Tumor necrosis factor a is not required for WY14,643-induced cell proliferation

It has been proposed that the cytokine tumor necrosis factor alpha (TNF alpha) 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 alpha 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 alpha knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNF alpha knockout mice displayed marked hepatic induction of fatty acyl-CoA oxidase activity (similar to8-fold) and mRNA content (similar to5-fold), Electron microscopic examination confirmed increased numbers of peroxisomes in hepatocytes in both mouse models. Moreover, WY14,643 markedly induced hepatic cell proliferation (similar to 15-fold) in both wild-type C57Bl/ 6 and TNF alpha knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNF alpha 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 alpha signaling.