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Toxicological Sciences 54, 262-273 (2000)
Copyright © 2000 by the Society of Toxicology

Acute Hepatotoxicant Exposure Induces TNFR-Mediated Hepatic Injury and Cytokine/Apoptotic Gene Expression

Thomas L. Horn*,{dagger}, Timothy D. O'Brien{ddagger}, Lawrence B. Schook*,{dagger} and Mark S. Rutherford*,{dagger},1

* Toxicology Graduate Program, {dagger} Department of Veterinary PathoBiology and {ddagger} Department of Veterinary Diagnostic Medicine, University of Minnesota, St. Paul, Minnesota 55108

Tumor necrosis factor receptor knockout (TNFR KO) mice were used to examine the role of tumor necrosis factor-{alpha} (TNF{alpha}) signaling during acute hepatotoxicant exposure. Mice were exposed intraperitoneally (ip) to either vehicle, phosphate-buffered saline (PBS), or dimethylnitrosamine (DMN, 100 mg/kg) for 24 h. Histological evaluation showed that DMN-treated TNFR-2 KO mice had increased liver damage compared to wild type (WT), TNFR-1 KO, or TNFR double KO (DKO) mice. Also, 3 of 8 TNFR-2 KO mice died following DMN treatment, suggesting that hepatic TNFR-2 signaling produces protective responses that counteract TNFR-1-mediated damage. DMN-induced cellular infiltration was absent in TNFR-1-deficient mice, indicating that infiltrating cells do not exacerbate acute hepatotoxic events. In separate experiments, mice were exposed ip to either DMN (5.0 or 100 mg/kg), carbon tetrachloride (CCl4, 0.3 or 1.0 ml/kg), or corresponding PBS/corn oil controls for 6 or 24 h to compare the hepatic mRNA expression of cytokine- and apoptotic-associated genes. Following 24 h of DMN (100 mg/kg) or 6–24 h of CCl4 treatment, hepatic transcripts for TNF{alpha}, interferon (IFN)-{gamma}, IL (interleukin)-1RI, and transforming growth factor (TGF)-ßRII were induced. Hepatotoxicant-treated WT and TNFR DKO mice induced liver transcripts for the pro- and anti-apoptotic genes, Bax and Bcl-XL, respectively, indicating TNF-independent gene activation. The anti-apoptotic gene, Bfl-1, was highly expressed in CCl4-treated, TNFR-positive strains, but minimally expressed in TNFR DKO mice, suggesting that hepatic Bfl-1 is TNF-regulated. Taken together, these data show that acute hepatotoxicant exposure is followed by upregulation of liver cytokine, cytokine receptor, and apoptotic transcripts, and that TNF{alpha} regulates various aspects of liver inflammation and injury in a TNFR-specific fashion.

Key Words: apoptosis; Bfl-1; carbon tetrachloride (CCl4); cytokines; dimethylnitrosamine (DMN); hepatotoxicity; inflammation; necrosis; TNF.


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