Recombinant IL-1 receptor antagonist protects against TNF-induced lethality in mice.
The possible role of induced IL-1 in a number of in vivo actions of TNF was investigated. We were particularly interested to know whether a species-specific induction of IL-1 might explain the important differences observed between murine TNF and human TNF in systems such as lethal shock and the induction of long lasting, high levels of circulating IL-6 in mice. We also studied the possible involvement of IL-1 in the sensitization to TNF observed in tumor-bearing mice or in combination with D(+)-galactosamine or RU38486, particularly because such sensitization results in the loss of species-specific differences between both TNF. Using a specific rIL-1R antagonist (IL-1ra), which inhibits the binding of IL-1 to the IL-1R type I, we were able to protect mice against a lethal murine TNF injection. However, the induction of high levels of circulating IL-6 by murine TNF was not affected, although IL-1ra almost completely blocked the induction of IL-6 by exogenously administered IL-1. Furthermore, the increased susceptibility of tumor-bearing mice to human TNF, relative to control mice, or the sensitization by co-administration of RU38486 or D(+)-galactosamine do not seem to be mediated by IL-1.
Everaerdt
B
B
Laboratory of Molecular Biology, University, Gent, Belgium.
Brouckaert
P
P
Fiers
W
W
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D005260:Female; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000633:toxicity; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone