CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli) and RANTES in rats

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)E2 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 PGE2 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 PGE2 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 PGE2. The inhibitory effects of celecoxib and ibuprofen suggest that PGE2 was generated via COX-2. As indomethacin dissociates fever and the decrease of PGE2 level during the RANTES-induced fever, an alternative COX-2-independent pathway or other mechanisms of action of celecoxib and ibuprofen might be considered.