Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-α during alcohol consumption

Background & Aims: Chronic alcohol abuse induces liver injury and increases the severity of viral hepatitis, but the precise mechanisms responsible are not well understood. In particular, little is known about the role of natural killer T cells in alcohol-induced liver injury. Natural killer T cells are mediators of important regulator and effector functions making use of Fas and tumor necrosis factor (TNF)-alpha in apoptosis induction. This report analyzes the role of natural killer T cells, Fas, and TNF-alpha in a model of chronic alcohol consumption. Methods: Mice fed alcohol by intragastric tube were assayed for serum alanine aminotransferase values, liver histology, and liver mononuclear cells before and after activation of natural killer T cells by ligand alpha-galactosylceramicle. Results: In alcohol-consuming animals, liver natural killer T cells increase, and further activation by alpha-galactosylceramide causes lethal liver injury. This is explained by alcohol-induced hepatocyte sensitization to cell-mediated lysis, which develops concomitant to increased cytolytic activity of natural killer T cells. Natural killer T cell-mediated apoptosis proceeds by the Fas pathway, and Fas is essential for alcohol-associated liver injury. TNF-alpha plays an additional role as a defect in TNF receptor-1 inhibits alcohol-associated liver injury. Alcohol-fed natural killer T cell-deficient Jalpha281(-/-) mice express a delay in alcohol-induced liver injury. Conclusions: Alcohol consumption induces an increase of natural killer T cells in the liver and a high sensitivity of hepatocytes to cell-mediated lysis. Stimulation of natural killer T cells during alcohol consumption induces serious liver injury by a mechanism that involves concomitant signals by Fas and tumor necrosis factor receptor-1 on alcohol-stressed hepatocytes.