保护和免疫调节的特性，而3-OH-KYN是一种细胞毒性化合物，能产生自由基。方法：检测55例IBD患者(溃疡性结肠炎(UC)27例，克罗恩病(CD)28例)缓解期和复发期淋巴细胞KYNA合成酶基因(Kat I-III)的表达和血清Trp及其代谢产物水平，并与50例正常对照进行比较。结果：KAT1和KAT3mRNA的表达增加是UC和CD患者以及复发-缓解亚群的全部特征。溃疡性结肠炎和缓解期CD患者KAT2基因表达增强。在UC或CD的整个队列中，Trp水平较低，而KYN、KYNA和3-OH-KYN没有变化。当分析UC和CD(活动期缓解)患者的亚组时，缓解期的KYNA水平显著低于复发期，但与对照组相比没有显著差异。在功能上，UC或CD患者的Trp/Kyn比值低于对照组，而Kyn/KYNA和KYNA/3-OH-Kyn的比值没有改变。在所有CD患者中，KYN/3-OH-KYN的比率增加了近两倍；此外，CD复发患者的KYNA/3-OH-KYN比率显著高于缓解期患者。结论：IBD与淋巴细胞中编码KYNA生物合成酶的基因表达增强有关；然而，其他机制似乎影响KYNA水平。IBD患者血清色氨酸代谢转化率较高，病情加重时KYN通路功能向产生KYNA的臂转移。我们认为，KYNA可能通过与芳烃受体或G蛋白偶联孤儿受体35相互作用，作为一种反调节机制，减少IBD的细胞毒性和炎症。进一步的纵向研究评估IBD患者中Trp和Kyn通路的个体动力学，以及调节KYNA合成的精确机制的性质，应该有助于更好地理解所观察到的变化背后的过程。
Background: Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals. Methods: The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I-III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn's disease (CD)] and in 50 control individuals. Results: The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse-remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase-remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission. Conclusion: The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.