Interferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleukin-1 (IL-1) family of proteins and functional properties with IL-12(1-4). Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells(1-3,5,6). IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-1 beta, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-1 beta) at an Asp-X site by interleukin-1 beta-converting enzyme(7,8) (ICE, recently termed caspase-1(9)), The Asp-X sequence at the putative processing site in proIGIF(2,3) suggests that a protease such as caspase-1 might be involved in the maturation of IGIF(4). Here we demonstrate that caspase-1 processes proIGIF and pron-1 beta with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1 beta and IFN-gamma production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccharide-induced IFN-gamma production, Our results thus implicate caspase-1 in the physiological production of IGIF and demonstrate that it plays a critical role in the regulation of multiple proinflammatory cytokines. Specific caspase-1 inhibitors would provide a new class of antiinflammatory drugs with multipotent action.