Journal Article

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

Jeffrey W. Lawrence, Gordon K. Wollenberg and John G. DeLuca

in Carcinogenesis

Volume 22, issue 3, pages 381-386
Published in print March 2001 | ISSN: 0143-3334
Published online March 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.3.381
Tumor necrosis factor α is not required for WY14,643-induced cell proliferation

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

Keywords: BrdU, bromodeoxyuridine; FACO, fatty acyl-CoA oxidase; FAM, 6-carboxyfluorescein; 4F1G, 4% neutral buffered formalin and 1% gluteraldehyde; IL-6, interleukin-6; LPS, lipopolysaccharide; PPARα, peroxisome proliferator-activated receptor α; TEM, transmission electron microscopy; TNFα, tumor necrosis factor α; TNF R, TNF receptor.

Journal Article.  3555 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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