Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice

Immunity. 1999 Sep;11(3):359-67. doi: 10.1016/s1074-7613(00)80111-9.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones
  • Animals
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Caspase Inhibitors
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors
  • Fas Ligand Protein
  • Female
  • Humans
  • Interleukin-18 / metabolism*
  • Liver Diseases / immunology*
  • Liver Diseases / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Solubility
  • fas Receptor / metabolism*


  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Interleukin-18
  • Membrane Glycoproteins
  • N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
  • Recombinant Proteins
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • fas Receptor
  • Caspase 1