| Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-alpha. | |
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MedLine Citation:
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PMID: 18187519 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-alpha, 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-1beta, IL-6, and TNF-alpha. Given the role of TNF-alpha in inflammatory bowel disease (IBD) and the association between increased permeability and IBD, recombinant TNF-alpha (10 ng/ml) was added to the DNP (0.1 mM) + E. coli (10(6) 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-kappabeta signaling (pyrrolidine dithiocarbamate, NF-kappabeta 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-kappabeta. 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-alpha released by activated immune cells, such as macrophages, that retain this ability even if they themselves are experiencing a degree of metabolic stress. |
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Authors:
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Kimberley Lewis; Jackie Caldwell; Van Phan; David Prescott; Aisha Nazli; Arthur Wang; Johan D Soderhölm; Mary H Perdue; Philip M Sherman; Derek M McKay |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-01-10 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 294 ISSN: 0193-1857 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-03-06 Completed Date: 2008-05-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
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Languages: eng Pagination: G669-78 Citation Subset: IM |
Affiliation:
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Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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biosynthesis Blotting, Western Caspases / metabolism Cell Death / drug effects Cell Line Cells, Cultured Dinitrophenols / toxicity* Electric Impedance Epithelium / drug effects, physiology* Escherichia coli Infections / metabolism, physiopathology* Feedback, Physiological / physiology Humans Interleukin-1beta / biosynthesis Interleukin-6 / biosynthesis Leupeptins / pharmacology Lipopolysaccharides / pharmacology Macrophages / drug effects, metabolism NF-kappa B / physiology Nitriles / pharmacology Permeability / drug effects Stress, Physiological / chemically induced, metabolism Sulfones / pharmacology Tetrazolium Salts Thiazoles Tumor Necrosis Factor-alpha / pharmacology* Uncoupling Agents / toxicity* |
| Chemical | |
Reg. No./Substance:
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0/3-(4-methylphenylsulfonyl)-2-propenenitrile; 0/Dinitrophenols; 0/Interleukin-1beta; 0/Interleukin-6; 0/Leupeptins; 0/Lipopolysaccharides; 0/NF-kappa B; 0/Nitriles; 0/Sulfones; 0/Tetrazolium Salts; 0/Thiazoles; 0/Tumor Necrosis Factor-alpha; 0/Uncoupling Agents; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 298-93-1/thiazolyl blue; 56-65-5/Adenosine Triphosphate; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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