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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
M. Kabátková, J. Svobodová, K. Pěnčíková, DS. Mohatad, L. Šmerdová, A. Kozubík, M. Machala, J. Vondráček,
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články
- MeSH
- aktivace enzymů MeSH
- buněčné linie MeSH
- časové faktory MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- fluoreny toxicita MeSH
- genetická transkripce účinky léků MeSH
- játra účinky léků metabolismus patologie MeSH
- konexin 43 genetika metabolismus MeSH
- krysa rodu rattus MeSH
- mezerový spoj účinky léků metabolismus patologie MeSH
- mezibuněčná komunikace účinky léků MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- molekulová hmotnost MeSH
- nádorová transformace buněk chemicky indukované metabolismus patologie MeSH
- nádory jater chemicky indukované metabolismus patologie MeSH
- proliferace buněk účinky léků MeSH
- receptory aromatických uhlovodíků agonisté genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- TNF-alfa toxicita MeSH
- transkripční faktory bHLH agonisté genetika metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zánět chemicky indukované genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
Department of Cytokinetics Institute of Biophysics AS CR Královopolská 135 61265 Brno Czech Republic
Citace poskytuje Crossref.org
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- $a Kabátková, Markéta $u 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.
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- $a 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.
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