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Protective Effect of a Single Interleukin-12 (IL-12) Predose Against the Toxicity of Subsequent Chronic IL-12 in Mice: Role of Cytokines and Glucocorticoids
Silvano Sacco,
Hubertine Heremans,
Berndt Echtenacher,
Wim A. Buurman,
Zoulikha Amraoui,
Michel Goldman, and
Pietro Ghezzi
From the Laboratory of Neuroimmunology, "Mario Negri" Institute for Pharmacological Research, Milano, Italy; Rega Institute, University of Leuven, Belgium; University of Regensburg, Regensburg, Germany; Department of Surgery, Limburg University, Maastricht, the Netherlands; and Laboratoire d'Immunologie Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
The mechanisms of interleukin-12 (IL-12) toxicity were studied in mice using a schedule (murine rIL-12, 400 ng/mouse, intraperitoneally [IP] once daily for 5 days) that markedly reduced body weight and food intake. On day 5, IL-12-treated mice had elevated serum and spleen IFN- and tumor necrosis factor (TNF). Serum sTNFR-P75 and corticosterone (CS) were also elevated. IL-12 toxicity was partially prevented by anti-IFN- antibodies or dexamethasone (DEX). A pre-dose of IL-12 (200 ng/mouse on day -14) completely prevented the toxicity of subsequent IL-12. The IL-12 predose also inhibited IL-12-induced IFN- levels, but did not modify IL-12-induced CS, TNF or sTNFR-P75. A protective effect was observed with a predose of lipopolysaccharide (LPS) or murine recombinant (r)IL-10. The protective effect of the IL-12 predose was reduced by coadministration of anti-IFN-, but a predose of murine rIFN- was not protective, suggesting that IFN- is necessary but not sufficient for the protective effect of IL-12. The IL-12 predose specifically protected against IL-12 toxicity and did not modify LPS toxicity. These data indicate that IL-12 can induce tolerance to its own toxicity, probably through a downregulation of IL-12-induced IFN- but independently of endogenous glucocorticoids. IFN-, and possibly IL-10, might be important in this tolerance.
Blood, Vol. 90 No. 11 (December 1), 1997:
pp. 4473-4479
© 1997 by The American Society of Hematology.
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