Document Detail


PepT1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-{gamma}-D-Glu-meso-DAP in intestinal epithelial cells.
MedLine Citation:
PMID:  20558765     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PepT1 is a di/tripeptide transporter highly expressed in the small intestine, but poorly or not expressed in the colon. However, during chronic inflammation, such as inflammatory bowel disease, PepT1 expression is induced in the colon. Commensal bacteria that colonize the human colon produce a large amount of di/tripeptides. To date, two bacterial peptides (N-formylmethionyl-leucyl-phenylalanine and muramyl dipeptide) have been identified as substrates of PepT1. We hypothesized that the proinflammatory tripeptide l-Ala-gamma-d-Glu-meso-DAP (Tri-DAP), a breakdown product of bacterial peptidoglycan, is transported into intestinal epithelial cells via PepT1. We found that uptake of glycine-sarcosine, a specific substrate of PepT1, in intestinal epithelial Caco2-BBE cells was inhibited by Tri-DAP in a dose-dependent manner. Tri-DAP induced activation of NF-kappaB and MAP kinases, consequently leading to production of the proinflammatory cytokine interleukin-8. Tri-DAP-induced inflammatory response in Caco2-BBE cells was significantly suppressed by silencing of PepT1 expression by using PepT1-shRNAs in a tetracycline-regulated expression (Tet-off) system. Colonic epithelial HT29-Cl.19A cells, which do not express PepT1 under basal condition, were mostly insensitive to Tri-DAP-induced inflammation. However, HT29-Cl.19A cells exhibited proinflammatory response to Tri-DAP upon stable transfection with a plasmid encoding PepT1. Accordingly, Tri-DAP significantly increased keratinocyte-derived chemokine production in colonic tissues from transgenic mice expressing PepT1 in intestinal epithelial cells. Finally, Tri-DAP induced a significant drop in intracellular pH in intestinal epithelial cells expressing PepT1, but not in cells that did not express PepT1. Our data collectively support the classification of Tri-DAP as a novel substrate of PepT1. Given that PepT1 is highly expressed in the colon during inflammation, PepT1-mediated Tri-DAP transport may occur more effectively during such conditions, further contributing to intestinal inflammation.
Authors:
Guillaume Dalmasso; Hang Thi Thu Nguyen; Laetitia Charrier-Hisamuddin; Yutao Yan; Hamed Laroui; Benjamin Demoulin; Shanthi V Sitaraman; Didier Merlin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-06-17
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  299     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-30     Completed Date:  2010-09-24     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G687-96     Citation Subset:  IM    
Affiliation:
Department of Medicine, Emory University, Atlanta, GA 30322, USA. gdalmas@emory.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Bacterial Proteins / metabolism*
Biological Transport / physiology*
Caco-2 Cells
Epithelial Cells / physiology*
Gene Expression Regulation
HT29 Cells
Humans
Hydrogen-Ion Concentration
Inflammation / metabolism
Intestinal Mucosa / cytology
Keratinocytes / metabolism
Mice
Mice, Transgenic
Symporters / metabolism*
Grant Support
ID/Acronym/Agency:
R01-DK55850/DK/NIDDK NIH HHS; R24-DK-064399/DK/NIDDK NIH HHS; R56 DK061941/DK/NIDDK NIH HHS; R56-DK-061941/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bacterial Proteins; 0/PepT1 protein; 0/Symporters
Comments/Corrections

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