The glucocorticoid antagonist RU38486 mimics interleukin-1 in its sensitization to the lethal and interleukin-6-inducing properties of tumor necrosis factor.
Although tumor necrosis factor (TNF) is undoubtedly a major mediator of the antitumor and shock-inducing activities of lipopolysaccharide (LPS), the outcome of a challenge with TNF is highly dependent on the presence or absence of other substances or conditions. We have previously shown that to obtain lethality in mice after TNF administration both TNF receptor (TNF-R) types have to be triggered. This is illustrated by the fact that recombinant human (rh) TNF, which is a selective murine (m) TNF-R55 agonist, is not lethal, whereas mTNF, which binds both mTNF-R55 and mTNF-R75, is lethal in mice. Triggering of TNF-R75 is, however, no longer needed when sensitizers such as galactosamine or low doses of LPS or interleukin (IL)-1 are also present. Here, we report that this selective species specificity of TNF is also reflected in patterns of induced IL-6: both rmTNF and rhTNF could induce considerable IL-6 peak levels in the plasma (up to 10 ng/ml) 2 to 3 h after TNF administration. However, only rmTNF was capable of inducing the same pattern of sustained IL-6 levels previously observed after lethal LPS doses, while rhTNF only caused induction of transient IL-6 levels, as found after nonlethal LPS doses. We also observed that the sensitizer IL-1 could complement rhTNF to induce such a sustained IL-6 induction. Since we were interested in sensitizers with a defined mechanism of action, we further investigated the effects of the glucocorticoid and progesterone inhibitor RU38486 on the lethal and IL-6-inducing properties of TNF. We observed that RU38486 closely mimicked IL-1: both had similar effects on IL-6 induction and sensitized mice to the lethal effects of TNF with comparable efficiency and kinetics. Using a monoclonal anti-IL-1R antibody, we finally observed that the effects of RU38486 were most probably not mediated by IL-1. These observations suggest that a glucocorticoid-antagonistic activity might be a key factor in the pathways leading to septic shock and that such activity could be a key target for the pharmacological manipulation of sepsis.
Brouckaert
P
P
Laboratory of Molecular Biology, State University, Gent, Belgium.
Everaerdt
B
B
Fiers
W
W
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000502:physiology; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D013045:Species Specificity; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone