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Investigation of the cellular and molecular mechanisms involved on fever induced by CCL3/MIP-1alpha

Grant number: 08/10323-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): March 01, 2009
Effective date (End): July 31, 2011
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Glória Emília Petto de Souza
Grantee:Denis de Melo Soares
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Fever is a highly complex response in mammalian host defense systems that results in a temporary rise of basal temperature and seems to be mediated by action of endogenous pyrogens including interleukin (IL)-1± and -1beta, IL-6, tumor necrosis factor-± (TNF-±), IL-8, C-C-ligands/macrophage inflammatory protein-1± and beta (CCL3 /MIP-1± and CCL4/MIP-1beta) and pre-formed pyrogenic factor (PFPF) on the central nervous system (for review Roth and Souza, 2001). These endogenous pyrogens can each affect, directly or indirectly, thermoregulation by acting on the thermoregulatory centre localized in the anterior hypothalamic, preoptic area (AH/POA) (Boulant, 2000).We demonstrated that CCL3/MIP-1a evokes an integrated febrile response accompanied by an increase of PGE2 levels in the CSF. Nonetheless, these events are dissociated because in indomethacin-treated animals the increase of PGE2 levels in the CSF were depressed, while the fever remained unaffected. On the other hand, celecoxib and dipyrone both abolish the fever induced by this chemokine. If PGE2 does not participate in the febrile response evoked by CCL3/MIP-1±, the inhibition of this response by celecoxib and dipyrone indicates additional mechanisms to well-known inhibition of COX enzymes for these drugs. Such mechanisms may not depend on cytokine synthesis and ulterior COX-2 induction, important targets of steroidal drugs. Although considerable studies regarding fever induced by central injection of chemokines have been performed, there are no available data indicating which cells or receptors in the CNS are the main targets of MIP-1± for developing its pyrogenicity in rats. It is known that MIP-1± binds on CCR1- and CCR5-receptors which are expressed on microglial cells and astrocytes within the CNS. Based on these facts, we hypothesize that MIP-1± by interacting with CCR1 or CCR5 of microglial cells or astrocytes in the AH/POA can activate those cells what might result in synthesis/release of brain-derived pyrogens (CRF, TNF-±, e IL-6) for fever induction. Therefore, the central goal of this study is to identify the receptor (CCR1, CCR5) and the cell types (microglial cells, astrocytes, or others) within the POA, which are responsible for the pyrogenic effects of the chemokine MIP-1± in this specific brain area. In addition, we aim to investigate, whether a putative synthesis/release of pyrogens (CRF, TNF-±, IL-6) from the POA induced by CCL3/MIP-1± is inhibited by celecoxib, acethaminophen or dipyrone. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SOARES, DENIS M.; CRISTOFOLETTI, RODRIGO; MELO, MIRIAM C. C.; LINDSEY, CHARLES J.; VEIGA-SOUZA, FABIANE H.; FABRICIO, ALINE S. C.; SOUZA, GLORIA E. P.. Cyclooxygenase-independent mechanism of ibuprofen-induced antipyresis: the role of central vasopressin V-1 receptors. FUNDAMENTAL & CLINICAL PHARMACOLOGY, v. 25, n. 6, p. 670-681, . (08/10323-3, 99/12466-5, 97/09837-6)
SOARES, DENIS MELO; OTT, DANIELA; MELO, MIRIAM C. C.; SOUZA, GLORIA E. P.; ROTH, JOACHIM. Chemokine ligand (CCL)-3 promotes an integrated febrile response when injected within pre-optic area (POA) of rats and induces calcium signaling in cells of POA microcultures but not TNF-alpha or IL-6 synthesis. BRAIN BEHAVIOR AND IMMUNITY, v. 34, p. 120-129, . (08/10323-3, 97/09837-6)
SOARES, DENIS DE MELO; SANTOS, DANIELLE R.; RUMMEL, CHRISTOPH; OTT, DANIELA; MELO, MIRIAM C. C.; ROTH, JOACHIM; CALIXTO, JOAO B.; SOUZA, GLORIA E. P.. The relevance of kalikrein-kinin system via activation of B-2 receptor in LPS-induced fever in rats. Neuropharmacology, v. 126, p. 84-96, . (08/10323-3, 97/09837-6)

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