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Endotoxin exacerbates immunologically induced liver injury in cooperation with interferon-gamma
1Department of Pharmacology for Chinese Materia Medica, China Pharmaceutical University, Nanjing, The People's Republic of China.
Objective And Design:
To investigate the role of endotoxin in the development of immunologically induced liver injury.
Materials And Methods:
A new model of liver injury induced in BALB/c mice by delayed-type hypersensitivity to picryl chloride and its in vitro assay for the interaction between liver nonparenchymal and parenchymal cells were used.
Results:
Plasma endotoxin in the injured liver correlated well with serum alanine transaminase (ALT) activity (r = 0.601). Tolerance to lipopolysaccharide led to a significant inhibition of serum ALT elevation. However, lipopolysaccharide in vitro increased the ALT release from hepatocytes caused by nonparenchymal cells only in the presence of IFN-gamma. When nonparenchymal cells were separated into Kupffer and non-Kupffer cell populations, the synergistic hepatotoxicity of lipopolysaccharide and IFN-gamma was still observed in the former but not in the latter cell type. Lipopolysaccharide with IFN-gamma also enhanced TNF-alpha levels. Anti-TNF-alpha almost completely inhibited the ALT release. Combined use of TNF-alpha and IFN-gamma caused marked hepatocyte damage, while these cytokines alone did not.
Conclusions:
We suggest that elevated endotoxin levels accompanying the development of liver injury may activate Kupffer cells to release TNF-alpha leading to exacerbation of hepatocyte damage in cooperation with IFN-gamma produced during liver injury.
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