Activation of TLR-4 and liver injury via NF-kappa B in rat with acute cholangitis.

BACKGROUND: Toll-like receptors (TLRs) are a family of type 1 transmembrane receptors, which can recognize different pathogen-associated molecular patterns. Among them, TLR-4 is specific to lipopolysaccharide. It transfers the infection signal into the cell and promotes the translocation of nuclear factor kappa B (NF-kappaB) to the nucleus and the subsequent transcriptional activation of genes encoding pro- and anti-inflammatory cytokines and chemokines. Acute cholangitis (AC) is a common biliary tract infection in oriental countries, and often leads to liver injury. The activation of TLR-4 and its significance in liver injury in rats with AC remain unclear.
METHODS: Rat models of AC (biliary tract obstruction+E. coli injection, n=36) and control models (biliary tract obstruction+saline, n=18) were made. Liver tissue injury was investigated by pathological examination. The levels of serum TNF-alpha and IL-10 were measured by enzyme-linked immunosorbent assay, and the expressions of TLR-4, NF-kappaB mRNAs and proteins in the liver were detected by RT-PCR, immunohistochemical staining and Western blotting, respectively.
RESULTS: Severe liver tissue injury in rats with AC was evident as shown by pathological examination. TLR-4 and NF-kappaB were strongly expressed in the cytoplasm of hepatocytes in the AC group. They were negative or slightly positive in the control group. TLR-4 mRNA and protein in the liver of rats with AC increased 1 hour after biliary tract ligation and E. coli injection, and peaked at 6 hours after surgery. Twenty-four hours later, they began to decrease. The expression of TLR-4 was paralleled by that of NF-kappaB in the liver and TNF-alpha in serum.
CONCLUSION: The higher expression of TLR-4 in the liver of rats with AC may be involved in liver injury through the activation of NF-kappaB and release of cytokines such as TNF-alpha.