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Pivotal role of nuclear factor κB signaling in anti‐CD40–induced liver injury in mice
Author(s) -
Kimura Kiminori,
Nagaki Masahito,
Takai Shinji,
Satake Shinichi,
Moriwaki Hisataka
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20432
Subject(s) - chemokine , cytokine , liver injury , tumor necrosis factor alpha , cd40 , inflammation , immune system , apoptosis , biology , immunology , cancer research , cytotoxic t cell , endocrinology , in vitro , biochemistry
Nuclear factor κB (NF‐κB) has a central role in coordinating the expression of a wide variety of genes that control immune responses and is also recognized as an antiapoptotic transcription factor. Here, we focused on the role of the NF‐κB signaling pathway in the interaction between inflammatory cells and hepatocytes in liver inflammation. We found that pretreatment of mice with adenoviruses expressing a mutant form of the inhibitor κB superrepressor (Ad5IκB), a NF‐κB inhibitor, reduced the migration of inflammatory cells and cytokine and chemokine expression in the liver 12 hours after a single intravenous injection of an anti‐CD40 antibody (αCD40) compared with mice infected with control adenoviruses (Ad5LacZ). We also confirmed reductions in cytokine production by macrophages, T cells, and natural killer (NK) cells in the liver of Ad5IκB‐treated mice by FACS analysis. However, αCD40 treatment in Ad5IκB‐infected mice induced elevation of serum alanine aminotransferase at 24 hours, and the liver injury was associated with massive hepatocyte apoptosis. Furthermore, interferon gamma (IFN‐γ) production by NK cells and T cells was increased and stimulated tumor necrosis factor alpha (TNF‐α) production by macrophages in the Ad5IκB‐infected liver. Moreover, the liver injury was completely suppressed by the administration of anti–IFN‐γ and anti–TNF‐α. These results suggest that inhibition of NF‐κB activity suppressed αCD40‐induced liver inflammation at an early phase, resulting in a reduction in cytokine and chemokine production, whereas it sensitized hepatocytes to TNF‐α–induced apoptosis and exacerbated liver injury at the late phase. In conclusion , NF‐κB exerts pivotal activities at inflammatory sites, and caution should be exercised in NF‐κB–targeted therapy of liver disease. (H EPATOLOGY 2004;40:1180–1189.)