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.
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-gamma and tumor necrosis factor (TNF). Serum sTNFR-P75 and corticosterone (CS) were also elevated. IL-12 toxicity was partially prevented by anti-IFN-gamma 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-gamma 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-gamma, but a predose of murine rIFN-gamma was not protective, suggesting that IFN-gamma 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-gamma but independently of endogenous glucocorticoids. IFN-gamma, and possibly IL-10, might be important in this tolerance.
Sacco
S
S
Laboratory of Neuroimmunology, "Mario Negri" Institute for Pharmacological Research, Milano, Italy.
Heremans
H
H
Echtenacher
B
B
Buurman
W A
WA
Amraoui
Z
Z
Goldman
M
M
Ghezzi
P
P
D000818:Animals; D000906:Antibodies / Q000276:immunology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D016753:Interleukin-10 / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology
D000906:Antibodies; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D003907:Dexamethasone; D007371:Interferon-gamma