Caspase-1-Independent, Fas/Fas Ligand–Mediated IL-18 Secretion from Macrophages Causes Acute Liver Injury in Mice

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.

IL‐18 associates to microvesicles shed from human macrophages by a LPS/TLR‐4 independent mechanism in response to P2X receptor stimulation

“…As reported for monocytes and differently from viral or IL-12-induced IL-18 production [47][48][49], ATP-stimulated IL-18 release is casp-1 independent [26]. Here we show that in human macrophages MV-associated pro-IL-18 was not cleaved by casp-1.…”

Production of a Biologically Active Human Interleukin 18 Requires Its Prior Synthesis as Pro-Il-18

“…12 A caspase-1-independent pathway of IL-18 secretion from FasL-stimulated macrophages was recently demonstrated, suggesting that FasL may induce alternative mechanisms for production of IL-18. 13 Unlike mouse IL-18, 2 we noticed that recombinant human IL-18 is poorly active as a co-inducer of IFN-. Low activity of recombinant proteins is usually due to their aberrant folding.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…In addition, Fas signaling contributes to the production of active IL-1b/IL-18; injection of FasL-expressing cells into the peritoneal cavity of mice induces the production of active IL-1b and the accumulation of neutrophils (Miwa et al 1998). FasL-Fas signaling also contributes to the production of active IL-18 in a mice model of graft-versus-host disease (Tsutsui et al 1999). In caspase-8/RIP3-deficient cells, Fas-activated caspase-8 has been shown to contribute to the processing of pro-IL-1b/ IL-18 to yield active cytokines (Bossaller et al 2012).…”