Van Dam A M, Bauer J, Tilders F J, Berkenbosch F
Research Institute Neurosciences Free University, Faculty of Medicine, Department of Pharmacology, Amsterdam, The Netherlands.
Neuroscience. 1995 Apr;65(3):815-26. doi: 10.1016/0306-4522(94)00549-k.
Interleukin-1 plays an important role as mediator of endotoxin-induced responses in the brain such as fever, sleep, anorexia, behavioural and neuroendocrine changes. In the present study, interleukin-1 beta immunocytochemistry has been performed at the light and electron microscopic level to study the cellular and subcellular localization of interleukin-1 beta in the brains of rats given endotoxin or saline. Light microscopic analysis of rats killed 4, 8 or 24h after endotoxin (2.5 mg/kg) given intraperitoneally or intravenously revealed a region-specific localization of immunoreactive interleukin-1 beta in macrophages and microglial cells. After saline treatment, no induction of interleukin-1 beta immunoreactivity occurred in the brain. After administration of endotoxin, many interleukin-1 beta-positive cells were found in the meninges, choroid plexus, circumventricular organs, cerebral cortex and hypothalamus. The number of interleukin-1 beta-positive microglial cells reached a maximum 8 h after administration of endotoxin, irrespective of the route of administration. In general, more interleukin-1 beta-positive microglial cells were found after intravenous than after intraperitoneal administration of endotoxin. Interleukin-1 beta-positive microglial cells were often grouped in patches in the vicinity of blood vessels. At the surface of the cerebral cortex, in the meninges, intermediate cell forms between interleukin-1 beta-positive macrophages and microglial cells were found. interleukin-1 beta-positive perivascular microglia were localized at the brain side of the basal lamina. Immunoreactive interleukin-1 beta was found at the luminal side of the endothelial cells lining the venules. Furthermore, microglial cells that extended their processes into the ependymal layer of the third ventricle were observed. Results of the electron microscopic studies revealed immunoreactive interleukin-1 beta in many cells with the cellular characteristics of microglial cells, but also, in some cells, identified as astrocytes. In microglial cells, immunoreactive interleukin-1 beta was found in the cytoplasm but not in the endoplasmatic reticulum or Golgi apparatus. These results show that after peripheral administration of endotoxin, immunoreactive interleukin-1 beta is induced in macrophages in the meninges and in the choroid plexus, as well as in microglial cells in parenchyma. Interleukin-1 beta produced by these cells may serve as a signal for adjacent or more distant targets (neurons, endothelial cells, microglial cells) to play a role in the induction of non-specific symptoms of sickness.
白细胞介素-1作为内毒素诱导的大脑反应（如发热、睡眠、厌食、行为和神经内分泌变化）的介质发挥着重要作用。在本研究中，已在光镜和电镜水平上进行了白细胞介素-1β免疫细胞化学研究，以探讨给予内毒素或生理盐水的大鼠脑中白细胞介素-1β的细胞和亚细胞定位。对腹腔或静脉注射内毒素（2.5mg/kg）后4、8或24小时处死的大鼠进行光镜分析，结果显示免疫反应性白细胞介素-1β在巨噬细胞和小胶质细胞中呈区域特异性定位。生理盐水处理后，脑中未诱导出白细胞介素-1β免疫反应性。给予内毒素后，在脑膜、脉络丛、室周器官、大脑皮层和下丘脑发现许多白细胞介素-1β阳性细胞。无论给药途径如何，内毒素给药后8小时，白细胞介素-1β阳性小胶质细胞数量达到最大值。一般来说，静脉注射内毒素后比腹腔注射后发现更多的白细胞介素-1β阳性小胶质细胞。白细胞介素-1β阳性小胶质细胞常成簇聚集在血管附近。在大脑皮层表面、脑膜中，发现了白细胞介素-1β阳性巨噬细胞和小胶质细胞之间的中间细胞形式。白细胞介素-1β阳性血管周围小胶质细胞位于基膜的脑侧。在小静脉内皮细胞的管腔侧发现了免疫反应性白细胞介素-1β。此外，还观察到小胶质细胞的突起延伸到第三脑室的室管膜层。电镜研究结果显示，许多具有小胶质细胞特征的细胞以及一些被鉴定为星形胶质细胞的细胞中存在免疫反应性白细胞介素-1β。在小胶质细胞中，免疫反应性白细胞介素-1β存在于细胞质中，但内质网或高尔基体中未发现。这些结果表明，外周给予内毒素后，脑膜和脉络丛中的巨噬细胞以及实质中的小胶质细胞中诱导出免疫反应性白细胞介素-1β。这些细胞产生的白细胞介素-1β可能作为相邻或更远距离靶标（神经元、内皮细胞、小胶质细胞）的信号，在疾病非特异性症状的诱导中发挥作用。
