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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

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

Published In Am J Physiol Gastrointest Liver Physiol, (2003 Nov)

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

PubMed ID: 12842828 Exiting the NIEHS site

MeSH Terms: Acetaminophen/pharmacology*; Acetaminophen/poisoning; Alanine Transaminase/blood; Animals; Antigens, CD/physiology*; Antioxidants/metabolism*; Enzyme Induction/drug effects; Glutathione/antagonists & inhibitors; Glutathione/metabolism; Heme Oxygenase (Decyclizing)/metabolism; Heme Oxygenase-1; Liver/drug effects; Liver/metabolism; Liver/pathology; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B/metabolism; Necrosis; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor/physiology*; Superoxide Dismutase/antagonists & inhibitors; Transcription Factor AP-1/metabolism

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