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

Kim, Jung Mogg; Lee, D. H.; Kim, J. S.; Lee, J. Y.; Park, Heum Gi; Kim, Y. J.; Oh, Yu‐Kyoung; Jung, Hyun Chae; Kim, S. I.

doi:10.1111/j.1365-2249.2008.03849.x

Cited by 21 publications

(41 citation statements)

References 35 publications

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“…The capacity of Hsp90 inhibitors to blunt IL-8 production was recently reported in the context of bacterial-and viralinduced inflammation, including Helicobacter pylori-infected gastric epithelial cells (Yeo et al 2004), Legionella pneumophila-infected lung epithelial cells (Teruya et al 2007), Bacteroides fragilis enterotoxin-treated intestinal epithelial cells (Kim et al 2009), and oncogenic herpes virusinfected endothelial cells and fibroblasts (Defee et al 2011). In these experimental studies, Hsp90 inhibitors acted via deactivation of NFκB, a client of Hsp90 and one of the major transcription factors for IL-8 (Hoffmann et al 2002;Salminen et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

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Section: Discussionmentioning

confidence: 99%

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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“…32 Purification of BFT and Cell Culture Conditions BFT was purified from the culture supernatant of a highly toxigenic ETBF strain as described previously. 10,[25][26][27][28][29][30]33 BFT preparation purity was confirmed by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). Typical preparations of BFT contained 0.5-1.2 mg protein/ml as measured by the BCA protein assay.…”

Section: Materials and Methods Reagentsmentioning

confidence: 99%

“…Moreover, there is no evidence of BFT-induced MAPKs or AP-1 activation leading to Lcn-2 expression, although those signaling molecules have been reported to be activated in intestinal epithelial cells exposed to BFT. 10,[25][26][27][28][29][30][31] In the studies reported here, we investigated the regulation of Lcn-2 expression in response to BFT stimulation, and found that stimulation with BFT upregulates Lcn-2 expression in intestinal epithelial cells through the activation of MAPKs and the AP-1 signaling pathway.…”

mentioning

confidence: 99%

Bacteroides fragilis enterotoxin upregulates lipocalin-2 expression in intestinal epithelial cells

Yoo

Jung

et al. 2013

Laboratory Investigation

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Enterotoxigenic Bacteroides fragilis (ETBF) produces an B20 kDa B. fragilis enterotoxin (BFT), which plays an essential role in mucosal inflammation. Lipocalin (Lcn)-2, a siderophore-binding antimicrobial protein, is critical for control of bacterial infection; however, expression of Lcn-2 in BFT-exposed intestinal epithelial cells has not been elucidated. In the present study, stimulation of human intestinal epithelial cells with BFT resulted in the upregulation of Lcn-2 expression that was a relatively late response of intestinal epithelial cells compared with human b-defensin (hBD)-2 expression. The upregulation of Lcn-2 was dependent on AP-1 but not on NF-kB signaling. Lcn-2 induction via AP-1 was regulated by mitogenactivated protein kinases (MAPKs) including ERK and p38. Lcn-2 was secreted from the apical and basolateral surfaces in BFT-treated cells. These results suggest that a signaling pathway involving MAPKs and AP-1 is required for Lcn-2 induction in intestinal epithelial cells exposed to BFT, after which the secreted Lcn-2 may facilitate antimicrobial activity within ETBF-infected mucosa.

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“…These ob-servations raise the possibility that the signaling molecules may be activated in BFT-exposed ECs to regulate the expression of adhesion molecules. However, there is no evidence that BFTinduced signaling leads to ICAM-1 expression in ECs, although some of those signaling molecules have been reported to be activated in intestinal epithelial cells stimulated with BFT (5,(21)(22)(23)(24)(25)(26)). In the current study, we investigated ICAM-1 induction in response to BFT stimulation, and found that EC exposure to BFT resulted in the upregulation of ICAM-1 through activation of a signaling pathway involving AR, JNK MAPK, IkB kinase (IKK), and NFkB, finally culminating in monocyte adhesion to ECs.…”

Section: Nfection By Enterotoxigenic Bacteroides Fragilis (Etbf)mentioning

confidence: 99%

“…In the current study, we investigated ICAM-1 induction in response to BFT stimulation, and found that EC exposure to BFT resulted in the upregulation of ICAM-1 through activation of a signaling pathway involving AR, JNK MAPK, IkB kinase (IKK), and NFkB, finally culminating in monocyte adhesion to ECs. Purification of BFT and cell culture conditions BFT was purified from the culture supernatants of a highly toxigenic strain of ETBF, as described previously (5,(21)(22)(23)(24)(25). The purity of the BFT preparations was confirmed by SDS-PAGE.…”

Section: Nfection By Enterotoxigenic Bacteroides Fragilis (Etbf)mentioning

confidence: 99%

Bacteroides fragilis Enterotoxin Upregulates Intercellular Adhesion Molecule-1 in Endothelial Cells via an Aldose Reductase-, MAPK-, and NF-κB–Dependent Pathway, Leading to Monocyte Adhesion to Endothelial Cells

Roh

Yoo

et al. 2011

The Journal of Immunology

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Enterotoxigenic Bacteroides fragilis (ETBF) produces a ∼20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although a variety of inflammatory cells is found at ETBF-infected sites, little is known about leukocyte adhesion in response to BFT stimulation. We investigated whether BFT affected the expression of ICAM-1 and monocytic adhesion to endothelial cells (ECs). Stimulation of HUVECs and rat aortic ECs with BFT resulted in the induction of ICAM-1 expression. Upregulation of ICAM-1 was dependent on the activation of IκB kinase (IKK) and NF-κB signaling. In contrast, suppression of AP-1 did not affect ICAM-1 expression in BFT-stimulated cells. Suppression of NF-κB activity in HUVECs significantly reduced monocytic adhesion, indicating that ICAM-1 expression is indispensable for BFT-induced adhesion of monocytes to the endothelium. Inhibition of JNK resulted in a significant attenuation of BFT-induced ICAM-1 expression in ECs. Moreover, inhibition of aldose reductase significantly reduced JNK-dependent IKK/NF-κB activation, ICAM-1 expression, and adhesion of monocytes to HUVECs. These results suggest that a signaling pathway involving aldose reductase, JNK, IKK, and NF-κB is required for ICAM-1 induction in ECs exposed to BFT, and may be involved in the leukocyte–adhesion cascade following infection with ETBF.

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

Abstract: SummaryEnterotoxin 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 (

Cited by 21 publications

References 35 publications

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Bacteroides fragilis enterotoxin upregulates lipocalin-2 expression in intestinal epithelial cells

Bacteroides fragilis Enterotoxin Upregulates Intercellular Adhesion Molecule-1 in Endothelial Cells via an Aldose Reductase-, MAPK-, and NF-κB–Dependent Pathway, Leading to Monocyte Adhesion to Endothelial Cells

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