| Autor: |
Ma, Thomas Y., Iwamoto, Gary K., Hoa, Neil T., Akotia, Vimesh, Pedram, Ali, Boivin, Michel A., Said, Hamid M. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Gastrointestinal & Liver Physiology; Mar2004, Vol. 286, pG367-G376, 10p, 7 Black and White Photographs, 2 Charts, 12 Graphs |
| Abstrakt: |
Crohn's disease (CD) patients have an abnormal increase in intestinal epithelial permeability. The defect in intestinal tight junction (TJ) barrier has been proposed as an important etiologic factor of CD. TNF-α increases intestinal TJ permeability. Because TNF-α levels are markedly increased in CD, TNF-α increase in intestinal TJ permeability could be a contributing factor of intestinal permeability defect in CD. Our purpose was to determine some of the intracellular mechanisms involved in TNF-α modulation of intestinal epithelial TJ permeability by using an in vitro intestinal epithelial system consisting of filtergrown Caco-2 monolayers. TNF-α produced a concentration- and time-dependent increase in Caco-2 TJ permeability. TNF-α-induced increase in Caco-2 TJ permeability correlated with Caco-2 NF-κB activation. Inhibition of TNF-α-induced NF-κB activation by selected NF-κB inhibitors, curcumin and triptolide, prevented the increase in Caco-2 TJ permeability, indicating that NF-κB activation was required for the TNF-α-induced increase in Caco-2 TJ permeability. This increase in Caco-2 TJ permeability was accompanied by downregulation of zonula occludens (ZO)-1 proteins and alteration in junctional localization of ZO-1 proteins. TNF-α modulation of ZO-1 protein expression and junctional localization were also prevented by NF-κB inhibitors. TNF-α did not induce apoptosis in Caco-2 cells, suggesting that apoptosis was not the mechanism involved in TNFα-induced increase in Caco-2 TJ permeability. These results demonstrate for the first time that TNF-α-induced increase in Caco-2 TJ permeability was mediated by NF-κB activation. The increase in permeability was associated with NF-κB-dependent downregulation of ZO-1 protein expression and alteration in junctional localization. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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