IL-18, which requires cleavage with caspase-1 to become active, was originally discovered as a factor that enhances IFN-gamma production from Th1 cells in the presence of anti-CD3 or anti-TcR Ab. However, it was later shown that IL-12 and IL-18 without TcR engagement can induce IFN-gamma in Th1 cells and nonpolarized T cells. Additional TcR engagement has no effect on this IFN-gamma response. Furthermore, a combination of IL-12 and IL-18 acts on B cells, NK cells, macrophages and dendritic cells to produce IFN-gamma. In contrast, IL-18 without help from IL-12 induces Th2 cytokines in T cells and NK cells. Moreover, IL-18 directly stimulates basophils and mast cells to produce Th2 cytokines and histamine independently of IgE. Most surprisingly, IL-18 causes high-level IgE production when administered to normal mice by causing CD4+ T cells to produce IL-4 and to express CD 40 ligand. We established skin-specific caspase-1 transgenic mice with elevated levels of IL-18 in their sera. We found high serum level of IgE, which is entirely dependent on stat 6 in these transgenic mice. These results indicate that caspase-1/IL-18 may be critically involved in regulation of IgE production in vivo, providing a potential therapeutic target for allergic disorders.