Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes.
OBJECTIVE
We examined whether antigen-nonspecific accumulation of dendritic cells (DCs) and macrophages in the liver by the overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) could prime severe liver injury after LPS injection.


METHODS
We injected a recombinant adenovirus encoding GM-CSF intravenously (AdGM), and LPS was administered 7 days later. Liver histology, serum alanine aminotransferase (ALT) levels and apoptosis of hepatocytes were examined.


RESULTS
Liver histology of the AdGM-primed mice showed marked infiltrates of mononuclear cells (DCs and macrophages) without granuloma formation on day 7. Expression of toll-like receptor-4 on intrahepatic mononuclear cells isolated from AdGM-primed mice was up-regulated. After LPS injection, serum ALT levels in AdGM-primed mice reached about 6000 IU/l at 12 h, and all those mice died within 24 h. Hemorrhagic liver injury with massive apoptosis of hepatocytes was histologically recognized. When AdGM and LPS were injected in FasL-deficient C57BL/6J-gld/gld mice, serum ALT levels were not elevated by the pretreatment with a neutralizing anti-TNF-alpha antibody.


CONCLUSIONS
Our present study provides a new model of severe liver injury, in which antigen-nonspecific accumulation of DCs and macrophages in the liver by overexpressing GM-CSF enhances the susceptibility to LPS, leading to hemorrhagic liver injury with massive hepatocyte apoptosis after LPS injection.
Hirano
Katsuharu
K
The Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Shimizu
Yukihiro
Y
Nakayama
Yasuhiro
Y
Minemura
Masami
M
Yasumura
Satoshi
S
Sugiyama
Toshiro
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D039521:CD11c Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007371:Interferon-gamma / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D039521:CD11c Antigen; D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor