title: Endotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: a light and electron microscopic study.
abstract: 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.
authors.affiliation: Research Institute Neurosciences Free University, Faculty of Medicine, Department of Pharmacology, Amsterdam, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Van Dam
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: F J
authors.initials: FJ
authors.lastname: Tilders
authors.forename: F
authors.initials: F
authors.lastname: Berkenbosch
mesh_terms: D000818:Animals; D001921:Brain; D004731:Endotoxins / Q000494:pharmacology*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000276:immunology*; D008297:Male; D017628:Microglia / Q000187:drug effects*; D008854:Microscopy, Electron; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004731:Endotoxins; D007375:Interleukin-1