Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases.
Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases.
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DOI：
10.1016/j.bbi.2017.02.010
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
McCusker RH
中科院分区：
文献类型：
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作者：
Brooks AK;Janda TM;Lawson MA;Rytych JL;Smith RA;Ocampo-Solis C;McCusker RH
大量的证据将抑郁症与免疫系统激活，压力和随后的犬尿氨酸水平升高联系起来。抗抑郁药，如三环去甲肾上腺素/5-羟色胺再摄取抑制剂地昔帕明（Desip），是在增加细胞外神经递质水平是缓解抑郁症的唯一机制的前提下开发的。然而，有证据表明，抗抑郁药有额外的作用，有助于其治疗潜力。犬尿氨酸途径产生色氨酸代谢物，其调节神经递质活性。这种识别鉴定了另一种推定的抗β-内酰胺酶靶向途径。考虑到犬尿氨酸途径在抑郁症中的公认作用，我们研究了Desip改变该途径限速酶：吲哚胺-2，3-双加氧酶（Ido 1和Ido 2）表达的潜力。给小鼠施用脂多糖（LPS）或合成糖皮质激素地塞米松（Dex）与Desip，以确定Desip是否在模拟免疫和应激反应后改变体内吲哚胺双加氧酶（DO）表达。随后用干扰素-γ（IFNγ）和Desip处理小鼠和人外周血单核细胞（PBMC）。在体内：Desip阻断LPS诱导的树突状细胞、星形胶质细胞、小胶质细胞和PBMC中的Ido 1表达以及PBMC的Ido 2表达。离体：Desip降低IFNγ诱导的小鼠PBMC中Ido 1和Ido 2表达。这种作用可直接转移到人体系统，因为Desip降低了人PBMC的IDO 1和IDO 2表达。这些数据首次表明，抗-β-内酰胺酶改变了Ido 1和Ido 2的表达，确定了抗-β-内酰胺酶活性背后可能的新机制。此外，我们提出了使用IDO表达作为生物标志物来评估PBMC的抗CD 45应答性。
Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker.