Bacteroides fragilis Enterotoxin Upregulates Matrix Metalloproteinase-7 Expression through MAPK and AP-1 Activation in Intestinal Epithelial Cells, Leading to Syndecan-2 Release.

Jong Ik Jeon,Jung Mogg Kim,Keun Hwa Lee

doi:10.3390/ijms222111817

Jong Ik Jeon, Jung Mogg Kim + Show 1 more

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https://doi.org/10.3390/ijms222111817

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Abstract

Bacteroides fragilis enterotoxin (BFT) produced by enterotoxigenic B. fragilis (ETBF) causes colonic inflammation. BFT initially contacts intestinal epithelial cells (IECs) and affects the intestinal barrier. Although molecular components of the gut epithelial barrier such as metalloproteinase-7 (MMP-7) and syndecan-2 are known to be associated with inflammation, little has been reported about MMP-7 expression and syndecan-2 shedding in response to ETBF infection. This study explores the role of BFT in MMP-7 induction and syndecan-2 release in IECs. Stimulating IECs with BFT led to the induction of MMP-7 and the activation of transcription factors such as NF-κB and AP-1. MMP-7 upregulation was not affected by NF-κB, but it was related to AP-1 activation. In BFT-exposed IECs, syndecan-2 release was observed in a time- and concentration-dependent manner. MMP-7 suppression was associated with a reduction in syndecan-2 release. In addition, suppression of ERK, one of the mitogen-activated protein kinases (MAPKs), inhibited AP-1 activity and MMP-7 expression. Furthermore, the suppression of AP-1 and ERK activity was related to the attenuation of syndecan-2 release. These results suggest that a signaling cascade comprising ERK and AP-1 activation in IECs is involved in MMP-7 upregulation and syndecan-2 release during exposure to BFT.

Highlights

Enterotoxin-producing Bacteroides fragilis (ETBF) causes several colonic diseases, including inflammation and cancer [1,2]
We found that signaling pathways comprising ERK mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) were essential for Matrix metalloproteinase (MMP)-7 induction following exposure to B. fragilis enterotoxin (BFT)
intestinal epithelial cells (IECs) exposed to BFT can express mediators, such as IL-8 and β-catenin, and transcription factors, AP-1 mediators, and NF-κB,such to regulate of those

Summary

Introduction

Enterotoxin-producing Bacteroides fragilis (ETBF) causes several colonic diseases, including inflammation and cancer [1,2]. BFT secreted by ETBF contacts intestinal epithelial cells (IECs), and the subsequent effects can induce colonic inflammation and breaks in the gut barrier. Maintaining a steady status of epithelial cell-to-cell junctions requires E-cadherin and β-catenin structures in the intestinal barrier [4]. BFT produced by ETBF cleaves the extracellular domain of E-cadherin that is involved in preserving the integrity of IEC barriers [6]. Matrix metalloproteinase (MMP)-7 is reported to mediate the degradation of E-cadherin in proximal tubular cells, which leads to the nuclear translocation of β-catenin [7]. The nuclear translocation of β-catenin can control MMP-7 expression in colorectal cancer tissues [8]

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