The regulatory effects of cytokines on the induction of a peripheral immunologic tolerance in mice.

Previous reports have demonstrated that injection of rIL-1 alpha into mice abrogates the ability of deaggregated human gamma-globulin (HGG) to induce a state of antigen specific immunologic tolerance in vivo. Our results demonstrate that human rIL-1 beta and a bioactive nonapeptide of human IL-1 beta inhibit the induction of tolerance to HGG suggesting that IL-1 affects tolerance induction through a noninflammatory mechanism of action because the immunoactive nonapeptide possesses only immunomodulatory properties. Further, TNF-alpha but not IL-6, cytokines with many bioactivities in common with IL-1, was found to inhibit the induction of tolerance. Therefore, it appears unlikely that IL-6 plays a role in the pathway by which either IL-1 or TNF-alpha interferes with tolerance induction. Although IL-2, IL-4, and IFN-gamma were incapable of directly affecting the induction of tolerance to HGG, it was determined that IL-4 and IFN-gamma were capable of inhibiting the ability of IL-1 to abrogate tolerance induction. It has been suggested that IL-1 induces the generation of endogenous IL-1 in vivo. Further, it has been demonstrated that IFN-gamma as well as IL-4 inhibits the synthesis of IL-1. Inasmuch as IL-4 and IFN-gamma inhibit the ability of IL-1 to abrogate tolerance induction, it appears that it is the endogenously generated IL-1 that interferes with tolerance induction. It was also determined that neither IL-4 nor IFN-gamma inhibits the activity of IL-1 which is consistent with results reported by others. Thus, results presented here suggest that the inhibition of tolerance induction to HGG by IL-1 may involve the stimulation of endogenous IL-1 synthesis.