Skip Navigation



ToxSci Advance Access published online on June 8, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm149
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow Supplementary Data
Right arrow All Versions of this Article:
99/1/79    most recent
kfm149v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Umannová, L.
Right arrow Articles by Vondrácek, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Umannová, L.
Right arrow Articles by Vondrácek, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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, Královopolská 135, 62165 Brno, Czech Republic {dagger} Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic {ddagger} Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA § Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY 40536-0200, USA Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0200, USA || Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Terezy Novákové 64, 62100 Brno, Czech Republic

1 To whom correspondence should be addressed at: Institute of Biophysics, Královopolská 135, 61265 Brno, Czech Republic, e-mail: kozubik{at}ibp.cz, phone: +420-541517182, fax: +420-541211293

Received March 2, 2007; revision received May 29, 2007; accepted May 31, 2007


  Abstract

Various liver diseases lead to an extensive inflammatory response and release of a number of pro-inflammatory 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 co-planar 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 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 NF-kB 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.