Sensitization and desensitization to lethal effects of tumor necrosis factor and IL-1.
BALB/c mice were sensitized to lethal effects of human rTNF-alpha and of human rIL-1 alpha by simultaneous treatment with sublethal doses of actinomycin D (Act D) or D-galactosamine (GalN). In contrast, treatment with sublethal doses of TNF or IL-1 themselves resulted in desensitization of the mice to the lethal effect of these cytokines: mice injected with TNF or IL-1 in the absence of Act D or GalN responded to a second injection of TNF or IL-1, this time together with Act D or GalN, by a significantly delayed death, or even survived. Desensitization developed rapidly (0.5-1.0 h) and abated 24 to 48 h postinjection. Each of the two cytokines induced hyporesponsiveness to its own lethal effect as well as to that of the other. Injection of TNF or IL-1 at sublethal doses resulted also in hyporesponsiveness to the lethal effect of LPS on mice primed with bacillus Calmette-Guérin, an effect which most likely is mediated by TNF and IL-1 produced in those mice in response to the LPS. TNF and IL-1 in combination had an additive effect both in lethality and in desensitization of the mice. These findings suggest that some of the deleterious effects of TNF and IL-1 are modulated by antagonistic mechanisms; mechanisms which can be suppressed by sensitizing agents, specifically by agents inhibiting the synthesis of RNA or protein; but which, in the absence of such agents, are found to be augmented in response to TNF and IL-1, thus resulting in desensitization.
Wallach
D
D
Department of Virology, Weizmann Institute of Science, Rehovot, Israel.
Holtmann
H
H
Engelmann
H
H
Nophar
Y
Y
D000818:Animals; D001500:BCG Vaccine / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005688:Galactosamine / Q000494:pharmacology; D007375:Interleukin-1 / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D001500:BCG Vaccine; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D005688:Galactosamine