STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior.
STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior.
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DOI：
10.1038/srep09009
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发表时间：
2015-03-11
影响因子：
4.6
通讯作者：
Pollak DD
中科院分区：
文献类型：
--
作者：
Kong E;Sucic S;Monje FJ;Savalli G;Diao W;Khan D;Ronovsky M;Cabatic M;Koban F;Freissmuth M;Pollak DD
实验证据表明免疫系统在抑郁症的病理生理学中发挥作用。已经提出促炎细胞因子白细胞介素 6 (IL6) 在患有该疾病的患者和相关动物模型中都有特定的参与。然而，目前尚不清楚 IL6 如何影响神经传递，从而导致抑郁症。在这里，我们测试了这样的假设：IL6 通过 STAT3 信号通路诱导的血清素神经传递调节有助于 IL6 在抑郁症中的作用。向内源表达 SERT 的 JAR 细胞中添加 IL6，可降低 SERT 活性并下调 SERT mRNA 和蛋白质水平。类似地，小鼠海马中的 SERT 表达在 IL6 处理后减少。相反，IL6-KO小鼠的海马组织中SERT水平升高，并且IL6-KO小鼠表现出抑郁样行为减少以及对急性抗抑郁治疗的反应减弱。 STAT3 IL6 依赖于 SERT 启动子，抑制 STAT3 可在体外阻断 IL6 的作用，并在体内调节抑郁样行为。这些观察结果表明，IL6 直接控制 SERT 水平，从而控制血清素再摄取，并确定 STAT3 依赖性 SERT 调节是 IL6 参与抑郁症的可能的神经生物学底物。
Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.