Attenuation of Clostridium difficile toxin‐induced damage to epithelial barrier by ecto‐5′‐nucleotidase (CD73) and adenosine receptor signaling

Background Clostridium difficile (Cdf) releases toxins (TcdA and TcdB) that damage the intestinal epithelial barrier. Ecto‐5′‐nucleotidase (CD73) is expressed on intestinal epithelial cells, and it is hypothesized to protect against toxin‐induced epithelial damage through the cleavage of 5′‐AMP to a...

Full description

Saved in:

Bibliographic Details
Published in:	Neurogastroenterology and motility Vol. 25; no. 6; pp. e441 - e453
Main Authors:	Patrick Schenck, L., Hirota, S. A., Hirota, C. L., Boasquevisque, P., Tulk, S. E., Li, Y., Wadhwani, A., Doktorchik, C. T. A., MacNaughton, W. K., Beck, P. L., MacDonald, J. A.
Format:	Journal Article
Language:	English
Published:	England Wiley Subscription Services, Inc 01-06-2013
Subjects:	5'-Nucleotidase - metabolism AdoRA Bacterial Proteins - pharmacology Bacterial Toxins - pharmacology Cdf infection–associated disease Cell Line, Tumor Cells Clostridium difficile Enterotoxins - pharmacology Epithelial Cells - drug effects Epithelial Cells - metabolism epithelial permeability Humans hypoxia‐inducible factor‐1 infectious colitis Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Permeability Proteins Receptors, Purinergic P1 - metabolism Signal Transduction Tight Junctions - drug effects Tight Junctions - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Background Clostridium difficile (Cdf) releases toxins (TcdA and TcdB) that damage the intestinal epithelial barrier. Ecto‐5′‐nucleotidase (CD73) is expressed on intestinal epithelial cells, and it is hypothesized to protect against toxin‐induced epithelial damage through the cleavage of 5′‐AMP to adenosine (Ado) and subsequent activation of adenosine receptors (AdoRs). Herein, we sought to assess the potential protective effects of CD73 and AdoR signaling on the injurious effects of Cdf toxins. Methods Barrier function was assessed with T84 colonocytes. Transepithelial electrical resistance (TEER), paracellular fluorescein isothiocyanate (FITC)‐dextran flux, and tight junction protein (ZO‐1) integrity were monitored. Intrarectal installation of Cdf toxin was used to assess epithelial damage in vivo. Key Results TcdA/B caused reduced TEER and increased paracellular flux in vitro. Concurrent treatment with 5′‐AMP attenuated these responses to Cdf toxin; an effect that was blocked with ZM241385 (AdoRA2 antagonist). APCP, a CD73 inhibitor, also suppressed the protective effects of 5′‐AMP on paracellular flux. 5′‐AMP reduced toxin‐induced disruption of ZO‐1, an effect that was abolished by APCP and ZM241385. Inhibition of CD73 with APCP during Cdf toxin exposure led to increased intestinal barrier permeability and epithelial damage in vivo. Intrarectal instillation of 5′‐AMP had no effect on toxin‐induced intestinal injury. Conclusions & Inferences Our data suggest that CD73 has a protective role against TcdA/B‐induced damage. 5′‐AMP treatment attenuated the damaging effects of Cdf toxin in vitro, and inhibitors of CD73 (APCP) and AdoRs (ZM241385) revealed that the cleavage of 5′‐AMP to Ado was necessary for the protective effects. Inhibition of CD73 in vivo increases colonic tissue damage and epithelial permeability during Cdf toxin exposure.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1350-1925 1365-2982
DOI:	10.1111/nmo.12139