Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.
Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.
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DOI：
10.1038/tp.2016.79
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发表时间：
2016-05-24
影响因子：
6.8
通讯作者：
Cole SW
中科院分区：
文献类型：
--
作者：
Mellon SH;Wolkowitz OM;Schonemann MD;Epel ES;Rosser R;Burke HB;Mahan L;Reus VI;Stamatiou D;Liew CC;Cole SW
重度抑郁症 (MDD) 与罹患心血管疾病、免疫损伤、感染、痴呆和过早死亡等严重疾病的风险显着升高相关。之前的研究已经证明重度抑郁症患者存在免疫失调。使用全基因组转录分析和基于启动子的生物信息学策略，我们评估了 20 名未接受药物治疗的 MDD 受试者与 20 名年龄、性别和种族匹配的健康对照者在开始抗抑郁治疗之前以及 17 名 MDD 受试者在舍曲林治疗 8 周后的白细胞转录因子 (TF) 活性。在来自未接受药物治疗的 MDD 受试者的白细胞中，转录控制通路活性的生物信息学分析表明 cAMP 反应元件结合/激活 TF (CREB/ATF) 的转录活性增加，并且与细胞氧化应激反应（核因子红细胞衍生 2-like 2、NFE2l2 或 NRF2）相关的 TF 活性增加。八周的抗抑郁治疗与汉密尔顿抑郁量表评分显着降低和 NRF2 活性降低相关，但与 CREB/ATF 活性无关。其他几种转录调节途径，包括糖皮质激素受体 (GR)、核因子 kappa-B 细胞 (NF-κB)、早期生长反应蛋白 1-4 (EGR1-4) 和干扰素反应性转录因子，在疾病或治疗的功能上没有表现出显着差异，或者与之前假设的与 MDD 病因或有效治疗有关的活动相反。我们的结果表明，CREB/ATF 和 NRF2 信号传导可能通过激活免疫细胞转录组动力学而导致 MDD，最终通过循环介质影响中枢神经系统 (CNS) 动机和情感过程。
Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1–4 (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.
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影响因子：
6.1
作者：
Correa, Fernando;Mallard, Carina;Nilsson, Michael;Sandberg, Mats
通讯作者：
Sandberg, Mats
影响因子：
5.8
作者：
Cole, SW;Yan, W;Zack, JA
通讯作者：
Zack, JA
影响因子：
7.6
作者：
Blom, JMC;Tascedda, F;Brunello, N
通讯作者：
Brunello, N
DOI：
10.1073/pnas.1218253109
发表时间：
2012-12-11
影响因子：
11.1
作者：
Cole, Steven W.;Conti, Gabriella;Suomi, Stephen J.
通讯作者：
Suomi, Stephen J.
DOI：
10.1073/pnas.0911515107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Cole, Steven W.;Arevalo, Jesusa M. G.;Seeman, Teresa E.
通讯作者：
Seeman, Teresa E.