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 rlL-12, 400 ng/mouse, intraperitoneally [IP] once daily for 5 days) that markedly reduced body weight and food int ake. On day 5, IL-12-treated mice had elevated serum and spleen IFN-ga mma and tumor necrosis factor (TNF). Serum sTNFR-P75 and corticosteron e (CS) were also elevated. IL-12 toxicity was partially prevented by a nti-IFN-gamma antibodies or dexamethasone (DEX). A pre-dose of IL-12 ( 200 ng/mouse on day -14) completely prevented the toxicity of subseque nt IL-12. The IL-12 predose also inhibited IL-12-induced IFN-gamma lev els, but did not modify IL-12-induced CS, TNF or sTNFR-P75. A protecti ve effect was observed with a predose of lipopolysaccharide (LPS) or m urine recombinant (r)IL-10. The protective effect of the IL-12 predose was reduced by coadministration of anti-IFN-gamma, but a predose of m urine rIFN-gamma was not protective, suggesting that IFN-gamma is nece ssary but not sufficient for the protective effect of IL-12. The IL-12 predose specifically protected against IL-12 toxicity and did not mod ify LPS toxicity. These data indicate that IL-12 can induce tolerance to its own toxicity, probably through a downregulation of IL-12-induce d IFN-gamma but independently of endogenous glucocorticoids. IFN-gamma , and possibly IL-10, might be important in this tolerance. (C) 1997 b y The American Society of Hematology.