Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes
Article first published online: 14 JUL 2005
Volume 25, Issue 5, pages 1027–1035, October 2005
How to Cite
Hirano, K., Shimizu, Y., Nakayama, Y., Minemura, M., Yasumura, S. and Sugiyama, T. (2005), Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes. Liver International, 25: 1027–1035. doi: 10.1111/j.1478-3231.2005.01136.x
- Issue published online: 14 JUL 2005
- Article first published online: 14 JUL 2005
- Received 26 September 2004, accepted 14 February 2005
Abstract: Background/Aims: 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-α 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.