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2.
Toxicol Appl Pharmacol ; 287(3): 258-66, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26080028

RESUMO

Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Metaloproteinase 2 da Matriz/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Ocludina/metabolismo , Bifenilos Policlorados/toxicidade , Proteína Fosfatase 2/metabolismo , Animais , Barreira Hematoencefálica/enzimologia , Barreira Hematoencefálica/patologia , Caveolina 1/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Masculino , Microdomínios da Membrana/enzimologia , Microdomínios da Membrana/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
3.
Am J Physiol Gastrointest Liver Physiol ; 306(11): G992-G1001, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24742991

RESUMO

The intestinal epithelium forms a selective barrier maintained by tight junctions (TJs) and separating the luminal environment from the submucosal tissues. N-acylhomoserine lactone (AHL) quorum-sensing molecules produced by gram-negative bacteria in the gut can influence homeostasis of the host intestinal epithelium. In the present study, we evaluated the regulatory mechanisms affecting the impact of two representative long- and short-chain AHLs, N-3-(oxododecanoyl)-homoserine lactone (C12-HSL) and N-butyryl homoserine lactone (C4-HSL), on barrier function of human intestinal epithelial Caco-2 cells. Treatment with C12-HSL, but not with C4-HSL, perturbed Caco-2 barrier function; the effect was associated with decreased levels of the TJ proteins occludin and tricellulin and their delocalization from the TJs. C12-HSL also induced matrix metalloprotease (MMP)-2 and MMP-3 activation via lipid raft- and protease-activated receptor (PAR)-dependent signaling. Pretreatment with lipid raft disruptors, PAR antagonists, or MMP inhibitors restored the C12-HSL-induced loss of the TJ proteins and increased permeability of Caco-2 cell monolayers. These results indicate that PAR/lipid raft-dependent MMP-2 and -3 activation followed by degradation of occludin and tricellulin are involved in C12-HSL-induced alterations of epithelial paracellular barrier functions.


Assuntos
Células Epiteliais/efeitos dos fármacos , Homosserina/análogos & derivados , Mucosa Intestinal/fisiologia , Lactonas/farmacologia , Metaloproteinases da Matriz/metabolismo , Acil-Butirolactonas/farmacologia , Células CACO-2 , Ativação Enzimática , Regulação da Expressão Gênica , Homosserina/farmacologia , Humanos , Mucosa Intestinal/citologia , Proteína 2 com Domínio MARVEL/metabolismo , Metaloproteinases da Matriz/genética , Microdomínios da Membrana/fisiologia , Ocludina/metabolismo , Permeabilidade , Proteínas de Junções Íntimas/metabolismo
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