Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN- γ production

Interferon-γ-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the inter-leukin-1 (IL-1) family of proteins and functional properties with IL-121–4. Like IL-12, IGIF is a potent inducer of interferon (IFN)-γ from T cells and natural killer cells1–3,5,6. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-lβ, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-lβ) at an Asp-X site by interleukin-lβ-converting enzyme7,8 (ICE, recently termed caspase-19). The Asp-X sequence at the putative processing site in proIGIF2,3 suggests that a protease such as caspase-1 might be involved in the maturation of IGIF4. Here we demonstrate that caspase-1 processes proIGIF and proIL-lβ with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1β and IFN-γ production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccharide-induced IFN-γ 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 anti-inflammatory drugs with multipotent action.