Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers.
Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers.
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DOI：
10.1016/j.bbi.2014.05.016
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Cole SW
中科院分区：
文献类型：
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作者：
Miller GE;Murphy ML;Cashman R;Ma R;Ma J;Arevalo JM;Kobor MS;Cole SW
慢性应激与多种疾病的发病率和死亡率有关，其中许多疾病的发病机制涉及持续性炎症。在这里，我们研究慢性压力如何影响调节单核细胞炎症的信号通路。样本包括 33 名照顾患有胶质母细胞瘤的家庭成员的成年人和 47 名生活中没有重大压力源的对照者。在八个月内对受试者进行了四次评估。与对照组相比，护理人员的单核细胞中携带核因子 kappa B（一种关键的促炎转录因子）反应元件的基因表达增加。与此同时，护理人员的糖皮质激素受体反应元件基因表达减少，糖皮质激素受体是一种将皮质醇的抗炎信号传递给单核细胞的转录因子。转录本起源分析显示，CD14+/CD16−细胞（一群未成熟的单核细胞）是护理人员炎症基因表达的主要来源。我们考虑了激素、分子和功能上的解释来解释护理人员糖皮质激素介导的转录减少。在十二天内，各组表现出相似的昼间皮质醇分布，表明肾上腺皮质活动不存在差异。此外，各组的单核细胞表达相似数量的糖皮质激素受体蛋白，表明不涉及受体可用性的差异。在离体研究中，受试者的单核细胞受到脂多糖的刺激，并且护理人员表现出与对照组相比，炎症细胞因子白细胞介素 6 的产生量更高。然而，功能性糖皮质激素敏感性没有明显的组间差异；氢化可的松在抑制护理人员和对照组细胞因子产生方面同样有效。这些发现可能有助于揭示护理增加对炎症相关疾病的脆弱性的机制。
Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol’s anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16− cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers’ decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups’ monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects’ monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.