Bacteroides fragilisToxin Induces IL-8 Secretion in HT29/C1 Cells through Disruption of E-cadherin Junctions

Abstract

Enterotoxigenic Bacteroides fragilis (ETBF) is a human gut commensal bacteria that causes inflammatory diarrhea and colitis. ETBF also promotes colorectal tumorigenesis in the Min mouse model. The key virulence factor is a secreted metalloprotease called B. fragilis toxin (BFT). BFT induces E-cadherin cleavage, cell rounding, activation of the β-catenin pathway and secretion of IL-8 in colonic epithelial cells. However, the precise mechanism by which these processes occur and how these processes are interrelated is still unclear. E-cadherin form homophilic interactions which tethers adjacent cells. Loss of E-cadherin results in detachment of adjacent cells. Prior studies have suggested that BFT induces IL-8 expression by inducing E-cadherin cleavage; cells that do not express E-cadherin do not secrete IL-8 in response to BFT. In the current study, we found that HT29/C1cells treated with dilute trypsin solution induced E-cadherin degradation and IL-8 secretion, consistent with the hypothesis that E-cadherin cleavage causes IL-8 secretion. However, physical damage to the cell monolayer did not induce IL-8 secretion. We also show that EDTA-mediated disruption of E-cadherin interactions without E-cadherin degradation was sufficient to induce IL-8 secretion. Finally, we determined that HT29/C1 cells treated with LiCl (β-catenin activator) induced IL-8 secretion in a dose-dependent and time-dependent manner. Taken together, our results suggest that BFT induced IL-8 secretion may occur by the following process: E-cadherin cleavage, disruption of cellular interactions, activation of the β-catenin pathway and IL-8 expression. However, we further propose that E-cadherin cleavage per se may not be required for BFT induced IL-8 secretion.

Modulation of Pectin on Mucosal Innate Immune Function in Pigs Mediated by Gut Microbiota

“…The bacteria enriched in the CON pigs, including Lawsonia, Bacteroides, Staphylococcus and Streptococcus, have previously been associated with inflammatory diarrhea and gut dysbiosis in pigs [46][47][48]. Notably, members of the genus Bacteroides have been shown to induces IL-8 secretion in intestinal epithelial cells via activation of the β-catenin pathway [49]. Our results showing correlations between the abundance of Bacteroides and IL-8, IL-12 and IL-18 suggest that these pro-inflammatory cytokines may also, in turn, play a role in expanding the niche for Bacteroides in the CON-fed animals.…”

Enterotoxigenic Bacteroides fragilis infection exacerbates tumorigenesis in AOM/DSS mouse model

“…BFT induces E-cadherin cleavage in colonic epithelial cells in vivo resulting in increased intestinal permeability and subsequent colitis. BFT activates β-catenin, NF-κB and MAPK pathways, leading to enhanced cellular proliferation and secretion of IL-8 in HT29/C1 cells [10,11]. In animal models, BFT is sufficient and necessary to induce colitis in both mice and gerbils [12][13][14].…”

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

“…Normally, adhesions between normal epithelial cells and the cellular matrix are strong; cell detachment may be achieved via downregulation of cell adhesion molecules (2). It has been reported that loss of E-cadherin results in the detachment of adjacent cells (3,4). Focal adhesion kinase (FAK) is a central regulator of focal adhesion, promoting cell adhesion and metastasis (5).…”