An altered peripheral IL6 response in major depressive disorder.
An altered peripheral IL6 response in major depressive disorder.
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DOI：
10.1016/j.nbd.2016.01.015
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发表时间：
2016-05
影响因子：
6.1
通讯作者：
Mirnics K
中科院分区：
文献类型：
--
作者：
Money KM;Olah Z;Korade Z;Garbett KA;Shelton RC;Mirnics K
重性抑郁障碍（MDD）是最常见的主要精神疾病之一，终生患病率为17%。最近的证据表明，MDD不仅是一种脑功能障碍，而且是一种影响全身的系统性疾病。中枢和外周炎症变化似乎是MDD病理学的核心：一部分患者显示血液细胞因子和趋化因子水平升高，在抗抑郁治疗过程中症状改善部分正常化。由于对MDD中的这种炎症过程知之甚少，我们假设MDD患者的外周组织对炎症刺激的反应不同，导致对升高的促炎细胞因子的异常转录反应。为了验证这一点，我们使用MDD患者和对照来源的真皮成纤维细胞培养物来研究其对IL 6、IL 1 β、TNFα或溶剂急性治疗的反应。在RNA分离和随后的cDNA合成之后，使用定量PCR来确定几个炎症应答基因家族的相对表达水平。我们的研究结果表明，MDD患者和对照组之间的基线测试基因的表达相当。相比之下，MDD患者成纤维细胞在所有测试的基因组（氧化应激反应、线粒体功能和脂质代谢）中对IL 6的转录反应减弱。我们还发现，基线和IL 6刺激的IL 6受体基因的转录水平显着增加。MDD成纤维细胞中的这种IL6受体转录物增加伴随着IL6刺激的SOCS3诱导增加，这抑制了IL6受体信号传导。总之，我们的研究结果表明，有一个改变的转录响应IL 6在MDD，这可能代表的分子机制之一，有助于疾病的病理生理。最终，我们希望这些研究将导致新的MDD药物靶点的验证，重点是使患者的IL 6反应正常化。
Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of antidepressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated proinflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.