Research ReportCCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli) and RANTES in rats
Introduction
A large body of evidence shows that fever induced by bacterial lipopolysaccharide (LPS) is mediated by a number of endogenous pyrogens (PEs) produced either centrally or peripherically. Among these pyrogens, there are interleukins IL-1α and β (Dinarello, 1984, Dinarello, 1994), IL-6 (Helle et al., 1988, Souza et al., 2002, Harre et al., 2002), tumor necrosis factor (TNF) (Dinarello et al., 1986), pre-formed pyrogenic factor (PFPF) (Zampronio et al., 2000, Fabricio et al., 2006), corticotrophin-releasing factor (CRF) (Zampronio et al., 2000, Souza et al., 2002), endothelins (ETs) (Fabricio et al., 2005a, Fabricio et al., 2006), and prostaglandins (PGs) (Morimoto et al., 1992, Souza et al., 2002, Rummel et al., 2005). PEs can act either direct or indirectly on thermoregulatory neurons in the preoptic area of the hypothalamus (POA) by altering the activity of these neurons (Roth et al., 2006).
Alongside these established fever-inducer mediators, the chemokines have come into view as a pyrogenic mediator for years (Davatelis et al., 1989, Miñano et al., 1990, Rothwell et al., 1990, Zampronio et al., 1994, Zampronio et al., 1995, Tavares and Miñano, 2000, Melo Soares et al., 2006). Chemokines are chemotactic cytokines that participate in immune and inflammatory responses by promoting leukocyte activation and migration (Luster, 1998, Baggiolini, 1998). On the basis of the relative position of their amino terminal cysteine residues (Rollins, 1997, Zlotnik and Yoshie, 2000), chemokines are divided into four subfamilies (CXC, CC, C and CX3C).
RANTES/CCL5, a member of the CC family of chemokines (8–10 kDa) promotes the recruitment and activation of inflammatory cells such as lymphocytes (Schall et al., 1990), monocytes (Meurer et al., 1993), eosinophils (Dinarello, 1994), natural killer cells and basophils (Nelson and Krensky, 1998), by acting on CCR1, CCR3 and CCR5 receptors (Wells et al., 1998). These receptors belong to a family of seven-transmembrane G-protein-coupled receptors leading to the activation of intracellular signaling pathways (Thelen, 2001). Chemokine receptors have been detected in the CNS on several cell subsets, including, microglia, astrocytes and neurons in the hypothalamus during disease and after endotoxin administration (Boddeke et al., 1999, Dorf et al., 2000, Simpson et al., 2000).
Previous in vitro studies (Jang et al., 2002, Kremlev et al., 2004) demonstrated that endotoxin (LPS from Gram-negative bacteria) induces, via activation of the nuclear factor-kB (NF-κB) transcription, the expression of RANTES and macrophage inflammatory protein (MIP)-1α in microglial cells. Furthermore, treatment of astrocytes with TNF-α or LPS induces mRNA expression of RANTES, monocyte chemoattractant protein (MCP)-1 and MIP-1β (Guo et al., 1998). In vivo, LPS induces MIP-1α and MIP-1β mRNAs in rat brain (Gourmala et al., 1999). In addition, immunoreactivity to MIP-1β was identified in the OVLT and AH/POA of rats (Miñano et al., 1996). Other kinds of stimuli, such as West Nile virus, were shown to increase mRNAs for RANTES, MIP-1α, MIP-1β, IP-10 (interferon inducible protein 10 kDa) and BMAC (B cell- and monocyte-activating chemokine) in mice brain homogenates (Shirato et al., 2004).
RANTES also promotes fever sensitive to steroidal and non-steroidal antipyretic drugs (Tavares and Miñano, 2000, Tavares and Miñano, 2002), suggesting the involvement of prostaglandins in its pyretic effect. Furthermore, the CCR5 receptor seems to be responsible for fever in response to RANTES, since a specific antibody against this receptor blocked fever induced by the chemokine (Tavares and Miñano, 2004).
The addition of a single methionine on the amino terminal of RANTES resulted in the production of Met-RANTES, a potent antagonist of CCR1 and CCR5 receptors (Proudfoot et al., 1999a), which is effective in reducing inflammation in rodent models of renal inflammation (Grone et al., 1999), reducing collagen-induced arthritis (Plater-Zyberk et al., 1997) and reducing significantly the colonic damage and bacterial translocation in experimental colitis (Kucuk et al., 2006).
In view of these considerations, the present study investigated the involvement of CCR1 and CCR5 chemokine receptors in the febrile response induced by LPS by treating rats with Met-RANTES. It was also investigated whether RANTES injected into the anterior hypothalamus preoptic area (AH/POA) would promote an integrated febrile response and the contribution of CCR1 and CCR5 receptors to this response. The effects of selective and non-selective cyclooxygenase blockers both on fever and on the level of prostaglandin (PG)E2 in the cerebrospinal fluid (CSF) after injection of RANTES into the AH/POA were also investigated.
Section snippets
Effect of intravenous injection of Met-RANTES on fever induced by LPS in rats
Fig. 1 shows that intravenous injection of LPS (5 μg kg− 1) promoted a rapid raise on fever, peaking 2 h after administration. Intravenous administration of the dose of 5 μg kg− 1 of Met-RANTES promoted no changes (Fig. 1A); the dose of 25 μg kg− 1 of this antagonist reduced the fever response for a short period (from 75 to 150 min, F = 35.43, P < 0.01; Fig. 1B) while the dose of 100 μg kg− 1 markedly reduced the fever induced by 5 μg kg− 1 of LPS (F = 1527, P < 0.01; Fig. 1C). Therefore, this dose of
Discussion
The present study shows, for the first time, that Met-RANTES, a CCR1 and CCR5 receptor antagonist, reduced the febrile response induced by LPS in rats, suggesting a contribution of these receptors to this response. Furthermore, it shows that the injection of RANTES into the AH/POA of rats increases the CSF PGE2 level and promotes an integrated febrile response sensitive to Met-RANTES, ibuprofen, celecoxib and in a feeble degree to indomethacin. The effect of all antipyretic drugs was
Animals
Experiments were conducted using male 180–200 g, Wistar rats, individually housed at 24 ± 1 °C under a 12:12-h light–dark cycle (lights on at 06:00 AM), with free access to chow and tap water until the day of the experiment proper, when only water was made available to them. Each animal was used only once. All experiments were previously approved by the institution's ethical committee for research on laboratory animals of the University of São Paulo and were performed in accordance with Brazilian
Acknowledgments
We are most grateful to Miriam C.C. Melo, Juliana Vercesi, Giuliana Bertozi and Frédéric Borlat for their expert technical assistance. This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Proc. Nr. 97/09837-6; 01/11014-5; 03/04838-7 and 05/55717-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (Proc. Nr. 305802/2004-6), Brazil.
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