Tumor Necrosis Factor-α Modulates Effects of Aryl Hydrocarbon Receptor Ligands on Cell Proliferation and Expression of Cytochrome P450 Enzymes in Rat Liver “Stem-Like” Cells

• Published in: Toxicological sciences Vol. 99; no. 1; pp. 79 - 89
• Main Authors: Umannová, Lenka, Zatloukalová, Jiřina, Machala, Miroslav, Krčmář, Pavel, Májková, Zuzana, Hennig, Bernhard, Kozubík, Alois, Vondráček, Jan
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2007
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; aryl hydrocarbon receptor; Carcinogens - metabolism; Carcinogens - toxicity; cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1; dioxin; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Gene Expression Regulation, Enzymologic - drug effects; Ligands; Liver - cytology; polychlorinated biphenyl; Polychlorinated Biphenyls - metabolism; Polychlorinated Biphenyls - toxicity; Polychlorinated Dibenzodioxins - metabolism; Polychlorinated Dibenzodioxins - toxicity; Rats; Rats, Inbred F344; Receptors, Aryl Hydrocarbon - drug effects; Receptors, Aryl Hydrocarbon - metabolism; Stem Cells - drug effects; Stem Cells - enzymology; Tumor Necrosis Factor-alpha - pharmacology; tumor necrosis factor-α; xenobiotic metabolizing enzymes; dioxin; polychlorinated biphenyl; cell proliferation; tumor necrosis factor-α; xenobiotic metabolizing enzymes; aryl hydrocarbon receptor
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfm149

Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-α 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-α 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-α 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-α temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-α significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-κB activation. These results suggest that TNF-α 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.