Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats.
Cytokine-induced neutrophil chemoattractant-1 (CINC-1), a member of the ELR+CXC subfamily [ELR motif (glutamic acid-leucine-arginine) adjacent to the cysteine-X-cysteine (CXC) motif located at the N-terminus of the protein], is an acute-phase protein and its synthesis is induced by endogenous and exogenous pyrogens. However, there are no studies on the pyrogenic property of CINC-1. Therefore, the present study evaluates whether centrally administered CINC-1 promotes an integrated febrile response along with an increase in the prostaglandin (PG)E2 content of the cerebrospinal fluid (CSF) of rats. The effects of antipyretic drugs on fever and on the PGE2 content of the CSF as well as the effectiveness of a neutralizing anti-CINC-1 antibody on the fever induced by CINC-1 have also been investigated. Intracerebroventricular (i.c.v.) injection of CINC-1 induced a dose-dependent bell-shaped rise on body temperature and increased PGE2 concentration in the CSF of conscious rats. Injected into the preoptic area of the anterior hypothalamus (AH/POA) (i.h.), CINC-1 also induced a dose-dependent bell-shaped increase in body temperature along with a decrease on tail skin temperature. Indomethacin (INDO, 2 mg kg(-1), i.p.) and ibuprofen (IBU, 10 mg kg(-1), i.p.) markedly reduced the fever evoked by i.c.v. injection of CINC-1 (25 ng/site). Orally given celecoxib (5 mg kg(-1), 30 min. before) abolished the fever induced by CINC-1 i.c.v. or i.h. (50 pg) injection. The antipyretic drugs also blocked the PGE(2) increase after CINC-1 i.c.v. injection. Co-injected anti-CINC antibody (10 ng/site) strongly reduced the febrile response induced by CINC-1 (50 pg/site) injected intrahypothalamically. This is the first time that centrally injected CINC-1 has been reported to act directly on the pyrogen-sensitive neurons of AH/POA, promoting a thermoregulatory response that seems to depend on other endogenous pyrogens synthesis and, as seen here, on PGE2.
Soares
Denis Melo
DM
Laboratory of Pharmacology, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences, USP, Ribeirão Preto, SP, Brazil.
Machado
Renes R
RR
Yamashiro
Lívia H
LH
Melo
Miriam C C
MC
Souza
Glória E P
GE
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001831:Body Temperature / Q000502:physiology; D000068579:Celecoxib; D054360:Chemokine CXCL1 / Q000008:administration & dosage / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000134:cerebrospinal fluid*; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000188:drug therapy / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D011301:Preoptic Area / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone