Interleukin-1β: A New Regulator of the Kynurenine Pathway Affecting Human Hippocampal Neurogenesis
Interleukin-1β: A New Regulator of the Kynurenine Pathway Affecting Human Hippocampal Neurogenesis
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DOI：
10.1038/npp.2011.277
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发表时间：
2012-03
影响因子：
7.6
通讯作者：
P. Zunszain;C. Anacker;A. Cattaneo;S. Choudhury;K. Musaelyan;A. Myint;S. Thuret;J. Price;C. Pariante
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文献类型：
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作者：
P. Zunszain;C. Anacker;A. Cattaneo;S. Choudhury;K. Musaelyan;A. Myint;S. Thuret;J. Price;C. Pariante
炎症增加和神经发生减少与抑郁症的病理生理学有关。在这里，我们第一次展示了IL-1β，一种在抑郁症患者中增加的促炎细胞因子，如何减少人类海马祖细胞的神经发生。IL-1β对神经发生有害，如双皮质素阳性神经母细胞（− 28%）和成熟微管相关蛋白2阳性神经元（− 36%）数量减少所示。对调节犬尿氨酸途径的酶的分析显示，IL-1β诱导吲哚胺-2，3-双加氧酶（IDO）、犬尿氨酸3-单加氧酶（KMO）和犬尿氨酸酶（在分化条件下分别增加42、12和30倍）的转录物上调，这些酶参与犬尿氨酸途径的神经毒性臂。此外，用IL-1β处理导致犬尿氨酸（IDO诱导的色氨酸代谢的分解代谢产物）增加。有趣的是，与KMO抑制剂Ro 61-8048共同治疗逆转了IL-1β对神经发生的不利影响。这些观察结果表明，IL-1β在调节神经发生方面具有关键作用，同时影响色氨酸的可用性和有助于有毒代谢物的酶的产生。我们的研究结果表明，抑制犬尿氨酸通路可能提供一种新的治疗方法来逆转炎症诱导的神经发生减少。
Increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. Here, we show for the first time how IL-1β, a pro-inflammatory cytokine shown to be increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. IL-1β was detrimental to neurogenesis, as shown by a decrease in the number of doublecortin-positive neuroblasts (− 28%), and mature, microtubule-associated protein-2-positive neurons (− 36%). Analysis of the enzymes that regulate the kynurenine pathway showed that IL-1β induced an upregulation of transcripts for indolamine-2, 3-dioxygenase (IDO), kynurenine 3-monooxygenase (KMO), and kynureninase (42-, 12-and 30-fold increase, respectively, under differentiating conditions), the enzymes involved in the neurotoxic arm of the kynurenine pathway. Moreover, treatment with IL-1β resulted in an increase in kynurenine, the catabolic product of IDO-induced tryptophan metabolism. Interestingly, co-treatment with the KMO inhibitor Ro 61-8048 reversed the detrimental effects of IL-1β on neurogenesis. These observations indicate that IL-1β has a critical role in regulating neurogenesis whereas affecting the availability of tryptophan and the production of enzymes conducive to toxic metabolites. Our results suggest that inhibition of the kynurenine pathway may provide a new therapy to revert inflammatory-induced reduction in neurogenesis.