Carcinogenesis, Vol. 22, No. 3, 381-386,
March 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Tumor necrosis factor 
is not required for WY14,643-induced cell proliferation
Department of Safety Assessment, Merck Research Laboratories, Merck and Co. Inc., Sumneytown Pike, WP45A-201, West Point, PA 19486, USA
It has been proposed that the cytokine tumor necrosis factor 
(TNF) stimulates peroxisome proliferator-induced hepatic cell proliferation. To test this hypothesis, induction of peroxisome proliferation and hepatocyte proliferation were compared in wild-type C57Bl/6 and TNF knockout mice. Animals were dosed with either vehicle or 100 mg/kg/day WY14,643 by oral gavage for 4 days. Liver to brain weight ratios increased in both wild-type and TNF knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNF knockout mice displayed marked hepatic induction of fatty acyl-CoA oxidase activity (~8-fold) and mRNA content (~5-fold). Electron microscopic examination confirmed increased numbers of peroxisomes in hepatocytes in both mouse models. Moreover, WY14,643 markedly induced hepatic cell proliferation (~15-fold) in both wild-type C57Bl/6 and TNF knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNF mRNA was observed in wild-type mice after treatment with WY14,643. These results suggest that the hepatocellular proliferation induced after peroxisome proliferator treatment occurs independently of TNF signaling.
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