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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/G669    most recent 00382.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Lewis, K. Articles by McKay, D. M. Search for Related Content PubMed PubMed Citation Articles by Lewis, K. Articles by McKay, D. M.

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Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-

¹Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; ²Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada; ³Department of Surgery, University Hospital Linköping, Sweden; ⁴Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Submitted 16 August 2007 ; accepted in final form 4 January 2008

A defect in mitochondrial activity contributes to many diseases. We have shown that monolayers of the human colonic T84 epithelial cell line exposed to dinitrophenol (DNP, uncouples oxidative phosphorylation) and nonpathogenic Escherichia coli (E. coli) (strain HB101) display decreased barrier function. Here the impact of DNP on macrophage activity and the effect of TNF-, DNP, and E. coli on epithelial permeability were assessed. DNP treatment of the human THP-1 macrophage cell line resulted in reduced ATP synthesis, and, although hyporesponsive to LPS, the metabolically stressed macrophages produced IL-1β, IL-6, and TNF-. Given the role of TNF- in inflammatory bowel disease (IBD) and the association between increased permeability and IBD, recombinant TNF- (10 ng/ml) was added to the DNP (0.1 mM) + E. coli (10⁶ colony-forming units), and this resulted in a significantly greater loss of T84 epithelial barrier function than that elicited by DNP + E. coli. This increased epithelial permeability was not due to epithelial death, and the enhanced E. coli translocation was reduced by pharmacological inhibitors of NF-β signaling (pyrrolidine dithiocarbamate, NF-β essential modifier-binding peptide, BAY 11–7082, and the proteosome inhibitor, MG132). In contrast, the drop in transepithelial electrical resistance was unaffected by the inhibitors of NF-β. Thus, as an integrative model system, our findings support the induction of a positive feedback loop that can severely impair epithelial barrier function and, as such, could contribute to existing inflammation or trigger relapses in IBD. Thus metabolically stressed epithelia display increased permeability in the presence of viable nonpathogenic E. coli that is exaggerated by TNF- released by activated immune cells, such as macrophages, that retain this ability even if they themselves are experiencing a degree of metabolic stress.

permeability; bacterial translocation; NFB; T84 cells; macrophages

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				M. Chichlowski and L. P. Hale Bacterial-mucosal interactions in inflammatory bowel disease--an alliance gone bad Am J Physiol Gastrointest Liver Physiol, December 1, 2008; 295(6): G1139 - G1149. [Abstract] [Full Text] [PDF]