Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Mol Psychiatry. 2013 Sep;18(9):1006-17. doi: 10.1038/mp.2012.131. Epub 2012 Oct 23.
Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.
内源性糖皮质激素对于动员能量资源、抑制炎症反应以及协调对免疫挑战的行为至关重要。糖皮质激素受体 (GR) 功能受损与代谢过程受损、炎症增强以及疾病和抑郁样行为夸大有关。为了辨别 GR 调节全身免疫挑战的生理和行为反应的分子机制，GR(dim) 小鼠，其中缺失的 GR 二聚化导致 GR-DNA 结合依赖性机制受损，但完整的 GR 蛋白-蛋白相互作用，给予低剂量脂多糖 (LPS)。GR(dim)-LPS 小鼠表现出升高和延长的血浆皮质酮 (CORT)、白细胞介素 (IL)-6 和 IL-10（但不是血浆肿瘤坏死因子-α (TNFα)）水平，增强了大脑 TNFα、IL-1β 和 IL-6 mRNA 水平的早期表达，并损害了中央 TNFα mRNA 的后期表达。GR(dim)-LPS 小鼠的夸大疾病行为（昏睡、直立毛、下垂）与早期大脑前炎症细胞因子表达增加和晚期血浆 CORT 水平升高有关，但与晚期大脑 TNFα 表达减少有关。GR(dim)-LPS 小鼠还表现出持续的开放场运动障碍、体重减轻和间接测热法测量的代谢改变，以及体温调节受损。总之，这些数据表明，GR 二聚化依赖性 DNA 结合机制以细胞因子和时间特异性的方式差异调节全身和中枢细胞因子表达，并且对于适当调节和恢复对低剂量内毒素的多种生理反应是必不可少的。此外，这些结果支持这样一种概念，即 GR 蛋白-蛋白相互作用对于糖皮质激素发挥其全部抗炎作用是不够的，并表明糖皮质激素反应仅限于 GR 单体介导的转录效应可能使个体易患增强炎症状态的长期行为和代谢后遗症。
