The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice.
Acetaminophen (APAP) causes a massive production of intrahepatic tumor necrosis factor alpha (TNF-alpha). However, it still remains elusive regarding the roles of TNF-alpha in APAP-induced liver injury. Hence, we examined pathogenic roles of the TNF-alpha-TNF receptor with a molecular weight of 55 kDa (TNF-Rp55) axis in APAP-induced hepatotoxicity using TNF-Rp55-deficient [TNF-Rp55-knockout (KO)] mice. When wild-type (WT) BALB/c and TNF-Rp55-KO mice were intraperitoneally injected with a lethal dose of APAP (750 mg/kg), the mortality of TNF-Rp55-KO mice was marginally but significantly reduced compared with WT mice. Upon treatment with a nonlethal dose (600 mg/kg), WT mice exhibited an increase in serum transaminase levels. Histopathologically, centrilobular hepatic necrosis with leukocyte infiltration was evident at 10 and 24 h after APAP challenge. Moreover, mRNA expression of adhesion molecules, several chemokines, interferon-gamma (IFN-gamma), and inducible nitric oxide synthase (iNOS) was enhanced in the liver. On the contrary, serum transaminase elevation and histopathological changes were attenuated in TNF-Rp55-KO mice injected with APAP (600 mg/kg). The gene expression of all molecules except for IFN-gamma and iNOS was significantly attenuated in TNF-Rp55-KO mice. Moreover, anti-TNF-alpha neutralizing antibodies alleviated liver injury when administered at 2 or 8 h after but not at 1 h before APAP challenge to WT mice. Collectively, the TNF-alpha-TNF-Rp55 axis has pathogenic roles in APAP-induced liver failure.
Ishida
Yuko
Y
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Ishikawa, Japan.
Kondo
Toshikazu
T
Tsuneyama
Koichi
K
Lu
Peirong
P
Takayasu
Tatsunori
T
Mukaida
Naofumi
N
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects; D007378:Interleukins / Q000235:genetics; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D007378:Interleukins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D000082:Acetaminophen; D000410:Alanine Transaminase