Research Report CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli ) and RANTES in rats Renes R. Machado a , Denis M. Soares a , Amanda E. Proudfoot b , Glória E.P. Souza a, ⁎ a Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Ribeirão Preto, SP, Brazil b Serono Pharmaceutical Research Institute, Geneva, Switzerland ARTICLE INFO ABSTRACT Article history: Accepted 8 May 2007 Available online 9 June 2007 This study, besides examining the involvement of CCR1 and CCR5 receptors in the LPS- induced fever (lipopolysaccharide, Escherichia coli) in male Wistar rats, evaluated if RANTES (regulated on activation, normal T cells expressed and secreted) injected into the preoptic area of the anterior hypothalamus (AH/POA) would promote an integrated febrile response via these receptors. Moreover, the effects of selective and non-selective cyclooxygenase blockers on both fever and the level of prostaglandin (PG)E 2 in the cerebrospinal fluid (CSF) after injection of RANTES into the AH/POA were also investigated. Met-RANTES, CCR1 and CCR5 receptor antagonist, reduced LPS-evoked fever dose dependently. RANTES microinjected into the AH/POA increased the rectal temperature of rats dose dependently and caused a significant decrease in the tail skin temperature and an increase (at 2.5 and 5 h) of the levels of PGE 2 in the CSF. Met-RANTES prevented the fever induced by RANTES. Ibuprofen abolished the fever caused by RANTES between 60 min and 2.5 h, and it reduced the temperature until the end of observation period. Celecoxib blocked the RANTES-induced fever, while indomethacin reduced it in the last 60 min of the experimental period. At 2.5 and 5 h all antipyretics brought the CSF PGE 2 level near to the control. These results indicate that CCR1 and CCR5 receptors are involved in the fever induced by systemic LPS and intrahypothalamic RANTES. RANTES promotes an integrated febrile response accompanied by an increase of CSF PGE 2 . The inhibitory effects of celecoxib and ibuprofen suggest that PGE 2 was generated via COX-2. As indomethacin dissociates fever and the decrease of PGE 2 level during the RANTES-induced fever, an alternative COX-2-independent pathway or other mechanisms of action of celecoxib and ibuprofen might be considered. © 2007 Published by Elsevier B.V. Keywords: RANTES/CCL5 Fever Lipopolysaccharide Hypothalamus Prostaglandin E 2 Cyclooxygenase inhibitor BRAIN RESEARCH 1161 (2007) 21 – 31 ⁎ Corresponding author. Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-Universidade de São Paulo, Av. do Café, s/n-Campus USP, 14.040-903, Ribeirão Preto, SP, Brazil. Fax: +55 16 3602 4880. E-mail address: gepsouza@fcfrp.usp.br (G.E.P. Souza). Abbreviations: AH/POA, preoptic area of the anterior hypothalamus; BMAC, B cell- and monocyte-activating chemokine; CNS, central nervous system; CCR, C–C chemokine receptor; ET, endothelin; i.p., intraperitoneal; IP-10, interferon inducible protein-10; i.v., intravenous; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; NF-κB, nuclear factor-κB; OVLT, Organum vasculosum laminae terminalis; PFPF, pre-formed pyrogenic factor; PGE 2 , prostaglandin E 2 ; RANTES, regulated on activation, normal T cells expressed and secreted 0006-8993/$ – see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.brainres.2007.05.054 available at www.sciencedirect.com www.elsevier.com/locate/brainres