CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression.
CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression.
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DOI：
10.1038/mp.2009.116
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发表时间：
2010-04
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
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细胞因子诱导的吲哚胺2，3双加氧酶（IDO）活化将L-色氨酸（TRP）分解代谢成L-犬尿氨酸（KYN），其代谢成喹啉酸（QUIN）和犬尿烯酸（KA）。QUIN和KA具有神经活性，可能导致某些患者在暴露于炎症刺激物（如干扰素（IFN）-α）期间发生行为变化。已经描述了IFN-α治疗期间抑郁症状与外周血TRP、KYN和KA之间的关系。然而，这些IDO catalysts中的外周血变化是否在脑中表现以及它们是否与中枢神经系统细胞因子应答和/或行为相关尚不清楚。因此，在用IFN-α治疗（n=16）或不治疗（n=11）约12周后，在27名丙型肝炎患者的脑脊液（CSF）和血液中测量TRP、KYN、QUIN和KA以及相关细胞因子、趋化因子和可溶性细胞因子受体的CSF浓度。采用蒙哥马利阿斯伯格抑郁评定量表评估抑郁症状。IFN-α显著增加外周血KYN，这伴随着CSF KYN的显著增加。CSF KYN增加反过来与CSF QUIN和KA显著增加相关。尽管外周血TRP显著降低，但IFN-α对CSF TRP浓度无影响。CSF KYN和QUIN升高与CSF IFN-α、可溶性肿瘤坏死因子-α受体2（sTNFR 2）和单核细胞趋化蛋白（MCP）-1升高以及抑郁症状增加相关。总之，IFN-α的外周给药与中枢细胞因子应答一致激活IDO，导致脑KYN、QUIN、KA增加，并最终导致抑郁症状。
Cytokine-induced activation of indoleamine 2,3 dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during IFN-alpha treatment has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ~12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 (sTNFR2) and monocyte chemoattractant protein (MCP)-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN, QUIN, KA, and ultimately depressive symptoms.
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影响因子：
3
作者：
Guillemin, Gilles J.;Meininger, Vincent;Brew, Bruce J.
通讯作者：
Brew, Bruce J.
影响因子：
6.1
作者：
Maes, M;Verkerk, R;Scharpé, S
通讯作者：
Scharpé, S
影响因子：
6.6
作者：
Kohl, C;Walch, T;Sperner-Unterweger, B
通讯作者：
Sperner-Unterweger, B
影响因子：
14.5
作者：
HEYES, MP;SAITO, K;TOURTELLOTTE, WW
通讯作者：
TOURTELLOTTE, WW
影响因子：
9.3
作者：
Guillemin GJ;Wang L;Brew BJ
通讯作者：
Brew BJ