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

It has been proposed that the cytokine tumor necrosis factor a (TNFa) 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 TNFa 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 TNFa knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNFa 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 TNFa knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNFa 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 TNFa signaling.