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)E-2 content of the cerebrospinal fluid (CSF) of rats. The effects of antipyretic drugs on fever and on the PGE(2) 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 PGE(2) 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 PGE(2). (c) 2008 Elsevier B.V. All rights reserved.