CCL3/MIP-1α is not involved in the LPS-induced fever and its pyrogenic activity depends on CRF

The fever induced by lipopolysaccharide (LPS) depends on both prostaglandin-dependent and -independent pathways. One of the prostaglandin-independent pathways is sequentially orchestrated by pre-formed pyrogenic factor derived from LPS-stimulated macrophages (PFPF), corticotrophin releasing factor (CRF), endothelin-1 (ET-1) and interleukin-1 (IL-1). As macrophage-inflammatory-protein (MIP)-1α (synonym CCL3) also induces a prostaglandin independent fever, the aim of the present study was to investigate a possible participation of CCL3/MIP-1α within the prostaglandin-independent pathway of LPS-induced fever which depends on PFPF, CRF and ET-1. Therefore, rats received intracerebroventricular (i.c.v.) pre-treatment with anti-CCL3 monoclonal antibody (1 and 5 ng) at 1 h and 15 min before injection of LPS (lipopolysaccharide from E. coli; 5, 50 or 100 μg kg− 1, i.v.) or CCL3/MIP-1α (500 pg, i.c.v.). Both doses of anti-CCL3 did not change the basal temperature but abolished the fever induced by CCL3/MIP-1α. When given at the higher dose, anti-CCL3 did not influence the fever induced by i.v. injection of different doses of LPS, or i.c.v. administration of PFPF (200 ng), CRF (3 μg) or ET-1 (1 pmol). Bosentan, a non-selective ETA/B receptors antagonist (10 μg kg− 1, i.v.), reduced the fever induced by LPS but not that induced by CCL3/MIP-1α. In contrast, α-helical CRF9−41 (a non-selective CRF R1/R2 receptor antagonist; 25 μg injected i.c.v.) reduced CCL3/MIP-1α-induced fever. In conclusion, the present results indicate that: i) CCL3/MIP-1α is not an endogenous mediator of LPS-induced fever; ii) it is even not involved in the prostaglandin-independent pathway of the LPS-fever cascade and iii) its pyrogenic activity depends on synthesis/release of CRF.