MECHANISM OF INTERLEUKIN 12-MEDIATED TOXICITIES DURING EXPERIMENTAL VIRAL-INFECTIONS - ROLE OF TUMOR-NECROSIS-FACTOR AND GLUCOCORTICOIDS

Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic cho riomeningitis virus (LCMV) These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8(+) T cell expansion a nd CTL activation, and up to 2 log increases in viral replication. The y are accompanied by induction of serum tumor necrosis factor (TNF). T he studies presented here were undertaken to characterize mechanisms f or the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated v irus-infected mice. IL-12 induced (a) decreases in body weights, >10% in uninfected and >20% in LCMV-infected mice; (b) elevation of circula ting glucocorticoid levels to >10 mu g/dl in uninfected and >20 mu g/d l in infected mice; and (c) decreases in thymic mass, >30% in uninfect ed and up to 95% in infected mice. These changes are known to be assoc iated with circulating TNF. Northern blot and in situ hybridization an alyses demonstrated that IL-12 induced TNF-alpha expression and that L CMV infection synergized with IL-12 for induction of this factor. Anti bodies neutralizing TNF reversed all of the IL-12-induced toxicities i n LCMV-infected mice including the immunotoxicities against CD8(+) T c ells and anti-viral defenses. The TNF-mediated immunotoxicities appear ed to result from an induced cellular sensitivity to the factor, as sp lenic leukocytes and CD8(+) T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiment s with the glucocorticoid type II receptor antagonist, RU486, demonstr ated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed th at the synergism was dependent upon endogenous IL-2. The results delin eate a unique mechanism of TNF-mediated toxicity. In addition, they ha ve significant implications concerning potential detrimental consequen ces of in vivo TNF induction and of IL-12 administration for protectiv e anti-viral responses.