Critical role of IL-18 in endotoxin-induced liver injury.

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IL-18 is a pleiotropic cytokine. IL-18 induces IFN-gamma in lymphocytes, upregulates functional Fas ligand expression of lymphocytes and also augments NK activity. Initially, IL-18 was discovered in the injured liver of the mice that had been sequentially administered with heat-killed Propionibacterium acnes (P.acnes) and endotoxin (LPS). IL- 18 is secreted by LPS-activated P.acnes-elicited Kupffer cells. IL-18 is produced by these cells as biologically inactive precursor form (prolL-18), and prolL-18 is cleaved into mature IL-18 by intracellular cysteine proteinase, caspase-l. In this study, we investigated the precise mechanism how IL-18 is involved in endotoxin-induced liver injury and found the followings. First, IL-18-deficient mice are resistant to endotoxin-induced liver injury, but highly sensitive to endotoxin-induced lethality, suggesting that IL-18 might be critical to endotoxin-induced liver injury. In addition, T cells in IL-18-deficient mice are impaired in the differentiation into Th1, a prototpe to inflammation, and NK activity of the mice also is defective, indicating that IL-18 is essential for functional development of immune system. Second, receptor for IL-18 is constitutively expressed on NK cells, whereas its expression on T cells is induced after stimulation with IL-12. MyD 88, an adapter molecule for the activation of receptor for IL-1 is critical for the signal transduction of IL-18. Lymphocytes from MyD88-deficient mice do not respond to IL-18 as well as IL-1. Third, caspase-1 deficient mice are resistant to the endotoxin-induced liver injury without showing early elevation of serum IL- 18 level, suggesting caspase- 1 is critical for IL- 18 secretion after stimulation with LPS.These results suggested that IL-18 might be an essential factor for endotoxin-induced liver injury.