IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor.
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.
Fantuzzi
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G
Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Giamila.Fantuzzi@UCHSC.edu
Reed
D A
DA
Dinarello
C A
CA
D000818:Animals; D020170:Caspase 1 / Q000502:physiology*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000096:biosynthesis*; D053590:Interleukin 1 Receptor Antagonist Protein; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D012795:Sialoglycoproteins / Q000494:pharmacology
D061945:Caspase Inhibitors; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D012795:Sialoglycoproteins; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1