Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.
Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.
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DOI：
10.1038/srep29920
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发表时间：
2016-07-20
影响因子：
4.6
通讯作者：
Saito K
中科院分区：
文献类型：
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作者：
Murakami Y;Ishibashi T;Tomita E;Imamura Y;Tashiro T;Watcharanurak K;Nishikawa M;Takahashi Y;Takakura Y;Mitani S;Fujigaki H;Ohta Y;Kubo H;Mamiya T;Nabeshima T;Kim HC;Yamamoto Y;Saito K
已知接受干扰素（IFN）-α治疗的慢性丙型肝炎病毒（HCV）患者经常发生抑郁症。在这项研究中，我们研究了吲哚胺2，3-双加氧酶1（IDO 1）介导的色氨酸（TRP）代谢是否在IFN-α治疗的副作用抑郁症中起关键作用。治疗后，抑郁症HCV患者血清犬尿氨酸（KYN）和3-羟基犬尿氨酸（3-HK）浓度以及KYN/TRP和3-HK/犬尿氨酸（KA）比值的升高幅度远大于非抑郁症患者。此外，将持续表达鼠IFN-γ的质粒转染到正常小鼠中显著增加了抑郁样行为。IFN-γ基因转移还导致小鼠血清TRP水平降低，而血清和额叶皮质中KYN和3-HK水平显著升高。在小鼠中IDO 1的基因缺失消除了抑郁样行为的增加和TRP代谢物水平的升高，以及IFN-γ基因转移后额叶皮质中5-羟色胺的周转。这些结果表明IDO 1介导的TRP代谢的KYN途径在与IFN-α治疗相关的抑郁症状中起关键作用。
Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites’ levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.