Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat.
Although a number of studies indicate that the pyrogenic activity of lipopolysaccharide (LPS) and/or interleukin (IL)-1 is mediated via induction of IL-6, this has been questioned by recent evidence demonstrating a dissociation between fever and circulating IL-6. The present study reexamines this relationship by use of human recombinant interleukin-1 receptor antagonist (IL-1ra). Injection of LPS (100 micrograms/kg ip) into rats induced fever (2.0 degrees C) that was significantly inhibited (P < 0.05) when IL-1ra (16 mg/kg ip) was given 1 and 2 h after LPS. The rise in plasma IL-6 preceded the febrile response by 1-1.5 h and, although the concentrations of bioactive IL-6 in plasma and cerebrospinal fluid (CSF) were not reduced at 4 h, at 2 h plasma and CSF IL-6 bioactivity was inhibited by 80 and 70%, respectively, after a single injection of IL-1ra (16 mg/kg ip). Intracerebroventricular injection of IL-1ra (200 micrograms/rat) inhibited LPS fever but did not affect the plasma IL-6 bioactivity measured 2 or 4 h after intraperitoneal LPS. These data show that peripheral IL-1 plays a part in the induction of both fever and the rise in plasma IL-6 that precedes it, and that IL-1 within the brain is also important in the induction of fever by LPS.
Luheshi
G
G
School of Biological Sciences, University of Manchester, United Kingdom.
Miller
A J
AJ
Brouwer
S
S
Dascombe
M J
MJ
Rothwell
N J
NJ
Hopkins
S J
SJ
D000818:Animals; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D005334:Fever / Q000139:chemically induced* / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000097:blood / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000097:blood* / Q000134:cerebrospinal fluid; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D013997:Time Factors
D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins