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This Article Full Text Full Text (PDF) All Versions of this Article: 285/5/G959    most recent 00219.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Chiu, H. Articles by Laskin, D. L. Search for Related Content PubMed PubMed Citation Articles by Chiu, H. Articles by Laskin, D. L.

INFLAMMATION/IMMUNITY/MEDIATORS

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

¹Environmental and Occupational Health Sciences Institute, Rutgers University and University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway 08854-8020; and ²Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey 08543

Submitted 12 May 2003 ; accepted in final form 27 June 2003

Tumor necrosis factor (TNF)- 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- 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-B 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-B activity were prolonged and did not return to control levels for 24 h. These data indicate that TNF- 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.

liver; cytokines; oxidative stress; tissue injury; transcription factors