Intracerebroventricular interleukin-6, macrophage inflammatory protein-1 beta and IL-18: pyrogenic and PGE(2)-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)-1 beta, and interleukin (IL)-18, a member of the pyrogenic IL-1 beta family. To this end, the core temperatures (Tc) 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-1 beta (20 pg/mouse), rmIL-18 (0.01-1 microgram/mouse), rmIL-1 beta (positive control; 0.1 microgram/mouse), or their vehicle (0.1% bovine serum albumin [BSA] in sterile phosphate-buffered saline [PBS]; 5 microl/mouse). rmIL-6 caused a approximately 1 degrees C T(c) rise in WT mice that peaked at approximately 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-1 beta induced a 1 degrees C 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 approximately 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-1 beta. IL-18 i.p. or i.c.v. is not pyrogenic.
Li
Shuxin
S
Department of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163 , USA. lshuxin@physiol.utmem.edu
Goorha
Sarita
S
Ballou
Leslie R
LR
Blatteis
Clark M
CM
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D054407:Chemokine CCL4; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced* / Q000201:enzymology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D007527:Isoenzymes / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D054407:Chemokine CCL4; D020382:Interleukin-18; D015850:Interleukin-6; D007527:Isoenzymes; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases