Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 155, Issue 3, Pages 541-551Publisher
WILEY
DOI: 10.1111/j.1365-2249.2008.03849.x
Keywords
Bacteroides fragilis enterotoxin; eupatilin; Hsp90; I kappa B kinase; NF-kappa B
Categories
Funding
- Seoul RBD Program
- Korea Science and Engineering Foundation (KOSEF)
- Korea government (MOST) [R11-2008-044-01004-0]
- National Research Foundation of Korea [R11-2008-044-01004-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Enterotoxin produced by enterotoxigenic Bacteroides fragilis (BFT) has been associated with mucosal inflammation and diarrhoeal diseases. In this study, the anti-inflammatory molecular mechanism of 5,7-dihydroxy-3,4,6-trimethoxyflavone (eupatilin) was characterized in an HT-29 intestinal epithelial cell line stimulated with BFT. Pre-treatment of HT-29 cells with eupatilin decreased the production significantly of both interleukin (IL)-8 and prostaglandin E-2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-kappa B) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-kappa B activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both I kappa B alpha and I kappa B kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-alpha and IKK-beta decreased the production of IL-8 and prostaglandin E-2; however, the transfection of IKK-beta siRNA showed a more significant reduction of BFT-induced I kappa B alpha phosphorylation compared with that of IKK-alpha siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-kappa B, suggesting that Hsp90 is associated with a pathway of IKK-NF-kappa B-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-gamma in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-kappa B signalling pathway by targeting the Hsp90-IKK-gamma complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.
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