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1.
Arch Toxicol ; 87(3): 491-503, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23085979

RESUMO

The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.


Assuntos
Carcinógenos/toxicidade , Comunicação Celular/efeitos dos fármacos , Conexina 43/metabolismo , Inibição de Contato/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/agonistas , Transdução de Sinais/efeitos dos fármacos , Animais , Benzo(a)Antracenos/toxicidade , Linhagem Celular , Proliferação de Células , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Conexina 43/genética , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fluorenos/toxicidade , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Técnicas de Silenciamento de Genes , Indóis/farmacologia , Ligantes , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Fosforilação , Dibenzodioxinas Policloradas/toxicidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , Ratos , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Tempo , Transfecção
2.
Toxicol Lett ; 206(2): 121-9, 2011 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-21745554

RESUMO

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-1ß 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.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Benzo(a)pireno/toxicidade , Adutos de DNA/metabolismo , Mediadores da Inflamação/metabolismo , Mutagênicos/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Células Epiteliais Alveolares/imunologia , Animais , Apoptose/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzo(a)pireno/metabolismo , Carcinógenos Ambientais/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Toxicol Sci ; 122(2): 349-60, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21602191

RESUMO

ß-catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/ß-catenin pathway, which plays an important role in liver biology. Using a model of contact-inhibited liver progenitor cells, we examined the interactions of Wnt/ß-catenin signaling with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which mediates the toxicity of dioxin-like compounds, including their effects on development and hepatocarcinogenesis. We found that AhR and Wnt/ß-catenin cooperated in the induction of AhR transcriptional targets, such as Cyp1a1 and Cyp1b1. However, simultaneously, the activation of AhR led to a decrease of dephosphorylated active ß-catenin pool, as well as to hypophosphorylation of Dishevelled, participating in regulation of Wnt signaling. A sustained AhR activation by its model ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), led to a downregulation of a number of Wnt/ß-catenin pathway target genes. TCDD also induced a switch in cytokeratin expression, where downregulation of cytokeratins 14 and 19 was accompanied with an increased cytokeratin 8 expression. Together with a downregulation of additional markers associated with stem-like phenotype, this indicated that the AhR activation interfered with differentiation of liver progenitors. The downregulation of ß-catenin was also related to a reduced cell adhesion, disruption of E-cadherin-mediated cell-cell junctions and an increased G1-S transition in liver progenitor cell line. In conclusion, although ß-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/ß-catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells.


Assuntos
Fígado/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Caderinas/genética , Adesão Celular , Diferenciação Celular , Linhagem Celular , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Regulação para Baixo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Ratos , Ratos Endogâmicos F344 , Receptores de Hidrocarboneto Arílico/genética , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética
4.
Curr Drug Metab ; 12(2): 89-103, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21401513

RESUMO

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays a major role in toxic effects of environmental pollutants. It is a pivotal regulator of several xenobiotic-metabolizing enzymes (XMEs), and is now considered to play an important role also in control of cell cycle, apoptosis and cell differentiation. The accumulating evidence suggests that there exists a multiple crosstalk between AhR activation and the signaling pathways activated by inflammatory mediators, such as nuclear factor-κB, a pleiotropic transcription factor controlling the immune/inflammatory responses. In this review, we summarize the current knowledge about the interactions of AhR with inflammatory mediators leading to deregulation of the AhR-dependent XMEs, as well as the evidence pointing to the role of AhR in modulation of inflammatory signals. These include altered expression of proinflammatory cytokines, such as tumor necrosis factor-alpha or interleukin-6, and deregulation of expression/activity of principle enzymes producing inflammatory mediators, such as cyclooxygenase-2. Recent studies also indicate that various classes of AhR ligands may differentially modulate AhR-dependent toxic responses and inflammation, which opens an interesting opportunity for a targeted synthesis of AhR ligands with anti-inflammatory properties. Although the role of activated AhR in the regulation of inflammation is still far from being completely understood, the close interactions between AhR and inflammatory signaling evidently can play a significant role in immune dysfunctions, metabolism of xenobiotics or carcinogenesis. The current review will focus mostly on the interaction of AhR and inflammation relative to mechanisms associated with the pathology of carcinogenesis.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Mediadores da Inflamação/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Transdução de Sinais/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Xenobióticos/metabolismo
5.
Mutat Res ; 640(1-2): 162-9, 2008 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-18336843

RESUMO

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant, which may contribute to the development of human cancer. The ultimate carcinogenic BaP metabolite produced by cytochrome P450 enzymes (CYP), such as CYP1A1 and CYP1B1, anti-BaP-7,8-diol-9,10-epoxide, binds covalently to DNA and causes mutations. The levels of various CYP isoforms can be significantly modulated under inflammatory conditions. As the chronic inflammation is known to contribute to carcinogenesis, we investigated interactions of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), and BaP in regulation of the expression of CYP1A1/1B1 and induction of DNA damage in rat liver epithelial WB-F344 cells. TNF-alpha enhanced induction of CYP1B1, while it simultaneously suppressed the BaP-induced CYP1A1 expression. The observed deregulation of CYP1 induction was found to be associated with a significantly enhanced formation of DNA adducts. The elevated DNA damage corresponded with increased phosphorylation of p53 tumor suppressor at Ser-15 residue, enhanced accumulation of cells in the S-phase of cell cycle and potentiation of BaP-induced apoptosis. Inhibition of CYP1B1 by fluoranthene significantly decreased both the formation of DNA adducts and the induction of apoptosis in WB-F344 cells treated with BaP and TNF-alpha, thus suggesting that this isoform might be responsible for genotoxic effects of BaP in nonparenchymal liver cells. Our results seem to indicate that inflammatory conditions might enhance genotoxic effects of carcinogenic polycyclic aromatic hydrocarbons through upregulation of CYP1B1 expression.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzo(a)pireno/toxicidade , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Linhagem Celular , Citocromo P-450 CYP1B1 , Sinergismo Farmacológico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Masculino , Ratos , Regulação para Cima
6.
Toxicol Sci ; 99(1): 79-89, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17557910

RESUMO

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


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Ligantes , Fígado/citologia , Bifenilos Policlorados/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de Hidrocarboneto Arílico/metabolismo , Células-Tronco/enzimologia
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