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

IL-18, produced as a biologically inactive precursor, is processed by caspa se-1 in LPS-activated macrophages. Here, we investigated caspase-1-independ ent 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 IFN gamm a-dependent manner, and these macrophages became competent to secrete matur e IL-18 upon stimulation with Fast. This was also the case for caspase-1-de ficient mice. Administration of recombinant soluble Fast (rFasL) after P. a cnes priming induced comparable elevation of serum IL-18 in parallel with e levated 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 Fast-stimulated macro phages and its critical involvement in Fast-induced liver injury.