Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor- -dependent mechanism

Wei HR, Wei H, Wang H, Tian Z, Sun R. Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 299: G275–G282, 2010. First published May 6, 2010; doi:10.1152/ajpgi.00026.2010.—Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl4)-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl4 model. Administration of poly I:C suppressed liver regeneration in CCl4-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl4-treated mice. Poly I:C and CCl4 cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFNand tumor necrosis factor (TNF). Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl4 treatment. Finally, blockage of TNFbut not IFNrestored liver regeneration in poly I:C/CCl4-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl4-induced liver injury model via induction of NK cell production of TNF.