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.
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.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic; Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlářská 2, 61137 Brno, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Kabátková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic; Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlářská 2, 61137 Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Svobodová
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Pěnčíková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic; Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlářská 2, 61137 Brno, Czech Republic.
authors.forename: Dilshad Shaik
authors.initials: DS
authors.lastname: Mohatad
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Šmerdová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic.
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.affiliation: Department of Cytokinetics, Institute of Biophysics AS CR, Královopolská 135, 61265 Brno, Czech Republic. Electronic address: vondracek@ibp.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005449:Fluorenes / Q000633:toxicity*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008970:Molecular Weight; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018031:Connexin 43; D005449:Fluorenes; D018336:Receptors, Aryl Hydrocarbon; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C000595703:Ahr protein, rat; C580592:Gja1 protein, rat; C007738:fluoranthene
keywords: Aryl hydrocarbon receptor; Cell proliferation; Gap junctions; Inflammation; PAHs