BRAIN RESEARCH ELSEVIER Brain Research 677 (1995) 171-176 Short communication Differential effects of IL-lra on sickness behavior and weight loss induced by IL-1 in rats Rose-Marie Bluth6 a,*, Claire Beaudu a, Keith W. Kelley b, Robert Dantzer a a INRA-INSERM U394, Domaine de Carreire, Rue Camille Saint-SaYns, 33077Bordeaux Cedex, France b Laboratory of Immunophysiology, Department of Animal Science, Plant and Animal Biotechnology Laboratory, UniL,ersity of Illinois, Urbana, IL 61801, USA Accepted 31 January 1995 Abstract Peripheral and central injections of recombinant human interleukin-1/3 (IL-1/3) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-lra. Intraperitoneal (i.p.) administration of IL-lra (8 mg/kg) blocked the effect of i.p. injection of IL-1/3 (4/zg/rat) on social behaviour but not on body weight. Central administration of IL-lra (60/zg/rat, i.c.v.) abrogated the effects of centrally administered IL-1/3 (30 ng/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-lra (4/xg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1/3 (4/zg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1/3 on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms. Keywords: Interleukin-1; Interleukin-1 receptor antagonist; Social behavior; Body weight; Rat Interleukin-1/3 (IL-1/3) is released locally from macrophages and monocytes during the course of an infection. It mediates the acute phase response and acts on immune cells and distant target organs [12]. Peripheral and central injections of IL-1/3 induce be- havioral changes which are reminiscent of sickness [10]. These changes include hypersomnia [27,34,37], de- crease in social activities [4,10], alteration of investiga- tion of a novel environment [42] and anorexia [3]. IL-1/3 acts on specific receptors which have been characterized on peripheral immune targets and are encoded by two different genes. A 80 kDa membrane receptor that binds both IL-la and IL-1/3 with similar affinity has been described on T cells and fibroblasts and is called the type I IL-1 receptor [15,23,31]. The type II receptor is a 68 kDa binding protein, originally identified on B cells, which has a higher affinity for IL-1/3 than for IL-la [16,32]. Type I IL-1 receptor mRNA has been identified in the brain and anterior * Corresponding author. Fax: (33) 56 00 02 58. Bitnet: RDINSERM at FRBDXll.Bitnet. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0006-8993(95)00194-8 pituitary by in situ hybridization techniques [9] and RT-PCR [38,39]. Although the distribution of type II IL-1 receptors in the rat brain has not yet been stud- ied, there is evidence that it is present in the pituitary and in the brain [38,39]. An IL-1 inhibitor has been extracted from the urine of patients with monocytic leukemia [41]. It was later purified from adherent monocytes, cloned and se- quenced [17,23], revealing a 26% conserved amino acid homology with IL-1/3. This inhibitor has been called the IL-1 receptor antagonist (IL-lra). It competes with IL-1 for occupancy of its cell surface receptors (with a greater affinity for type I IL-1 receptors) and has no agonist activity. This molecule, in its recombinant forms, blocks IL-1 activity both in vitro and in vivo. In vitro, IL-lra blocks IL-l-induced lymphocyte pro- liferation [2,31], and synthesis of IL-1, TNF, IL-6 and GM-CSF from monocytes [21]. It also inhibits the binding of IL-1 to T-cell lines possessing the type I IL-1 receptors present on T cells and fibroblasts. How- ever, its ability to bind to the type II IL-1 receptors is more controversial and appears to depend on the cell type and species of origin [6,16,22].