Abstract
IL-18, produced as a biologically inactive precursor, is processed by caspase-1 in LPS-activated macrophages. Here, we investigated caspase-1-independent processing of IL-18 in Fas ligand (FasL)-stimulated macrophages and its involvement in liver injury. Administration of Propionibacterium acnes (P. acnes) upregulated functional Fas expression on macrophages in an IFNgamma-dependent manner, and these macrophages became competent to secrete mature IL-18 upon stimulation with FasL. This was also the case for caspase-1-deficient mice. Administration of recombinant soluble FasL (rFasL) after P. acnes priming induced comparable elevation of serum IL-18 in parallel with elevated serum liver enzyme levels. However, liver injury was not induced in IL-18-deficient mice after rFasL administration. These results indicate a caspase-1-independent pathway of IL-18 secretion from FasL-stimulated macrophages and its critical involvement in FasL-induced liver injury.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones
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Animals
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Caspase 1 / genetics
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Caspase 1 / metabolism*
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Caspase Inhibitors
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Cells, Cultured
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Cysteine Proteinase Inhibitors
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Fas Ligand Protein
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Female
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Humans
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Interleukin-18 / metabolism*
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Liver Diseases / immunology*
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Liver Diseases / pathology
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Macrophages / drug effects
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Macrophages / metabolism*
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Solubility
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fas Receptor / metabolism*
Substances
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Amino Acid Chloromethyl Ketones
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Interleukin-18
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Membrane Glycoproteins
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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Recombinant Proteins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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fas Receptor
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Caspase 1