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-gamma), and tumor necrosis factor alpha (TNF-alpha)] 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-alpha 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.