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

Tariq Ghayur, Subhashis Banerjee, Margaret Hugunin, Deborah Butler, Linda Herzog, Adam Carter, Lucia Quintal, Les Sekut, Robert Talanian, Michael Paskind, Winnie Wong, Robert Kamen, Daniel Tracey and Hamish Alien
Additional contact information
Tariq Ghayur: BASF Bioresearch Corporation
Subhashis Banerjee: BASF Bioresearch Corporation
Margaret Hugunin: BASF Bioresearch Corporation
Deborah Butler: BASF Bioresearch Corporation
Linda Herzog: BASF Bioresearch Corporation
Adam Carter: BASF Bioresearch Corporation
Lucia Quintal: BASF Bioresearch Corporation
Les Sekut: BASF Bioresearch Corporation
Robert Talanian: BASF Bioresearch Corporation
Michael Paskind: BASF Bioresearch Corporation
Winnie Wong: BASF Bioresearch Corporation
Robert Kamen: BASF Bioresearch Corporation
Daniel Tracey: BASF Bioresearch Corporation
Hamish Alien: BASF Bioresearch Corporation

Nature, 1997, vol. 386, issue 6625, 619-623

Abstract: Abstract 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.

Date: 1997
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DOI: 10.1038/386619a0

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