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Published online before print October 13, 2003

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0403152

Received for publication April 15, 2003.
Revised September 12, 2003.
Accepted for publication September 15, 2003.

Article

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

Yuko Ishida ^*, Toshikazu Kondo , Koichi Tsuneyama , Peirong Lu ^*, Tatsunori Takayasu , and Naofumi Mukaida ^*@

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

^@ To whom correspondence should be addressed. E-mail: naofumim{at}kenroku.kanazawa-u.ac.jp.

	Abstract

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

Key Words: drug-induced hepatotoxicity • TNF- • cytokines • chemokines • inducible nitric oxide synthase

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