The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice

Journal of Leukocyte Biology

Koichi Tsuneyama³  Peirong Lu²  Tatsunori Takayasu⁵  Yuko Ishida¹  Toshikazu Kondo⁴  Naofumi Mukaida² 

[1] Division of Molecular Bioregulation, Cancer Research Institute, and Department of Forensic Medicine, Wakayama Medical University, Japan; and Division of Molecular Bioregulation, Cancer Research Institute, and Division of Molecular Bioregulation, Cancer Research Institute, and Department of Forensic Medicine, Wakayama Medical University, Japan; and Department of Forensic Medicine, Wakayama Medical University, Japan; and Division of Molecular Bioregulation, Cancer Research Institute, and Department of Forensic Medicine, Wakayama Medical University, Japan; and;Division of Molecular Bioregulation, Cancer Research Institute, and Division of Molecular Bioregulation, Cancer Research Institute, and Division of Molecular Bioregulation, Cancer Research Institute, and;Department of Pathology, Toyama Medical and Pharmaceutical University Hospital, Japan Department of Pathology, Toyama Medical and Pharmaceutical University Hospital, Japan Department of Pathology, Toyama Medical and Pharmaceutical University Hospital, Japan;Department of Forensic Medicine, Wakayama Medical University, Japan; and Department of Forensic Medicine, Wakayama Medical University, Japan; and Department of Forensic Medicine, Wakayama Medical University, Japan; andDepartment of Forensic & Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan; Department of Forensic & Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan; Department of Forensic & Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan;

关键词: drug-induced hepatotoxicity;    TNF-α;    cytokines;    chemokines;    inducible nitric oxide synthase;   

DOI  :  10.1189/jlb.0403152

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Acetaminophen (APAP) causes a massive production of intrahepatic tumor necrosis factor α (TNF-α). However, it still remains elusive regarding the roles of TNF-α in APAP-induced liver injury. Hence, we examined pathogenic roles of the TNF-α–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-γ (IFN-γ), 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-γ and iNOS was significantly attenuated in TNF-Rp55-KO mice. Moreover, anti-TNF-α 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-α–TNF-Rp55 axis has pathogenic roles in APAP-induced liver failure.

【 授权许可】

Unknown