IL-18 (interferon-inducing factor) and IL-12 exhibit a marked synergism in interferon-γ induction in T cells. Investigations into the mechanism of this synergism have revealed that IL-12 upregulates expression of the IL-18 receptor on cells producing interferon-γ. Although IL-18 does not induce the development of Th1 cells, it is essential for the effective induction and activation of Th1 cells by IL-12. As for natural killer cells, IL-18 seems to activate them independently of IL-12. Although IL-12 and IL-18 activate both innate and acquired immunity, their excessive production by activated macrophages may induce multiple organ disorders including disruption of the immune system.