Sackler Program for Epigenetics and Psychobiology at McGill University, Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, Quebec H4H 1R3, Canada.
Sackler Program for Epigenetics and Psychobiology at McGill University, Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, Quebec H4H 1R3, Canada; Singapore Institute for Clinical Sciences, Singapore 117609, Singapore.
Brain Behav Immun. 2017 Oct;65:239-250. doi: 10.1016/j.bbi.2017.05.007. Epub 2017 May 10.
Early life adversity increases the risk for later infection. The febrile response is a potent mechanism to combat infection. We found that variations in maternal care influence the febrile response to 50µg/kg lipopolysaccharide (LPS) challenge in adult male rats. Offspring from low-licking/grooming (LG) mothers had an increased febrile response compared to offspring from high-LG mothers challenged with LPS. Low-LG offspring had reduced plasma IL-6 at one and two hours post challenge compared to high-LG offspring. IL-6 gene expression in the anterior hypothalamus was induced following LPS challenge in low-LG offspring but not in high-LG offspring at two hours post challenge. Occupancy of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) to the IL-6 promoter region in the anterior hypothalamus was greater in low-LG offspring treated with LPS than in high-LG offspring. These findings suggest greater activation of thermoregulatory neurons in the anterior hypothalamus of low-LG compared to high-LG offspring following LPS challenge. Low-LG offspring had greater plasma corticosterone levels following LPS challenge and they had enhanced glucocorticoid receptors (GR) in the spleen compared to high-LG offspring. Enhanced glucocorticoids and glucocorticoid receptor sensitivity associated with reduced IL-6 induction early post challenge in low-LG offspring. Challenge with RU-486 prior to LPS challenge eliminated differences in the febrile response between offspring of high and low-LG mothers. Individual differences in GR sensitivity may modulate differences in the febrile response to LPS challenge, exerting a long-term influence on the capacity to recover from infection.
早期生活逆境会增加后期感染的风险。发热反应是对抗感染的有效机制。我们发现，母体护理的差异会影响成年雄性大鼠对 50µg/kg 脂多糖 (LPS) 挑战的发热反应。与接受 LPS 挑战的高舔舐/梳理 (LG) 母亲的后代相比，来自低舔舐/梳理 (LG) 母亲的后代发热反应增加。与高 LG 后代相比，低 LG 后代在 LPS 挑战后 1 小时和 2 小时的血浆 IL-6 减少。在 LPS 挑战后 2 小时，低 LG 后代的前下丘脑 IL-6 基因表达被诱导，但高 LG 后代没有。低 LG 后代在 LPS 处理后，前下丘脑的转录因子核因子 kappa 轻链增强子 B 细胞 (NFκB) 对 IL-6 启动子区域的占据大于高 LG 后代。这些发现表明，与高 LG 后代相比，LPS 挑战后，低 LG 后代的前下丘脑体温调节神经元的激活更大。与高 LG 后代相比，LPS 挑战后，低 LG 后代的血浆皮质酮水平更高，且脾脏中的糖皮质激素受体 (GR) 增强。低 LG 后代在 LPS 挑战后早期，由于增强的糖皮质激素和糖皮质激素受体敏感性，IL-6 的诱导减少。在 LPS 挑战前用 RU-486 处理可消除高 LG 和低 LG 母亲后代发热反应之间的差异。GR 敏感性的个体差异可能会调节 LPS 挑战时发热反应的差异，对从感染中恢复的能力产生长期影响。
