2011
Umannová, Lenka; Machala, Miroslav; Topinka, Jan; Schmuczerová, Jana; Krčmář, Pavel; Neča, Jiří; Šujanová, Klára; Kozubík, Alois; Vondráček, Jan
In: Toxicology letters, vol. 206, no. 2, pp. 121–129, 2011, ISSN: 1879-3169 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Alveolar Epithelial Cells/*drug effects/immunology/*metabolism, Animals, Apoptosis/drug effects, Aryl Hydrocarbon Hydroxylases/genetics/metabolism, Benzo(a)pyrene/metabolism/*toxicity, Carcinogens, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, DNA Adducts/*metabolism, Environmental/toxicity, Enzyme Activation/drug effects, Gene Expression Regulation/drug effects, Inflammation Mediators/*metabolism, Messenger/metabolism, Mutagens/*toxicity, p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism, Phosphorylation/drug effects, Post-Translational/drug effects, Protein Kinase Inhibitors/pharmacology, Protein Processing, Rats, RNA, Tumor Necrosis Factor-alpha/*metabolism, Tumor Suppressor Protein p53/metabolism
@article{umannova_benzopyrene_2011,
title = {Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells.},
author = {Lenka Umannová and Miroslav Machala and Jan Topinka and Jana Schmuczerová and Pavel Krčmář and Jiří Neča and Klára Šujanová and Alois Kozubík and Jan Vondráček},
doi = {10.1016/j.toxlet.2011.06.029},
issn = {1879-3169 0378-4274},
year = {2011},
date = {2011-10-01},
journal = {Toxicology letters},
volume = {206},
number = {2},
pages = {121–129},
abstract = {Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity.},
note = {Place: Netherlands},
keywords = {Alveolar Epithelial Cells/*drug effects/immunology/*metabolism, Animals, Apoptosis/drug effects, Aryl Hydrocarbon Hydroxylases/genetics/metabolism, Benzo(a)pyrene/metabolism/*toxicity, Carcinogens, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, DNA Adducts/*metabolism, Environmental/toxicity, Enzyme Activation/drug effects, Gene Expression Regulation/drug effects, Inflammation Mediators/*metabolism, Messenger/metabolism, Mutagens/*toxicity, p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism, Phosphorylation/drug effects, Post-Translational/drug effects, Protein Kinase Inhibitors/pharmacology, Protein Processing, Rats, RNA, Tumor Necrosis Factor-alpha/*metabolism, Tumor Suppressor Protein p53/metabolism},
pubstate = {published},
tppubtype = {article}
}
Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity.