2015
Kabátková, Markéta; Svobodová, Jana; Pěnčíková, Kateřina; Mohatad, Dilshad Shaik; Šmerdová, Lenka; Kozubík, Alois; Machala, Miroslav; Vondráček, Jan
In: Toxicology letters, vol. 232, no. 1, pp. 113–121, 2015, ISSN: 1879-3169 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/genetics/metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/genetics/metabolism, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Proliferation/*drug effects, Cell Transformation, Connexin 43/genetics/metabolism, Dose-Response Relationship, Drug, Enzyme Activation, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/*toxicity, Gap junctions, Gap Junctions/*drug effects/metabolism/pathology, Gene Expression Regulation/drug effects, Genetic/*drug effects, Inflammation, Inflammation/chemically induced/genetics/metabolism/pathology, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Molecular Weight, Neoplastic/chemically induced/metabolism/pathology, p38 Mitogen-Activated Protein Kinases/metabolism, PAHs, Rats, Receptors, Signal Transduction/drug effects, Time Factors, Transcription, Tumor Necrosis Factor-alpha/*toxicity
@article{kabatkova_interactive_2015,
title = {Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription.},
author = {Markéta Kabátková and Jana Svobodová and Kateřina Pěnčíková and Dilshad Shaik Mohatad and Lenka Šmerdová and Alois Kozubík and Miroslav Machala and Jan Vondráček},
doi = {10.1016/j.toxlet.2014.09.023},
issn = {1879-3169 0378-4274},
year = {2015},
date = {2015-01-01},
journal = {Toxicology letters},
volume = {232},
number = {1},
pages = {113–121},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.},
note = {Place: Netherlands},
keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/genetics/metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/genetics/metabolism, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Proliferation/*drug effects, Cell Transformation, Connexin 43/genetics/metabolism, Dose-Response Relationship, Drug, Enzyme Activation, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/*toxicity, Gap junctions, Gap Junctions/*drug effects/metabolism/pathology, Gene Expression Regulation/drug effects, Genetic/*drug effects, Inflammation, Inflammation/chemically induced/genetics/metabolism/pathology, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Molecular Weight, Neoplastic/chemically induced/metabolism/pathology, p38 Mitogen-Activated Protein Kinases/metabolism, PAHs, Rats, Receptors, Signal Transduction/drug effects, Time Factors, Transcription, Tumor Necrosis Factor-alpha/*toxicity},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.