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1.
Cell Tissue Res ; 336(1): 67-77, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19214581

RESUMO

Our aim has been to characterize the molecular mechanisms regulating the expression of the channel-forming tight-junctional protein claudin-2 in response to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFalpha), which is elevated, for example, in active Crohn's disease. TNFalpha caused an 89% decrease of the paracellular resistance in colonic HT-29/B6 cells, whereas transcellular resistance was unaltered. The claudin-2 protein level was increased by TNFalpha without changes in subcellular tight-junctional protein localization as revealed by confocal laser scanning microscopy. Enhanced gene expression was identified as the source of this increase, since claudin-2-specific mRNA and promoter activity was elevated, whereas mRNA stability remained unaltered. Specific inhibitors and phospho-specific antibodies revealed that the increased gene expression of claudin-2 after TNFalpha treatment was mediated by the phosphatidylinositol-3-kinase pathway. Thus, the up-regulation of claudin-2 by TNFalpha is attributable to the regulation of the expression of the gene, as a result of which epithelial barrier function is disturbed, for example, during chronic intestinal inflammation.


Assuntos
Proteínas de Membrana/genética , Fosfatidilinositol 3-Quinases/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Cromonas/farmacologia , Claudinas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Proteínas de Membrana/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/genética , Junções Íntimas/metabolismo , Distribuição Tecidual , Regulação para Cima/efeitos dos fármacos
2.
Gut ; 58(2): 220-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18936106

RESUMO

BACKGROUND AND AIMS: Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. The purpose of this study was to investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms. METHODS: Epithelial barrier function was characterised by impedance spectroscopy and [(3)H]mannitol fluxes in duodenal biopsies from 11 untreated and 8 suppressively treated HIV-infected patients, and 9 HIV-seronegative controls. The villus/crypt ratio was determined microscopically. Epithelial apoptoses were analysed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) and caspase-3 staining. Tight junction protein expression was quantified by densitometric analysis of immunoblots. Mucosal cytokine production was determined by cytometric bead array. RESULTS: Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13 (1) vs 23 (2) ohm cm(2), p<0.01) and mannitol permeability was increased compared with HIV-negative controls (19 (3) vs 9 (1) nm/s, p<0.05). As structural correlates, epithelial apoptoses and expression of the pore-forming claudin-2 were increased while expression of the sealing claudin-1 was reduced in untreated compared with treated patients and HIV-negative controls. Furthermore, villous atrophy was evident and mucosal production of interleukin 2 (IL2), IL4 and tumour necrosis factor alpha (TNFalpha) was increased in untreated but not in treated HIV-infected patients. Incubation with IL2, IL4, TNFalpha and IL13 reduced the transepithelial resistance of rat jejunal mucosa. CONCLUSIONS: Suppressive HAART abrogates HIV-induced intestinal barrier defect and villous atrophy. The HIV-induced barrier defect is due to altered tight junction protein composition and elevated epithelial apoptoses. Mucosal cytokines are mediators of the HIV-induced mucosal barrier defect and villous atrophy.


Assuntos
Células Epiteliais/metabolismo , Infecções por HIV/metabolismo , Mucosa Intestinal/metabolismo , Adulto , Animais , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Apoptose , Western Blotting/métodos , Estudos de Casos e Controles , Permeabilidade da Membrana Celular/efeitos dos fármacos , Claudina-1 , Claudina-4 , Claudinas , Citocinas/imunologia , Citocinas/farmacologia , Progressão da Doença , Duodeno , Impedância Elétrica , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Interleucina-13/análise , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/virologia , Masculino , Manitol/metabolismo , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Ocludina , Ratos , Ratos Wistar , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/virologia , Replicação Viral/efeitos dos fármacos
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