Tumor necrosis factor alpha is not required for WY14,643-induced cell proliferation.
It has been proposed that the cytokine tumor necrosis factor alpha (TNFalpha) 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 TNFalpha 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 TNFalpha knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNFalpha knockout mice displayed marked hepatic induction of fatty acyl-CoA oxidase activity (approximately 8-fold) and mRNA content (approximately 5-fold). Electron microscopic examination confirmed increased numbers of peroxisomes in hepatocytes in both mouse models. Moreover, WY14,643 markedly induced hepatic cell proliferation (approximately 15-fold) in both wild-type C57Bl/6 and TNFalpha knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNFalpha 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 TNFalpha signaling.
Department of Safety Assessment, Merck Research Laboratories, Merck and Co. Inc., Sumneytown Pike, WP45A-201, West Point, PA 19486, USA. jeff_lawrence@merck.com
J W
JW
Lawrence
G K
GK
Wollenberg
J G
JG
DeLuca
D000818:Animals; D017931:DNA Primers; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects / Q000648:ultrastructure; D011743:Pyrimidines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C006253:pirinixic acid