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B Is Activated in Cholestasis and Functions to Reduce Liver Injury
From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Selected bile acids activate a nuclear factor-kappa B
(NF-
B)-dependent survival signaling cascade in cultured hepatocytes.
These data suggest that in cholestasis where liver tissue bile acid
concentrations are increased, NF-B should be activated and
inhibition of NF-B should potentiate liver injury. Our aims were to
test these two predictions. Cholestasis was obtained by common bile
duct ligation in mice. NF-B activation was demonstrated in nuclear
extracts by the electrophoretic mobility gel shift assay from
3-day bile duct-ligated (BDL) mice but not in controls.
Immunohistochemistry for NF-B demonstrated nuclear localization in
hepatocytes of BDL mice consistent with its activation in this liver
cell type. Electrophoretic mobility gel shift assay and
immunohistochemistry for NF-B in BDL tumor necrosis factor-receptor
1 knockout mice demonstrated hepatocyte NF-B activation,
suggesting that tumor necrosis factor-
was not responsible for the
activation of this transcription factor. Liver injury was assessed in
BDL mice after administration of the adenovirus 5 inhibitor of kappa B
superrepressor (Ad5IBsr) to inhibit NF-B. TUNEL-positive cells
and serum alanine aminotransferase values were increased at least
threefold in mice treated with the Ad5IBsr
versus the empty virus. Liver histology also
demonstrated increased liver injury in the BDL mice treated with the
Ad5IBsr. In conclusion, NF-B is activated in hepatocytes
during obstructive cholestasis and functions to reduce liver
injury.
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