Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.

中文翻译：

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慢性压力和非压力中年女性免疫相关基因的 HPA 轴调控和表观遗传编程

下丘脑-垂体-肾上腺 (HPA) 轴失调与免疫功能改变有关，但潜在的分子机制尚不清楚。包括 DNA 甲基化在内的表观遗传过程对 HPA 轴的糖皮质激素终产物（人体皮质醇）有反应，并可能参与这种神经内分泌-免疫串扰。在这里，我们检查了 57 名长期受压的护理人员和 67 名对照女性的 HPA 轴调节变化与外周血 DNA (CpG) 甲基化变化的相关程度。使用 Illumina 450k 阵列对一组与 HPA 轴和免疫功能有关的基因进行 DNA 甲基化测定。HPA 轴反馈通过低剂量地塞米松抑制试验 (DST) 进行评估，测量合成糖皮质激素地塞米松抑制皮质醇分泌的程度。在整个队列中进行多次测试校正后，更高的 DST 后皮质醇，反映钝化的 HPA 轴负反馈，但不是基线清醒皮质醇，与八个 TNF 和两个 FKBP5 CpG 位点的较低 DNA 甲基化相关。看护组状态与两个 IL6 CpG 位点的甲基化程度较低有关。由于与 TNF 甲基化（450k 覆盖位点中的 32%）相关性最强，我们进一步检查了 33 名参与者培养的外周血单核细胞中这种表观遗传特征的功能。有趣的是，较低的 TNF 甲基化导致免疫刺激后较高的离体 TNF mRNA。综合起来，