Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.
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.
Ghayur
T
T
BASF Bioresearch Corporation, Worcester, Massachusetts 01605-4314, USA. ghayur@biovax.dnet.basf-ag.de
Banerjee
S
S
Hugunin
M
M
Butler
D
D
Herzog
L
L
Carter
A
A
Quintal
L
L
Sekut
L
L
Talanian
R
R
Paskind
M
M
Wong
W
W
Kamen
R
R
Tracey
D
D
Allen
H
H
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D020170:Caspase 1; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007369:Interferon Inducers / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D007375:Interleukin-1 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D020382:Interleukin-18; D015850:Interleukin-6 / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D007369:Interferon Inducers; D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009842:Oligopeptides; D011498:Protein Precursors; D011994:Recombinant Proteins; C096429:L 709049; D018664:Interleukin-12; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D020170:Caspase 1