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Alpha-Galactosylceramide (α-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from α-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of α-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)−4 and a delayed elevation in the levels of interferon-gamma (IFN-γ), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, genetic deletion of both IL-4 and IFN-γ aggravated, rather than abolished, α-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated α-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-γ, the IFN-γ receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated α-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-γ knockout mice. Conclusion: Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-γ, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-γ may have the potential to improve the efficacy of α-Galcer in the treatment of liver disease. (Hepatology 2013;58:1474–1485)