Transforming growth factor-β regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157: H7-induced increased permeability

Kathryn L. Howe, Colin Reardon, Arthur Wang, Aisha Nazli, Derek M. McKay

Research output: Contribution to journalArticle

132 Scopus citations

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)-β, can enhance or protect epithelial barrier function. Our aims were to delineate the mechanism(s) behind TGF-β-induced barrier enhancement and to determine whether TGF-β could prevent EHEC-induced barrier disruption. Using monolayers of the human T84 colonic epithelial cell line, we found that TGF-β induced a significant increase in transepithelial electrical resistance (a measure of paracellular permeability) through activation of ERK MAPK and SMAD signaling pathways and upregulation of the tight junction protein claudin-1. Additionally, TGF-β pretreatment of epithelia blocked the decrease in transepithelial electrical resistance and the increase in transepithelial passage of [3H]-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-β pretreatment prevented these changes. These studies provide insight into EHEC pathogenesis by illustrating the mechanisms underlying TGF-β-induced epithelial barrier enhancement and identifying TGF-β as an agent capable of blocking EHEC-induced increases in epithelial permeability via maintenance of claudin-2, occludin, and zonula occludens-1 levels.

Original languageEnglish (US)
Pages (from-to)1587-1597
Number of pages11
JournalAmerican Journal of Pathology
Volume167
Issue number6
StatePublished - Dec 2005
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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