Hepatocyte nuclear factor-kappa β (NF-κB) activation is protective but is decreased in the cholestatic liver with endotoxemia

Background

Obstructive jaundice (OJ) is an important clinical consideration associated with a high risk of bacteremia. Hepatocyte nuclear factor-kappa B (NF-κB) activation confers an antiapoptotic function. Although the occurrence of hepatocyte apoptosis has been shown in OJ, the activation and role of NF-κB over the time course of OJ in conjunction with endotoxemia have not yet been well defined. We hypothesized that NF-κB activation may be decreased over the time course of OJ and endotoxemia, which leads to severe liver injury. The aim of the current study was to examine whether NF-κB activation can decrease hepatocyte apoptosis and liver injury over the time course of OJ in response to lipopolysaccharide (LPS) administration.

Methods

Male C57BL/6 mice were subjected to bile duct ligation and were administered LPS intravenously at 3 days (OJ3) or 14 days (OJ14) after bile duct ligation. NF-κB activation; protein expressions of NF-κB p65, IκB-α, Iκβ-b, and Pin1; immunohistochemistry of poly adenosine diphosphate (ADP)-ribose polymerase p85 fragment (PARP); and serum alanine transaminase (ALT) levels were examined.

Results

Hepatocyte NF-κB activation was observed during OJ. After LPS administration, the hepatic NF-κB activation defined by electrophoretic mobility shift assay was decreased in the OJ14 group compared with the OJ3 group, which is consistent with a decrease in NF-κB p65 protein expression. Changes in phosphorylated Iκ-B-β but not phosphorylated IκB-α mirrored these results. Significant hepatocyte apoptosis defined by PARP immunohistochemistry was observed in the LPS-treated OJ14 relative to the LPS-treated OJ3. Hepatic expressions of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the LPS OJ14 mice were upregulated relative to those in the LPS OJ3. Serum ALT levels increased significantly in the LPS OJ14 relative to other mice. The survival rate was significantly less in the LPS OJ14 relative to other mice.

Conclusion

After prolonged OJ, exposure to endotoxemia was associated with a decrease in hepatocyte NF-κB activation and an increase in hepatocyte apoptosis and secondary necrosis, thus resulting in liver dysfunction.