Department of Biochemistry and Biophysics, University of California, 600 16thStreet, San Francisco, CA 94158, United States.
Division of Experimental Medicine, University of California San Francisco, Building 100, 1001 Potrero Ave, San Francisco, CA, 94110, United States.
Psychoneuroendocrinology. 2018 Oct;96:179-187. doi: 10.1016/j.psyneuen.2018.06.020. Epub 2018 Jun 26.
The chronic psychological stress of caregiving leads to higher risks for many diseases. One of the mechanisms through which caregiving is associated with disease risk is chronic inflammation. Chronic inflammation may accelerate cellular aging via telomere dysfunction and cell senescence, although this has not been examined in human cells from healthy people. We examined peripheral blood mononuclear cells (PBMCs) from 20 healthy mothers of children with autism (caregivers) and 19 mothers of neurotypical children (controls) in an in vitro culture system where PBMCs were stimulated with phytohaemagglutinin (PHA). We measured RNA expression levels of a panel of immune function genes before and after PHA stimulation, as well as telomere length from PBMCs collected from the participants at baseline and 15 months later. Caregivers and controls had similar gene expression profiles in unstimulated PBMCs, but after PHA stimulation, caregivers had increased RNA levels of the master inflammatory regulator NF-κB and its proinflammatory cytokine targets IL-1β, IL-6 and its receptor IL-6R as well as inflammatory chemokines IL-8, CXCL1 and CXCL2. Gene expression analysis suggested caregivers have increased Treg and Th17 T cell differentiation. Additionally, key signaling molecules involved in the upregulation of COX-2, a critical enzyme in the synthesis of the inflammatory mediator prostaglandin, were elevated. When both groups were examined together, higher expression levels of proinflammatory genes were associated with shorter telomere length in PBMCs from blood drawn 15 months later, independent of baseline telomere length. Taken together, these results suggest that chronic stress is associated with an exaggerated inflammatory response in PBMCs, which in turn is associated with shorter telomere length measured from PBMCs collected 15 months later. To our knowledge, this is the first human study that shows increased proinflammatory expression predicts future telomere shortening.
长期的护理心理压力会导致许多疾病的风险增加。护理与疾病风险相关的机制之一是慢性炎症。慢性炎症可能通过端粒功能障碍和细胞衰老加速细胞衰老，尽管这在健康人群的人源细胞中尚未得到检验。我们在体外培养系统中检查了 20 名自闭症儿童（护理者）和 19 名神经典型儿童（对照者）的健康母亲的外周血单核细胞（PBMC），在此系统中，用植物血球凝集素（PHA）刺激 PBMC。我们测量了 PHA 刺激前后一组免疫功能基因的 RNA 表达水平，以及从参与者基线和 15 个月后收集的 PBMC 中测量的端粒长度。未受刺激的 PBMC 中，护理者和对照者的基因表达谱相似，但 PHA 刺激后，护理者的主炎症调节因子 NF-κB 及其促炎细胞因子靶标 IL-1β、IL-6 和其受体 IL-6R 以及炎症趋化因子 IL-8、CXCL1 和 CXCL2 的 RNA 水平增加。基因表达分析表明，护理者的 Treg 和 Th17 T 细胞分化增加。此外，参与 COX-2 上调的关键信号分子，COX-2 是炎症介质前列腺素合成中的关键酶，也升高了。当将两组一起检查时，更高水平的促炎基因与 15 个月后从血液中提取的 PBMC 中的端粒长度较短相关，与基线端粒长度无关。综上所述，这些结果表明，慢性应激与 PBMC 中炎症反应的过度增强有关，而这种反应与 15 个月后从 PBMC 中测量的端粒长度较短有关。据我们所知，这是第一项表明促炎表达增加预测未来端粒缩短的人类研究。
