Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense

Hawjyh Chiu, Carol R. Gardner, Donna M. Dambach, Jennie A. Brittingham, Stephen K. Durham, Jeffrey D. Laskin, Debra L. Laskin

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50 Scopus citations


Tumor necrosis factor (TNF)-α is a macrophage-derived proinflammatory cytokine implicated in hepatotoxicity. In the present studies, p55 TNF receptor 1 (TNFR1) -/- mice were used to assess the role of TNF-α in acetaminophen-induced antioxidant defense. Treatment of wild-type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increased serum alanine transaminases. This was correlated with a rapid depletion of hepatic glutathione (GSH). Whereas in WT mice GSH levels returned to control after 6-12 h, in TNFR1-/- mice recovery was delayed for 48 h. Delayed induction of heme oxygenase-1 and reduced expression of CuZn superoxide dismutase were also observed in TNFR1-/- compared with WT mice. This was associated with exaggerated hepatotoxicity. In WT mice, acetaminophen caused a time-dependent increase in activator protein-1 nuclear binding activity and in c-Jun expression. This response was significantly attenuated in TNFR1-/- mice. Constitutive NF-κB binding activity was detectable in livers of both WT and TNFR1-/- mice. A transient decrease in this activity was observed 3 h after acetaminophen in WT mice, followed by an increase that was maximal after 6-12 h. In contrast, in TNFR1-/- mice, acetaminophen-induced decreases in NF-κB activity were prolonged and did not return to control levels for 24 h. These data indicate that TNF-α signaling through TNFR1 plays an important role in regulating the expression of antioxidants in this model. Reduced generation of antioxidants may contribute to the increased sensitivity of TNFR1-/- mice to acetaminophen.

Original languageEnglish (US)
Pages (from-to)G959-G966
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5 48-5
StatePublished - Nov 2003

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


  • Cytokines
  • Liver
  • Oxidative stress
  • Tissue injury
  • Transcription factors


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