title: CCL3/MIP-1 alpha is not involved in the LPS-induced fever and its pyrogenic activity depends on CRF.
abstract: 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)-1 alpha (synonym CCL3) also induces a prostaglandin independent fever, the aim of the present study was to investigate a possible participation of CCL3/MIP-1 alpha 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 microg kg(-1), i.v.) or CCL3/MIP-1 alpha (500 pg, i.c.v.). Both doses of anti-CCL3 did not change the basal temperature but abolished the fever induced by CCL3/MIP-1 alpha. 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 microg) or ET-1 (1 pmol). Bosentan, a non-selective ET(A/B) receptors antagonist (10 microg kg(-1), i.v.), reduced the fever induced by LPS but not that induced by CCL3/MIP-1 alpha. In contrast, alpha-helical CRF(9-41) (a non-selective CRF R1/R2 receptor antagonist; 25 microg injected i.c.v.) reduced CCL3/MIP-1 alpha-induced fever. In conclusion, the present results indicate that: i) CCL3/MIP-1 alpha 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.
authors.affiliation: Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Av. do Café, s/n - Campus USP, 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Denis Melo
authors.initials: DM
authors.lastname: Soares
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Figueiredo
authors.forename: Juliano Manvailer
authors.initials: JM
authors.lastname: Martins
authors.forename: Renes Resende
authors.initials: RR
authors.lastname: Machado
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kanashiro
authors.forename: David do Carmo
authors.initials: Ddo C
authors.lastname: Malvar
authors.forename: Andréa Carla
authors.initials: AC
authors.lastname: Pessini
authors.forename: Joachim
authors.initials: J
authors.lastname: Roth
authors.forename: Glória Emília Petto
authors.initials: GE
authors.lastname: Souza
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D054405:Chemokine CCL3 / Q000276:immunology* / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D019332:Endothelin-1 / Q000378:metabolism; D005334:Fever / Q000139:chemically induced* / Q000276:immunology*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000959:Antihypertensive Agents; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D019332:Endothelin-1; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013449:Sulfonamides; D003346:Corticotropin-Releasing Hormone; D000077300:Bosentan