Intracerebroventricular interleukin-6, macrophage inflammatory protein-1β and IL-18:: pyrogenic and PGE2-mediated?

This study was undertaken to determine whether cyclooxygenase (COX)-2, the critical enzyme in the production of febrigenic prostaglandin (PG) E-2, may be involved centrally in the fever induced in mice by homologous interleukin (IL)-6, macrophage inflammatory protein (MIP)-1beta, and interleukin (IL)-18, a member of the pyrogenic IL-1beta family. To this end, the core temperatures (T-c) of COX-1 and COX-2 gene-ablated mice and of their normal wild-type (WT) counterparts were recorded after intracerebroventricular (i.c.v.) challenge with recombinant murine (rm) IL-6 (10 ng/mouse), rmMIP-1beta (20 pg/mouse), rmIL-18 (0.01-1 mug/mouse), rmIL-1beta (positive control; 0.1 mug/ mouse), or their vehicle (0.1% bovine serum albumin [BSA] in sterile phosphate-buffered saline [PBS]; 5 mul/mouse). rmIL-6 caused a similar to 1 degreesC T-c rise in WT mice that peaked at similar to 120 min and gradually recovered over the next 3 h; COX-1(-/-) mice exhibited a relatively faster (peak at 45 min) and shorter (recovery at 150 min) febrile course, whereas COX-2(-/-) mice did not develop fever. rmMIP-1beta induced a 1 degreesC fever (peak at 60 min) with a long time course (recovery incomplete at 300 min) in both WT and COX-2(-/-) mice; COX-1(- / -) mice displayed a quick-onset (peak at 40 min) and shorter (recovery at - 240 min) fever. rmIL-18 did not cause any thermal response at any dose whether administered intraperitoneally (i.p.) or i.c.v. in WT mice; COX gene-ablated mice, therefore, were not tested. These data indicate that COX-2-dependent PGE(2) is critical for the febrile response to IL-6, but not to MIP-1beta. IL-18 i.p. or i.c.v. is not pyrogenic. (C) 2003 Elsevier B.V. All rights reserved.