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ToxSci Advance Access originally published online on June 8, 2007
Toxicological Sciences 2007 99(1):79-89; doi:10.1093/toxsci/kfm149
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tumor Necrosis Factor-{alpha} Modulates Effects of Aryl Hydrocarbon Receptor Ligands on Cell Proliferation and Expression of Cytochrome P450 Enzymes in Rat Liver "Stem-Like" Cells

Lenka Umannová*,{dagger}, Jirina Zatloukalová*, Miroslav Machala{dagger}, Pavel Krcmár{dagger}, Zuzana Májková{ddagger},§, Bernhard Hennig§,¶, Alois Kozubík*,||,1 and Jan Vondrácek*,{dagger}

* Laboratory of Cytokinetics, Institute of Biophysics, 62165 Brno, Czech Republic {dagger} Department of Chemistry and Toxicology, Veterinary Research Institute, 62100 Brno, Czech Republic {ddagger} Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0305 § Molecular and Cell Nutrition Laboratory, College of Agriculture Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536-0200 || Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, 62100 Brno, Czech Republic

1 To whom correspondence should be addressed at Institute of Biophysics, Královopolská 135, 61265 Brno, Czech Republic. Fax: +42-05-41-21-12-93. E-mail: kozubik{at}ibp.cz.

Received March 2, 2007; accepted May 31, 2007


  Abstract

Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-{alpha} with ligands of the aryl hydrocarbon receptor (AhR) and known liver carcinogens, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126). These compounds have been previously found to disrupt cell cycle control in contact-inhibited rat liver WB-F344 cells, an in vitro model of adult liver progenitor cells. TNF-{alpha} itself had no significant effect on the proliferation/apoptosis ratio in the WB-F344 cell line. However, it significantly potentiated proliferative effects of low picomolar range doses of both TCDD and PCB 126, leading to an increase in cell numbers, as well as an increased percentage of cells entering the S-phase of the cell cycle. The combination of TNF-{alpha} with low concentrations of AhR ligands increased both messenger RNA (mRNA) and protein levels of cyclin A, a principle cyclin involved in disruption of contact inhibition. TNF-{alpha} temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-{alpha} significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-{kappa}B activation. These results suggest that TNF-{alpha} can significantly amplify effects of AhR ligands on deregulation of cell proliferation control, as well as on expression of CYP1B1, which is involved in metabolic activation of a number of mutagenic compounds.

Key Words: cell proliferation; tumor necrosis factor-{alpha}; aryl hydrocarbon receptor; polychlorinated biphenyl; dioxin; xenobiotic metabolizing enzymes.


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