Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism

Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., interleukin 4 (IL-4), IL-5, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α)] have been shown to play vital roles in Con A–induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A–induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A–induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15–treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d−/− mice restored liver injury, whereas transfer of IL-15–treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-α production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A–induced liver injury. In conclusion, IL-15 protects against Con A–induced liver injury via an NKT cell–dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis. (HEPATOLOGY 2006;43:1211–1219.)