In vivo evidence that activation of tyrosine kinase is a trigger for lipopolysaccharide-induced fever in rats.
We measured the rectal temperature of free-moving, conscious rats after intracerebroventricular (i.c.v.) injections of lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta) with or without various antagonists to investigate the mechanisms involved in LPS-induced fever. LPS (3 microg) elicited significant increases in rectal temperature, which lasted from 0.5 h to more than 8 h after administration. This febrile response was inhibited by pretreatment with L-nitro-arginine (LNA), indomethacin (IND), genistein (GEN), tyrphostin 46 and anti-rat IL-1beta antibody (anti-IL-1beta Ab), but was not inhibited by pretreatment with daidzein or chelerythrine (CHE) into the ventricle. LPS (0.3 microg) following orthovanadate (i.c.v.) produced fever, although the small amount of LPS (0.3 microg) or orthovanadate alone showed no effect on rectal temperature. I.c.v. injections of IL-1beta also induced fever of approximately 4-h duration. This effect was inhibited by pretreatment with IND and anti-IL-1beta Ab, but was not inhibited by pretreatment with LNA, GEN or CHE into the ventricle. These findings demonstrate that in the central nervous system, LPS increases IL-1beta production after activation of tyrosine kinase and NO synthase, and IL-1beta promotes prostaglandin production resulting in increased rectal temperature. Activation of tyrosine kinase in the central nervous system is probably a trigger for the febrile response induced by LPS.
Tsushima
H
H
Department of Pharmacology, Nagoya City University Medical School, Nagoya, Aichi, Japan.
Mori
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000906:Antibodies; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; C064769:N-acetylsphingosine; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D013110:Sphingosine