Mitogen‐activated protein kinase and activator protein‐1 dependent signals are essential for <i>Bacteroides fragilis</i> enterotoxin‐induced enteritis

Kim, Jung Mogg; Jung, Hwoon Yong; Lee, Jin Young; Youn, Jeehee; Lee, Chul-Hoon; Kim, Kyoung-Ho

doi:10.1002/eji.200526321

Cited by 81 publications

(112 citation statements)

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“…In addition, transfection experiments using an adenovirus vector containing dominant-negative p38 mutants demonstrated that the suppression of p38 MAPK not only increased DNA fragmentation but also decreased PGE 2 production. These results are consistent with our previous report showing that a p38 inhibitor, SB203580, prevented BFT-induced colitis in the mouse ileum, as evidenced by significant decreases in villous destruction, neutrophil infiltration, and mucosal congestion [8]. These results suggest that MAPK is involved in cell protection in BFT-stimulated epithelial cells, and p38 seems to play a major role in the transcriptional regulation of c-IAP2.…”

Section: Discussionsupporting

confidence: 93%

“…To support this hypothesis, the role of IL-8 was at first explored by Sanfilippo et al [10]. In addition, we have reported BFT-induced proinflammatory signals in IEC [6][7][8][9]. In the studies reported here, we found that one of the late responses to BFT stimulation in human IEC is apoptosis in a dose-and timedependent manner.…”

Section: Discussionsupporting

confidence: 68%

“…BFT activates the MAPK family, including ERK, p38, and JNK [8,11], and MAPK are known to play a role in cytoprotection during the apoptotic process [26][27][28]. Therefore, we asked whether MAPK are the upstream molecules that regulate expression of c-IAP2 in BFT-stimulated HT-29 cells.…”

Section: Mapk Is Associated With C-iap2 Induction and Cell Protectionmentioning

confidence: 99%

“…BFT was purified from the culture supernatants of a highly toxigenic strain of ETBF as previously described [6][7][8][9]. The purity of the BFT preparations was confirmed by SDS-PAGE.…”

Section: Purification Of Bft and Cell Culturesmentioning

confidence: 99%

“…Following BFT stimulation, signals for NF-jB and mitogen-activated protein kinase (MAPK) are activated within 30 min and enhance interleukin (IL)-8 secretion, which leads to mucosal transmigration of neutrophils [6][7][8][9][10][11]. In addition, BFT stimulation induces the expression of cyclooxygenase (COX)-2 and increases the release of prostaglandin E 2 (PGE 2 ) in intestinal epithelial cells (IEC) [9].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

2008

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Enterotoxigenic Bacteroides fragilis produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in generating mucosal inflammation. Although it is well known that proinflammatory signals are expressed in BFT-stimulated intestinal epithelial cells, cell death processes have not been elucidated. BFT induced apoptosis in HT-29 cells, but the apoptosis was first apparent 36 h after stimulation. During the early period of BFT stimulation, expression of cellular inhibitor of apoptosis protein-2 (c-IAP2) increased, and inhibition of c-IAP2 augmented the apoptotic cell death. Inhibition of BFT-induced COX-2 expression decreased prostaglandin E 2 (PGE 2 ) production, which led not only to a decrease of c-IAP2 activity but also to an enhancement of DNA fragmentation in the early period of BFT stimulation. Furthermore, apoptosis inhibition through PGE 2 and c-IAP2 was mainly regulated by a p38 mitogen-activated protein kinase (MAPK). These results suggest that the inhibition of apoptosis may be mediated by a sequential pathway, including MAPK, COX-2, PGE 2 and c-IAP2, in the early period of stimulation. The delay in the onset of epithelial cell apoptosis after enterotoxigenic B. fragilis infection may be important to the host since it can provides sufficient time for epithelial cells to generate signals for the activation of mucosal inflammation and it may increase the chances of bacterial colonization.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 68%

Section: Mapk Is Associated With C-iap2 Induction and Cell Protectionmentioning

confidence: 99%

“…BFT was purified from the culture supernatants of a highly toxigenic strain of ETBF as previously described [6][7][8][9]. The purity of the BFT preparations was confirmed by SDS-PAGE.…”

Section: Purification Of Bft and Cell Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

2008

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Dissecting Gut‐Microbial Community Interactions using a Gut Microbiome‐on‐a‐Chip

Lee,

Menon,

Lim

2024

Advanced Science

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While the human gut microbiota has a significant impact on gut health and disease, understanding of the roles of gut microbes, interactions, and collective impact of gut microbes on various aspects of human gut health is limited by the lack of suitable in vitro model system that can accurately replicate gut‐like environment and enable the close visualization on causal and mechanistic relationships between microbial constitutents and the gut. , In this study, we present a scalable Gut Microbiome‐on‐a‐Chip (GMoC) with great imaging capability and scalability, providing a physiologically relevant dynamic gut‐microbes interfaces. This chip features a reproducible 3D stratified gut epithelium derived from Caco‐2 cells (µGut), mimicking key intestinal architecture, functions, and cellular complexity, providing a physiolocially relevant gut environment for microbes residing in the gut. Incorporating tumorigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), into the GMoC enable the observation of pathogenic behaviors of ETBF, leading to µGut disruption and pro‐tumorigenic signaling activations. Pre‐treating the µGut with a beneficial gut microbe Lactobacillus spp., effectively prevent ETBF‐mediated gut pathogenesis, preserving the healthy state of the µGut through competition‐mediated colonization resistance. The GMoC holds potential as a valuable tool for exploring unknown roles of gut microbes in microbe‐induced pathogenesis and microbe‐based therapeutic development.

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Bacteroides fragilisenterotoxin induces cyclooxygenase‐2 and fluid secretion in intestinal epithelial cells through NF‐κB activation

et al. 2006

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Bacteroides fragilis produces an approximately 20-kDa heat-labile toxin (B. fragilis enterotoxin, BFT) which is known to be associated with diarrhea. To determine whether cyclooxygenase (COX)-2, via NF-jB activation, can contribute to BFT-induced diarrhea, the relationship between COX-2 expression and fluid secretion in BFT-stimulated human intestinal epithelial cells was examined. BFT stimulation increased the expression of COX-2, but not COX-1, in human intestinal epithelial cells. Suppression of the NF-jB signal significantly decreased COX-2 expression in response to BFT stimulation. Prostaglandin E 2 (PGE 2 ) levels were increased in parallel with COX-2 expression, and, conversely, PGE 2 production was significantly inhibited when COX-2 or NF-jB activities were suppressed using COX-2 small interfering RNA (siRNA), p65 NF-jB subunit siRNA, or a retrovirus encoding the IjBa superrepressor. In addition, a selective COX-2 inhibitor, NS-398, significantly inhibited the increased cAMP level induced by BFT stimulation. Furthermore, a selective COX-2 inhibitor prevented BFTinduced PGE 2 production and ileal fluid secretion in a mouse ileal loop model. These results suggest that the secretory response to BFT stimulation may be mediated by the production of PGE 2 , through NF-jB activation and the up-regulation of COX-2 in intestinal epithelial cells. IntroductionEnterotoxigenic Bacteroides fragilis (ETBF) has been shown to be associated with non-invasive diarrheal diseases in animals and young children [1][2][3][4][5], and B. fragilis enterotoxin (BFT), an approximately 20-kDa heat-labile metalloprotease, is regarded as a virulence factor for this diarrheal disease. BFT stimulates NF-jB activation and IL-8 secretion [6][7][8][9], which is predicted to lead to mucosal transmigration of neutrophils with release of prostaglandins (PG). In addition, animal loop experiments and gnotobiotic piglet infection indicate that BFT is proinflammatory and BFT stimulates a brief chloride current and a loss of barrier function in vitro [3,10], suggesting that these findings are potential mechanisms accounting for ETBF-induced diarrhea. Several studies have shown that secretion of PG from intestinal mucosal epithelial cells is closely associated with diarrheal diseases [11,12], and administration of PG analogues, such as PGE 2 , causes increased fluid secretion in human subjects [13,14]. In addition, the roles of PG in the secretory response to cholera toxin and enterotoxigenic Escherichia coli have been demonstrated [15][16][17]. These results suggest the hypothesis that the diarrhea associated with ETBF may be PG-derived. PGE 2 is a metabolite of arachidonic acid and is synthesized by cyclooxygenase (COX). There are two isoforms of this enzyme [18]: COX-1, which is constitutively expressed in crypt epithelial cells, and COX-2, which can be induced in a variety of cell types, including epithelial cells, macrophages and fibroblasts. COX-2 is induced by proinflammatory cytokines, lipopolysaccharide and infectious agents [19]. The expr...

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Mitogen‐activated protein kinase and activator protein‐1 dependent signals are essential for Bacteroides fragilis enterotoxin‐induced enteritis

Cited by 81 publications

References 54 publications

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

Dissecting Gut‐Microbial Community Interactions using a Gut Microbiome‐on‐a‐Chip

Bacteroides fragilisenterotoxin induces cyclooxygenase‐2 and fluid secretion in intestinal epithelial cells through NF‐κB activation

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