Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
Brain Behav Immun. 2012 Aug;26(6):979-87. doi: 10.1016/j.bbi.2012.05.010. Epub 2012 Jun 6.
The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme indolamine 2,3-dioxygenase (IDO) have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, and has been suggested as the link between inflammation and a serotonergic deficit in depression. Studies also indicate that inflammatory cytokines upregulate the serotonin transporter (SERT), representing another mechanism by which inflammation could influence serotonin availability. Here we examined circulating concentrations of inflammatory cytokines (IFN-γ, TNF-α, IL-1β, IL-6), and the acute phase protein CRP alongside plasma tryptophan, kynurenine, kynurenic acid (KYNA) and 3-hydroxyanthranilic acid (3-HAA) concentrations, and whole blood mRNA expression of IDO, kynurenine aminotransferases (KAT I and II), kynurenine-3-monooxygenase (KMO), kynureninase and SERT in patients with major depressive disorder (MDD) compared with age and sex-matched controls. Whilst no changes in TNF-α or IL-1β were observed, plasma concentrations of IL-6, IFN-γ and CRP were increased in the depressed cohort. Despite this inflammatory phenotype, IDO expression or plasma kynurenine were not significantly different between MDD patients and controls. In addition, there was no difference between controls and depressives in concentrations of KYNA and 3-HAA, or in expression of enzymes KAT, KMO or kynureninase that drive their production. Nonetheless, a depletion in tryptophan was evident in depressed patients and was correlated with HAM-D scores. In addition, we failed to observe any difference in SERT mRNA expression in the blood cells from patients with MDD relative to controls. These data support the idea that a mild inflammatory signature is evident in MDD and is accompanied by reduced circulating tryptophan concentrations. However, we found no indication of KP activation in the depressed cohort suggesting that an alternative mechanism mediates the depletion of tryptophan observed. Taken together these data question the ability of the mild inflammatory phenotype observed in depression to induce molecules such as IDO and SERT that could negatively impact upon serotonergic functioning.
犬尿氨酸途径 (KP) 及其限速酶色氨酸分解酶吲哚胺 2,3-双加氧酶 (IDO) 与抑郁症的发病机制有关。IDO 的表达受炎症细胞因子驱动，并被认为是炎症与抑郁症中 5-羟色胺能缺陷之间的联系。研究还表明，炎症细胞因子上调了 5-羟色胺转运体 (SERT)，这代表了炎症影响 5-羟色胺可利用性的另一种机制。在这里，我们检测了循环炎症细胞因子 (IFN-γ、TNF-α、IL-1β、IL-6) 的浓度以及急性相蛋白 CRP 以及血浆色氨酸、犬尿氨酸、犬尿氨酸酸 (KYNA) 和 3-羟基邻氨基苯甲酸 (3-HAA) 的浓度，以及 IDO、犬尿氨酸氨基转移酶 (KAT I 和 II)、犬尿氨酸-3-单加氧酶 (KMO)、犬尿氨酸酶和 SERT 的全血 mRNA 表达在与年龄和性别匹配的对照组相比，患有重度抑郁症 (MDD) 的患者中。虽然 TNF-α 或 IL-1β 没有变化，但抑郁组的血浆 IL-6、IFN-γ 和 CRP 浓度升高。尽管存在这种炎症表型，但 MDD 患者和对照组之间 IDO 的表达或血浆犬尿氨酸没有显着差异。此外，在对照组和抑郁症患者之间，KYNA 和 3-HAA 的浓度或驱动其产生的酶 KAT、KMO 或犬尿氨酸酶的表达没有差异。尽管如此，在抑郁患者中明显出现色氨酸耗竭，并且与 HAM-D 评分相关。此外，我们未能观察到 MDD 患者血液细胞中 SERT mRNA 表达与对照组相比有任何差异。这些数据支持这样一种观点，即 MDD 中存在轻度炎症特征，并伴有循环色氨酸浓度降低。然而，我们没有发现抑郁组中 KP 激活的迹象，这表明观察到的色氨酸耗竭是由替代机制介导的。总之，这些数据质疑了抑郁症中观察到的轻度炎症表型诱导 IDO 和 SERT 等分子的能力，这些分子可能对 5-羟色胺能功能产生负面影响。
