CCL3/Macrophage inflammatory protein-1 alpha induces fever and increases prostaglandin E sub(2) in cerebrospinal fluid of rats: Effect of antipyretic drugs

The aim of this study was to investigate whether the increase in body temperature caused by intracerebroventricular (i.c.v.) injection of recombinant mouse CCL3/MIP1 alpha [C-C (two adjacent conserved cysteines) ligand 3/macrophage inflammatory protein-1 alpha ] constitutes solely a hyperthermic response or a true integrated fever. Additionally, we examined the effects of systemic administration of different antipyretic drugs including the glucocorticoid dexamethasone, on cerebrospinal fluid (CSF) concentration of prostaglandin (PG) E sub(2) and on febrile response induced by CCL3/MIP1 alpha . I.c.v. administration of CCL3/MIP1 alpha evokes an integrated fever accompanied by a reduction in tail skin temperature and an increase in PGE sub(2) concentration in the CSF. Dexamethasone and indomethacin markedly reduced the fever and the elevation of CSF PGE sub(2) concentration induced by lipopolysaccharide (LPS) whereas both response evoked by i.c.v. CCL3/MIP1 alpha were insensitive to this steroid. Indomethacin only blocked the PGE sub(2) increase in the CSF whereas ibuprofen and celecoxib each blocked the fever and the elevation of CSF PGE sub(2). In this study, we have demonstrated for the first time that CCL3/MIP1 alpha evokes an integrated febrile response accompanied by an increase of PGE sub(2) levels in the CSF. These events are dissociated, especially in animals treated with indomethacin. If PGE sub(2) does not participate in the febrile response evoked by CCL3/MIP1 alpha , the inhibition of this response by celecoxib and ibuprofen indicates additional mechanisms to the well-known inhibition of COX enzymes by these drugs. Such mechanisms do not seem to depend on cytokine synthesis and subsequent COX-2 induction.