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

Nature. 1997 Apr 10;386(6625):619-23. doi: 10.1038/386619a0.


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. Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-1beta, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-1beta) at an Asp-X site by interleukin-1beta-converting enzyme (ICE, recently termed caspase-1). The Asp-X sequence at the putative processing site in proIGIF suggests that a protease such as caspase-1 might be involved in the maturation of IGIF. Here we demonstrate that caspase-1 processes proIGIF and proIL-1beta with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1beta 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 anti-inflammatory drugs with multipotent action.

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Caspase 1
  • Cloning, Molecular
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytokines / metabolism*
  • Humans
  • Interferon Inducers / metabolism*
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / blood
  • Interferon-gamma / genetics
  • Interleukin-1 / blood
  • Interleukin-12 / blood
  • Interleukin-18
  • Interleukin-6 / blood
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / enzymology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mutagenesis, Site-Directed
  • Oligopeptides / pharmacology
  • Protein Precursors / metabolism
  • Protein Processing, Post-Translational*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Cysteine Proteinase Inhibitors
  • Cytokines
  • Interferon Inducers
  • Interleukin-1
  • Interleukin-18
  • Interleukin-6
  • Lipopolysaccharides
  • Oligopeptides
  • Protein Precursors
  • Recombinant Proteins
  • L 709049
  • Interleukin-12
  • Interferon-gamma
  • Cysteine Endopeptidases
  • Caspase 1