Raber J, O'Shea R D, Bloom F E, Campbell I L
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci. 1997 Dec 15;17(24):9473-80. doi: 10.1523/JNEUROSCI.17-24-09473.1997.
Interleukin-6 (IL-6) and IL-6 receptor mRNA and protein have been reported in different brain regions under normal and pathophysiological conditions. Although much is known about the hypothalamic-pituitary-adrenal (HPA) axis stimulation after acute administration, less is known about the chronic effects of IL-6 on the function of the HPA axis. In the present study, we examined the function of the HPA axis in transgenic mice in which constitutive expression of IL-6 under the control of the glial fibrillary acidic protein (GFAP) promoter was targeted to astrocytes in the CNS. GFAP-IL6 mice heterozygous or homozygous for the IL-6 transgene had normal basal plasma corticosterone levels but, after restraint stress, showed abnormally increased levels in a gene dose-dependent manner. The increased plasma corticosterone levels in the IL-6 transgenic mice were associated with increased adrenal corticosterone content and hyperplasia of both adrenal cortex and medulla. Notably, plasma adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content were either not changed or decreased in these mice, whereas plasma arginine vasopressin (AVP) was increased, supporting a role for AVP in response to acute immobilization stress. The reduced ACTH response together with the adrenal hyperplasia in the IL-6 transgenic mice suggests direct activation at the level of the adrenal gland that may be directly activated by AVP or sensitized to ACTH. A similar mechanism may play a role in the blunted ACTH response and elevated corticosterone levels under pathophysiological conditions observed in humans with high brain levels of IL-6.
在正常和病理生理条件下，不同脑区已报道有白细胞介素-6（IL-6）及其受体的mRNA和蛋白质。尽管急性给药后下丘脑-垂体-肾上腺（HPA）轴刺激方面已了解很多，但IL-6对HPA轴功能的慢性影响知之甚少。在本研究中，我们检测了转基因小鼠中HPA轴的功能，在这些小鼠中，在胶质纤维酸性蛋白（GFAP）启动子控制下的IL-6组成型表达靶向于中枢神经系统中的星形胶质细胞。IL-6转基因杂合或纯合的GFAP-IL6小鼠基础血浆皮质酮水平正常，但在束缚应激后，以基因剂量依赖方式显示出异常升高。IL-6转基因小鼠血浆皮质酮水平升高与肾上腺皮质酮含量增加以及肾上腺皮质和髓质增生有关。值得注意的是，这些小鼠的血浆促肾上腺皮质激素（ACTH）水平和垂体ACTH含量要么未改变要么降低，而血浆精氨酸加压素（AVP）增加，支持AVP在应对急性固定应激中的作用。IL-6转基因小鼠中ACTH反应降低以及肾上腺增生表明在肾上腺水平存在直接激活，这可能由AVP直接激活或对ACTH敏感。类似机制可能在脑内IL-6水平高的人类病理生理条件下观察到的ACTH反应迟钝和皮质酮水平升高中起作用。
