Recombinant human tumor necrosis factor causes long-lasting and prostaglandin-mediated fever, with little tolerance, in rabbits.
The pyrogenic properties of high purified recombinant human tumor necrosis factor (rHu-TNF) were investigated in rabbits. rHu-TNF produced a clear biphasic fever reaching maximal values at 1 and 5 hr after bolus i.v. injections of 10 and 33 micrograms/kg; the initial febrile response was short-lasting, and not dose-related, but the second one was dose-related and lasted for 10 hr or more. The febrile response to rHu-TNF, unlike lipopolysaccharide, did not decrease after a single or two consecutive doses. A significant reduction in the febrile response, however, was seen after four consecutive doses starting from 7 days after the second dose; the febrile response 3 hr after rHu-TNF was much smaller, but the first peak was hardly smaller. Low anti-rHu-TNF levels were found in serum of rabbits treated repeatedly with rHu-TNF, suggesting that antibody production against rHu-TNF is not responsible for the tolerance formation although it may make some contribution. There was no cross-tolerance between rHu-TNF and lipopolysaccharide. On the other hand, the febrile response to rHu-TNF (33 micrograms/kg i.v.) was inhibited partially or completely blocked by i.v. administration of cyclooxygenase inhibitors or dexamethasone. rHu-TNF produced a marked increase in the cerebrospinal fluid prostaglandin E2 level after bolus i.v. injection. A significant level of rHu-TNF (1.6 and 6.4% of that in serum) was found in cerebrospinal fluid after bolus i.v. injection of 33 and 1000 micrograms/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Nakamura
H
H
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Seto
Y
Y
Motoyoshi
S
S
Kadokawa
T
T
Sunahara
N
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015232:Dinoprostone; D005334:Fever / Q000139:chemically induced*; D008297:Male; D011453:Prostaglandins / Q000378:metabolism*; D011458:Prostaglandins E / Q000134:cerebrospinal fluid; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D011453:Prostaglandins; D011458:Prostaglandins E; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone