Endotoxin exacerbates immunologically induced liver injury in cooperation with interferon-gamma.
OBJECTIVE
To investigate the role of endotoxin in the development of immunologically induced liver injury.


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.
Chen
X
X
Department of Pharmacology for Chinese Materia Medica, China Pharmaceutical University, Nanjing, The People's Republic of China.
Cao
J
J
Xu
Q
Q
D000410:Alanine Transaminase / Q000096:biosynthesis / Q000097:blood; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000097:blood / Q000502:physiology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000097:blood / Q000139:chemically induced* / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007728:Kupffer Cells / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008107:Liver Diseases / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D010853:Picryl Chloride / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D000410:Alanine Transaminase; D010853:Picryl Chloride