5,7-dihydroxy-3,4,6-trimethoxyflavone inhibits the inflammatory effects induced by Bacteroides fragilis enterotoxin via dissociating the complex of heat shock protein 90 and IκBα and IκB kinase-γ in intestinal epithelial cell culture

J. M. Kim, D. H. Lee, J. S. Kim, J. Y. Lee, H. G. Park, Y. J. Kim, Y. K. Oh, H. C. Jung, S. I. Kim

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Abstract

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 E2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-κB) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-κB activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both IκBα and IκB kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-α and IKK-β decreased the production of IL-8 and prostaglandin E2; however, the transfection of IKK-β siRNA showed a more significant reduction of BFT-induced IκBα phosphorylation compared with that of IKK-α siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-κB, suggesting that Hsp90 is associated with a pathway of IKK-NF-κB-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-γ in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-κB signalling pathway by targeting the Hsp90-IKK-γ complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.

Original languageEnglish
Pages (from-to)541-551
Number of pages11
JournalClinical and Experimental Immunology
Volume155
Issue number3
DOIs
StatePublished - 1 Mar 2009

Fingerprint

HSP90 Heat-Shock Proteins
HT29 Cells
Phosphotransferases
Cell Culture Techniques
Epithelial Cells
Interleukin-8
Small Interfering RNA
Prostaglandin-Endoperoxide Synthases
Dinoprostone
Transfection
Phosphorylation
Bacteroides fragilis
Enterotoxins
fragilysin
eupatilin
Anti-Inflammatory Agents
Inflammation
Cell Line
Genes

Keywords

  • Bacteroides fragilis enterotoxin
  • Eupatilin
  • Hsp90
  • IκB kinase
  • NF-κB

Cite this

@article{afc2fc6213be4677a36eb92e0549aa78,
title = "5,7-dihydroxy-3,4,6-trimethoxyflavone inhibits the inflammatory effects induced by Bacteroides fragilis enterotoxin via dissociating the complex of heat shock protein 90 and IκBα and IκB kinase-γ in intestinal epithelial cell culture",
abstract = "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 E2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-κB) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-κB activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both IκBα and IκB kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-α and IKK-β decreased the production of IL-8 and prostaglandin E2; however, the transfection of IKK-β siRNA showed a more significant reduction of BFT-induced IκBα phosphorylation compared with that of IKK-α siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-κB, suggesting that Hsp90 is associated with a pathway of IKK-NF-κB-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-γ in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-κB signalling pathway by targeting the Hsp90-IKK-γ complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.",
keywords = "Bacteroides fragilis enterotoxin, Eupatilin, Hsp90, IκB kinase, NF-κB",
author = "Kim, {J. M.} and Lee, {D. H.} and Kim, {J. S.} and Lee, {J. Y.} and Park, {H. G.} and Kim, {Y. J.} and Oh, {Y. K.} and Jung, {H. C.} and Kim, {S. I.}",
year = "2009",
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doi = "10.1111/j.1365-2249.2008.03849.x",
language = "English",
volume = "155",
pages = "541--551",
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T1 - 5,7-dihydroxy-3,4,6-trimethoxyflavone inhibits the inflammatory effects induced by Bacteroides fragilis enterotoxin via dissociating the complex of heat shock protein 90 and IκBα and IκB kinase-γ in intestinal epithelial cell culture

AU - Kim, J. M.

AU - Lee, D. H.

AU - Kim, J. S.

AU - Lee, J. Y.

AU - Park, H. G.

AU - Kim, Y. J.

AU - Oh, Y. K.

AU - Jung, H. C.

AU - Kim, S. I.

PY - 2009/3/1

Y1 - 2009/3/1

N2 - 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 E2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-κB) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-κB activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both IκBα and IκB kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-α and IKK-β decreased the production of IL-8 and prostaglandin E2; however, the transfection of IKK-β siRNA showed a more significant reduction of BFT-induced IκBα phosphorylation compared with that of IKK-α siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-κB, suggesting that Hsp90 is associated with a pathway of IKK-NF-κB-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-γ in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-κB signalling pathway by targeting the Hsp90-IKK-γ complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.

AB - 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 E2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-κB) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-κB activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both IκBα and IκB kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-α and IKK-β decreased the production of IL-8 and prostaglandin E2; however, the transfection of IKK-β siRNA showed a more significant reduction of BFT-induced IκBα phosphorylation compared with that of IKK-α siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-κB, suggesting that Hsp90 is associated with a pathway of IKK-NF-κB-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-γ in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-κB signalling pathway by targeting the Hsp90-IKK-γ complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.

KW - Bacteroides fragilis enterotoxin

KW - Eupatilin

KW - Hsp90

KW - IκB kinase

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