NK cell-mediated, Kupffer cell-dependent inhibition of liver injury attending biliary obstruction and cholestasis (134.25)

Abstract

Abstract Natural killer (NK) cells are innate immune effector cells that participate in the first line of host defenses. In addition to expressing cytotoxic activity, NK cells produce cytokines and engage other cell populations to modulate adaptive immunity. Compared to other organs, the liver contains a large percentage of NK cells suggesting that NK cells play a unique role in the liver; the function of hepatic NK cells, however, is not well understood. Here we examined the contribution of NK cells to the tissue injury that occurs following bile duct ligation (BDL) in a mouse model of biliary obstruction. The number of activated hepatic NK cells was increased markedly at 18 hours following BDL. NK cells activation was suppressed in mice rendered Kupffer cell-depleted prior to ligation. Higher plasma alanine aminotransferase activity, an indictor of increased liver injury, occurred in NK cell-depleted mice. In contrast, IL-6 mRNA expression and protein production in the livers of BDL, NK cell-depleted mice were suppressed. Purified Kupffer cells derived from NK cell-depleted mice following BDL produced less IL-6 in culture than did Kupffer cells derived from non-depleted animals. Treatment with recombinant murine IL-6 reduced liver injury in BDL, NK cell-depleted mice. Taken together, these data suggest that hepatic NK cells suppress cholestatic liver injury by stimulating IL-6 production by Kupffer cells.