Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.
Treatment of rats with recombinant human TNF initially causes a marked decrease in food intake, a loss of body weight, and a negative nitrogen balance. These alterations normalize with continued twice daily intraperitoneal injections of the same dose. Rats tolerized to TNF in this manner are refractory to a lethal dose of TNF. Also, TNF-pretreated and -tolerized rats have prolonged survival and reversed histopathologic changes after injection of a lethal dose of endotoxin compared with control animals. The TNF-tolerant state is dependent on the dose of TNF used and the length of TNF pretreatment. TNF-induced tolerance is relatively short lived, being present 2-4 d after TNF pretreatment and dissipating by 2 wk. Rats made tolerant to endotoxin are also tolerant to a lethal dose of TNF. A bidirectional crossreacting tolerance exists between TNF and endotoxin. The mechanism of TNF tolerance is unclear, but it does not appear to be due to a humoral immune response or a perturbation of the uptake and clearance of injected TNF.
Fraker
D L
DL
Surgical Metabolism Section, National Cancer Institute, Bethesda, Maryland 20892.
Stovroff
M C
MC
Merino
M J
MJ
Norton
J A
JA
D000818:Animals; D001835:Body Weight; D004361:Drug Tolerance; D004435:Eating; D004731:Endotoxins / Q000494:pharmacology* / Q000633:toxicity; D004926:Escherichia coli; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007700:Kinetics; D008297:Male; D009584:Nitrogen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*
D004731:Endotoxins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009584:Nitrogen