Acta Pharmacologica Sinica 2006 April; 27 (4): 460-468; doi: 10.1111/j.1745-7254.2006.00301.x

Aim: To investigate the mechanism of immunological liver injury induced by bacille Calmette-Guerin (BCG) plus lipopolysaccharide (LPS).

Methods: Mice were injected via the tail vein with 125 mg/kg BCG, and 12 d later, the mice were injected intravenously with different doses of LPS (125, 250, or 375 µg/kg). Serum alanine aminotransferase (ALT) activity and liver pathological changes were examined. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, lipopolysaccharide binding protein (LBP) and CD14 mRNA, and NF-kB and IkB-α protein in mouse liver at different time points after BCG and LPS injection were measured using RT-PCR, immunohistochemistry and Western blotting analysis, respectively.

Results: The activity of serum ALT in mice treated with BCG and LPS was significantly increased. Different degrees of liver injury, such as inflammatory cell infiltration, spotty necrosis, piecemeal necrosis, even bridging necrosis, could be seen in liver sections from mice after BCG and LPS administration. Furthermore, the levels of TNF-α and IL-6 mRNA in mouse liver were significantly elevated after administration of BCG plus LPS (P<0.05). The levels of LBP and CD14 mRNA in mouse liver were markedly upregulated after treatment with BCG and LPS, and treatment with BCG alone led to an increase in CD14 mRNA in mouse liver. Finally, immunoreactivity for NF-kB p65 was predominantly detected in hepatocyte nuclei from mice treated with BCG plus LPS, compared with the normal group. Protein levels of IkB-α were strikingly decreased by LPS or BCG plus LPS treatment, compared with the normal group or BCG group.

Conclusion: TNF-α and IL-6 mRNA were partially involved in early immunological liver injury induced by challenge with small doses of LPS after BCG priming. Upregulation of TNF-α and IL-6 mRNA might be related to increases in LBP and CD14 mRNA expression and activation of NF-kB. Furthermore, BCG priming in immunological liver injury may occur via upregulation of CD14 mRNA expression in mononuclear cell infiltration into the liver.

Keywords: liver injury; lipopolysaccharide binding protein; CD14; tumor necrosis factor-alpha; interleukin-6; NF-kappa B