Tumour Necrosis Factor Receptor 1 and Hepatocyte Regeneration in Acetaminophen Toxicity: A Kinetic Study of Proliferating Cell Nuclear Antigen and Cytokine Expression

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Abstract
To determine the importance of tumour necrosis factor receptor 1 in hepatocyte regeneration in acetaminophen toxicity, wild type and tumour necrosis factor receptor 1 knock-out mice were dosed with acetaminophen (300 mg/kg intraperitoneally) and sacrificed at 4, 24, 48, 72, and 96 hr. Biochemical parameters (alanine aminotransferase, ALT) and histologic evidence of hepatocellular injury were comparable in the two groups of mice. To examine the effects of tumour necrosis factor receptor 1 on hepatocyte regeneration, immunohistochemical staining with proliferating cell nuclear antigen was performed. Immunohistochemical staining for proliferating cell nuclear antigen was significantly reduced at multiple time points in the knock-out mice and did not normalize until 96 hr. To evaluate the effect of tumour necrosis factor receptor 1 depletion on cytokines known to be involved in regeneration, levels of macrophage inhibitory protein 2, interferon-gamma-inducible protein-10 and monocyte chemoattractant protein 1 were compared in the two groups of mice. Significant elevation of all cytokines was observed in both groups of mice; however, higher levels were present in the knock-out mice. Depletion of tumour necrosis factor receptor 1 has long-lasting effects on hepatocyte regeneration in acetaminophen toxicity but multiple other factors appear to orchestrate eventual recovery in these mice.