| Title: | Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3 |
| Author(s): | Beck PL; Ihara E; Hirota SA; MacDonald JA; Meng D; Nanthakumar NN; Podolsky DK; Xavier RJ; |
| Address: | "Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1. plbeck@ucalgary.ca" |
| Journal Title: | Am J Physiol Gastrointest Liver Physiol |
| ISSN/ISBN: | 1522-1547 (Electronic) 0193-1857 (Print) 0193-1857 (Linking) |
| Abstract: | "Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3(-/-) mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII(-/-) mice) were generated by mating TFF3(-/-) and Fuc-TVII(-/-) mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII(-/-), TFF3(-/-), Fuc-TVII(-/-), or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3(-/-) mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3(-/-) mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/beta-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response" |
| Keywords: | "Animals *Chemotaxis, Leukocyte Colitis/chemically induced/*enzymology/genetics/immunology/pathology/prevention & control Dextran Sulfate Diarrhea/enzymology/genetics/immunology Disease Models, Animal Fucosyltransferases/deficiency/genetics/*metabolism *Im;" |
| Notes: | "MedlineBeck, P L Ihara, E Hirota, S A MacDonald, J A Meng, D Nanthakumar, N N Podolsky, D K Xavier, R J eng DK043351/DK/NIDDK NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 DK060049/DK/NIDDK NIH HHS/ CAPMC/CIHR/Canada HD059126/HD/NICHD NIH HHS/ R01 HD059126/HD/NICHD NIH HHS/ HD12437/HD/NICHD NIH HHS/ P30 DK040561-15/DK/NIDDK NIH HHS/ DK83756/DK/NIDDK NIH HHS/ DK70260/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010/03/20 Am J Physiol Gastrointest Liver Physiol. 2010 Jul; 299(1):G43-53. doi: 10.1152/ajpgi.00228.2009. Epub 2010 Mar 18" |
