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
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P42 ES007380
NIEHS NIH HHS - United States
PubMed
17557910
DOI
10.1093/toxsci/kfm149
PII: kfm149
Knihovny.cz E-resources
- MeSH
- Aryl Hydrocarbon Hydroxylases genetics metabolism MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Cytochrome P-450 CYP1B1 MeSH
- Epithelial Cells drug effects enzymology MeSH
- Drug Combinations MeSH
- Liver cytology MeSH
- Carcinogens metabolism toxicity MeSH
- Stem Cells drug effects enzymology MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Drug Interactions MeSH
- Ligands MeSH
- Polychlorinated Biphenyls metabolism toxicity MeSH
- Polychlorinated Dibenzodioxins metabolism toxicity MeSH
- Rats, Inbred F344 MeSH
- Cell Proliferation drug effects MeSH
- Receptors, Aryl Hydrocarbon drug effects metabolism MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Tumor Necrosis Factor-alpha pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- 3,4,5,3',4'-pentachlorobiphenyl MeSH Browser
- Aryl Hydrocarbon Hydroxylases MeSH
- Cyp1b1 protein, rat MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1B1 MeSH
- Drug Combinations MeSH
- Carcinogens MeSH
- Ligands MeSH
- Polychlorinated Biphenyls MeSH
- Polychlorinated Dibenzodioxins MeSH
- Receptors, Aryl Hydrocarbon MeSH
- Tumor Necrosis Factor-alpha MeSH
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-kappaB 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.
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