IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor

J Clin Invest. 1999 Sep;104(6):761-7. doi: 10.1172/JCI7501.


IL-12 and IL-18 are IFN-gamma-inducing cytokines. In the present study, the role of endogenous IL-18 in the induction of IFN-gamma by IL-12 was investigated in mice. In the presence of a specific inhibitor of caspase-1 (also known as IL-1beta-converting enzyme, or ICE) IL-12-induced IFN-gamma from splenocytes was reduced by 85%. Using splenocytes from ICE-deficient mice, IL-12-induced IFN-gamma was reduced by 80%. However, the role of ICE was not through processing and release of IL-1beta. Neutralizing anti-IL-18 IgG reduced IL-12-induced IFN-gamma in splenocytes by 85%. Splenocytes cultured in vitro spontaneously released IL-18 into the extracellular compartment over time. Extracellular levels of IL-18 significantly correlated with IL-12-induced IFN-gamma and were reduced in cells obtained from ICE-deficient mice. In vivo, IL-12 administration increased circulating levels of IL-18 in wild-type mice but not in ICE-deficient mice. Both neutralization of IL-18 and ICE deficiency significantly reduced induction of circulating IFN-gamma in mice receiving IL-12. The IL-18 precursor was constitutively expressed in the livers and spleens of untreated mice. Furthermore, administration of IL-12 significantly increased liver-associated IL-18 levels. These data demonstrate that endogenous, ICE-cleaved IL-18 significantly contributes to induction of IFN-gamma by IL-12.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caspase 1 / physiology*
  • Caspase Inhibitors
  • Cells, Cultured
  • Interferon-gamma / biosynthesis*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-12 / pharmacology*
  • Interleukin-18 / antagonists & inhibitors
  • Interleukin-18 / biosynthesis*
  • Mice
  • Mice, Knockout
  • Sialoglycoproteins / pharmacology


  • Caspase Inhibitors
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-18
  • Sialoglycoproteins
  • Interleukin-12
  • Interferon-gamma
  • Caspase 1