Involvement of the liver, but not of IL-6, in IL-1-induced desensitization to the lethal effects of tumor necrosis factor.
C57BL/cnb mice were found to be protected against a lethal combination of recombinant murine (m) TNF and GalN by pretreatment with several cytokines. At certain doses, rmTNF and human (h) TNF protected completely. The clearest protection was induced by rIL-1: all four rIL-1 species (both m and h, as well as alpha and beta) protected when given 12 h before the challenge. LPS and rmIFN-gamma protected weakly, whereas rmIL-6 and rhIL-6 did not protect at all. Also adrenocorticotropic hormone, dexamethasone, or dexamethasone in combination with rhIL-6 could not protect. A single IL-1 injection also completely protected mice against a lethal dose of mTNF in the absence of GalN sensitization. The desensitization by IL-1 cannot be explained by a faster clearance of the challenge TNF. In addition, we demonstrate that the IL-1-induced desensitization was only observed when a functioning liver was present, that IL-1-pretreated animals did not show decreased numbers of hepatocyte TNF receptors, and that the amount of TNF-induced IL-6 was not reduced.
Libert
C
C
Laboratory of Molecular Biology, State University, Gent, Belgium.
Van Bladel
S
S
Brouckaert
P
P
Shaw
A
A
Fiers
W
W
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D007375:Interleukin-1; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone