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Overexpression of granulocyte‐macrophage colony‐stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes
Author(s) -
Hirano Katsuharu,
Shimizu Yukihiro,
Nakayama Yasuhiro,
Minemura Masami,
Yasumura Satoshi,
Sugiyama Toshiro
Publication year - 2005
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2005.01136.x
Subject(s) - liver injury , lipopolysaccharide , apoptosis , hepatocyte , granulocyte macrophage colony stimulating factor , immunology , fas ligand , macrophage , tumor necrosis factor alpha , granulocyte , peripheral blood mononuclear cell , biology , medicine , cytokine , endocrinology , programmed cell death , in vitro , biochemistry
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.