Pivotal role of nuclear factor kappaB signaling in anti-CD40-induced liver injury in mice.
Nuclear factor kappaB (NF-kappaB) 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-kappaB 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 kappaB superrepressor (Ad5IkappaB), a NF-kappaB 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 (alphaCD40) 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 Ad5IkappaB-treated mice by FACS analysis. However, alphaCD40 treatment in Ad5IkappaB-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-gamma) production by NK cells and T cells was increased and stimulated tumor necrosis factor alpha (TNF-alpha) production by macrophages in the Ad5IkappaB-infected liver. Moreover, the liver injury was completely suppressed by the administration of anti-IFN-gamma and anti-TNF-alpha. These results suggest that inhibition of NF-kappaB activity suppressed alphaCD40-induced liver inflammation at an early phase, resulting in a reduction in cytokine and chemokine production, whereas it sensitized hepatocytes to TNF-alpha-induced apoptosis and exacerbated liver injury at the late phase. In conclusion, NF-kappaB exerts pivotal activities at inflammatory sites, and caution should be exercised in NF-kappaB-targeted therapy of liver disease.
First Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu-shi, Gifu 501-1194, Japan.
Kiminori
K
Kimura
Masahito
M
Nagaki
Shinji
S
Takai
Shinichi
S
Satake
Hisataka
H
Moriwaki
D000818:Animals; D017209:Apoptosis; D019013:CD40 Antigens / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D022781:Hepatocytes / Q000187:drug effects; D020672:I-kappa B Proteins / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019013:CD40 Antigens; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma