NF-kappa B is activated in cholestasis and functions to reduce liver injury

Selected bile acids activate a nuclear factor-kappa B (NF-kappaB)-dependent survival signaling cascade in cultured hepatocytes. These data suggest tha t in cholestasis where liver tissue bile acid concentrations are increased, NF-kappaB should be activated and inhibition of NF-kappaB should potentiat e liver injury. Our aims were to test these two predictions. Cholestasis wa s obtained by common bile duct ligation in mice. NF-kappaB activation was d emonstrated in nuclear extracts by the electrophoretic mobility gel shift a ssay from 3-day bile duct-ligated (BDL) mice but not in controls. Immunohis tochemistry for NF-kappaB demonstrated nuclear localization in hepatocytes of BDL mice consistent with its activation in this liver cell type. Electro phoretic mobility gel shift assay and immunohistochemistry for NF-kappaB in BDL tumor necrosis factor-receptor 1 knockout mice demonstrated hepatocyte NF-kappaB activation, suggesting that tumor necrosis factor-alpha was not responsible for the activation of this transcription factor. Liver injury w as assessed in BDL mice after administration of the adenovirus 5 inhibitor of kappa B superrepressor (Ad5I kappa Bsr) to inhibit NF-kappaB. TUNEL-posi tive cells and serum alanine aminotransferase values were increased at leas t threefold in mice treated with the Ad5I kappa Bsr versus the empty virus. Liver histology also demonstrated increased liver injury in the BDL mice t reated with the Ad5I kappa Bsr. In conclusion, NF-kappaB is activated in he patocytes during obstructive cholestasis and functions to reduce liver inju ry.