Transforming Growth Factor-β Regulation of Epithelial Tight Junction Proteins Enhances Barrier Function and Blocks Enterohemorrhagic Escherichia coli O157:H7-Induced Increased Permeability

Abstract

Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is an enteric pathogen that causes potentially fatal symptoms after intimate adhesion, modulation of intestinal epithelial signal transduction, and alteration of epithelial function (eg, barrier disruption). Although the epithelial barrier is critical to gut homeostasis, only a few agents, such as transforming growth factor (TGF)-beta, can enhance or protect epithelial barrier function. Our aims were to delineate the mechanism(s) behind TGF-beta-induced barrier enhancement and to determine whether TGF-beta could prevent EHEC-induced barrier disruption. Using monolayers of the human T84 colonic epithelial cell line, we found that TGF-beta induced a significant increase in transepithelial electrical resistance (a measure of paracellular permeability) through activation of ERK MAPK and SMAD signaling pathways and up-regulation of the tight junction protein claudin-1. Additionally, TGF-beta pretreatment of epithelia blocked the decrease in transepithelial electrical resistance and the increase in transepithelial passage of [(3)H]-mannitol caused by EHEC infection. EHEC infection was associated with reduced expression of zonula occludens-1, occludin, and claudin-2 (but not claudin-1 or claudin-4); TGF-beta pretreatment prevented these changes. These studies provide insight into EHEC pathogenesis by illustrating the mechanisms underlying TGF-beta-induced epithelial barrier enhancement and identifying TGF-beta as an agent capable of blocking EHEC-induced increases in epithelial permeability via maintenance of claudin-2, occludin, and zonula occludens-1 levels.

Campylobacter jejuni Mediated Disruption of Polarized Epithelial Monolayers is Cell-Type Specific, Time Dependent, and Correlates With Bacterial Invasion

“…The findings in the present study show that, similar to other intestinal pathogens (18,21), C. jejuni infection inflicts changes in epithelial barrier function, thereby leading to potential exposure of the subepithelial immune components to chronic antigenic stimulation. Such changes in epithelial permeability are well documented in humans with IBD (13), to which C. jejuni infection has been linked (2,5,6).…”

Colonization of germ-free mice with a mixture of three lactobacillus strains enhances the integrity of gut mucosa and ameliorates allergic sensitization

“…52 In vitro studies have indicated that the proallergic cytokine IL-4 contributes to barrier impairment in contrast with TGF-b, which enhances the barrier function and activates the expression of proteins comprising intercellular junctions. 53 In our study, the improvement of the gut barrier in the Lmix-colonized mice was accompanied by the reduced secretion of pro-allergic cytokines and the significant enhancement of TGF-b.…”

Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

“…Exposure of MDCK cells to TGF-␤1 significantly increased claudin-1 and ZO-2 expression, correlating with the effect of CsA on these tight junction components, which further strengthens our hypothesis that CsA regulates tight junction function, at least partially, via this cytokine. Another study (37) demonstrated that TGF-␤ upregulated claudin-1 expression two-to three-fold in T84 monolayers, but expression of claudin-2 and claudin-4 was unaltered. In addition, we found that treatment of MDCK cells with the MEK 1 inhibitor U0126 decreased claudin-1 expression compared with control level (data not shown).…”