Brain Research, 588 (1992) 291-296 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00 291 BRES 25303 Short Communications Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Anne-Marie van Dam, Madeleine Brouns, Simone Louisse and Frank Berkenbosch Department of Pharmacology, Medical Faculty, Free Unicersity, Amsterdam (Netherlands) (Accepted 19 May 1992) Key words: |nterleukin-1; Brain; Macrophage; Perivascular ceil; Microglia; Endotoxin; Sickness The presence and cellular localization of interleukin-I/3 immunoreactivity (irlL-1) in and around the brain was investigated using immunocyto- chemistry oil Bouin's fixed vibratome brain sections of control and endotoxin-treated rats. Peripheral administration of endotoxin resulted in the appearence of irlL-1 in cells in the meninges, choroid plexus, brain blood vessels and in non-neuronal cells in the brain parenchyma. Using monoclonal and polyclonal antibodies to macrophage and astrocyte antigens, the endotoxin-induced irIL-I positive cells could be identified as macrophages in the meninges and choroid plexus (ED2), perivascular cells (ED2) and ramified microg!ial cells (GSA-I-B4 isolectin). Our data demonstrate a pathway for the induction of non-specific sickness symptoms in response to endotoxin. Non-specific sickness symptoms are marked mani- festations of the host defense reaction (also termed acute phase response) to pathogens and injury. The overt non-specific sickness symptoms include physio- logical responses such as fever, neuro-endocrine changes and modifications in behaviour consisting of increased sleepiness, behavioural depression and anorexia m~. These non-specific sickness symptoms are not a maladaptive response or the effects of debilita- tion, but rather an organized evolved strategy to facili- tate the defense in combating pathogens and injuries 5't3. Interleukin-lfl, a cytokine predominantly produced by cells of the macrophage lineage, appears to play a pivotal role in the orchestration of the sick- ness symptoms because most of the symptoms can be induced by peripheral and central administration of recombinant IL-1 preparations 2'~6'~8. Since centrally administered IL-1 is much more potent than peripher- ally administered IL-1, it is thought that IL-1 acts within the brain. As yet, data on IL-1 passage through the blood-brain barrier in vivo are conflicting 16. IL-1 can be produced by a variety of cells of the central nervous system 17 in vitro and IL-1 secreted from these different cellular sources in vivo may form a pathway for the induction of some of the non-specific manifes- tations of sickness !°. In the present study, this hypothe- sis is supported by the demonstration of induction of irIL-1/3 in macrophages in the meninges and choroid plexus, perivascular cells and ramified microglia but not in astrocytes in response to peripheral administra- tion of pyrogenic doses of endotoxin. Immunocytochemical studies were performed on brains obtained from male Wistar rats (Harlan, Zeist, Netherlands) weighing approximately 200 g. The ani- mals used were kept under controlled light conditions in which the light period was from 07.00 h to 19.00 h. Food and water were available ad libitum. Endotoxin (E. coli, 055 B5 Westphal, Difco, Detroit, USA) dis- solved in saline, was administered intravenously (dose range: 0.01-2.5 mg/kg) and animals were perfused 1.5, 4, 8 and 24 h after endotoxin administration. In con- trast to the lowest dose (0.01 mg/kg), the higher doses of endotoxin clearly resulted in marked changes (mea- sured in regular time intervals up to 8 h) in rectal Correspondence: F. Berkenbosch, Department of Pharmacology, Medical Faculty, Free University, v/d Boechorsstraat 7, 1081 BT Amsterdam, Netherlands.