CASPASE-1 PROCESSES IFN-GAMMA-INDUCING FACTOR AND REGULATES LPS-INDUCED IFN-GAMMA PRODUCTION

Interferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleuki n-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 b iologically inactive precursor molecule (proIGIF). The cellular produc tion 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 ter med 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 in volved in the maturation of IGIF(4). Here we demonstrate that caspase- 1 processes proIGIF and pron-1 beta with equivalent efficiencies in vi tro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-in duced IL-1 beta and IFN-gamma production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccha ride-induced IFN-gamma production, Our results thus implicate caspase- 1 in the physiological production of IGIF and demonstrate that it play s a critical role in the regulation of multiple proinflammatory cytoki nes. Specific caspase-1 inhibitors would provide a new class of antiin flammatory drugs with multipotent action.