Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

Hdl Handle:
http://hdl.handle.net/10147/207703
Title:
Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.
Authors:
Burke, J P; Watson, R W G; Mulsow, J J; Docherty, N G; Coffey, J C; O'Connell, P R
Affiliation:
Department of Surgery, St Vincent's University Hospital, Dublin, Ireland.
Citation:
Br J Surg. 2010 Jun;97(6):892-901.
Journal:
The British journal of surgery
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207703
DOI:
10.1002/bjs.6996
PubMed ID:
20473999
Abstract:
BACKGROUND: Fibroblasts isolated from strictures in Crohn's disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn's stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.
Language:
eng
MeSH:
Adult; Aged; Aged, 80 and over; Antigens, CD/metabolism/*physiology; Blotting, Western; Cells, Cultured; Crohn Disease/metabolism; Fibroblasts/*metabolism; Humans; Microscopy, Confocal; Middle Aged; Receptors, Cell Surface/metabolism/*physiology; Transforming Growth Factor beta1/*metabolism
ISSN:
1365-2168 (Electronic); 0007-1323 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorBurke, J Pen_GB
dc.contributor.authorWatson, R W Gen_GB
dc.contributor.authorMulsow, J Jen_GB
dc.contributor.authorDocherty, N Gen_GB
dc.contributor.authorCoffey, J Cen_GB
dc.contributor.authorO'Connell, P Ren_GB
dc.date.accessioned2012-02-01T10:35:25Z-
dc.date.available2012-02-01T10:35:25Z-
dc.date.issued2012-02-01T10:35:25Z-
dc.identifier.citationBr J Surg. 2010 Jun;97(6):892-901.en_GB
dc.identifier.issn1365-2168 (Electronic)en_GB
dc.identifier.issn0007-1323 (Linking)en_GB
dc.identifier.pmid20473999en_GB
dc.identifier.doi10.1002/bjs.6996en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207703-
dc.description.abstractBACKGROUND: Fibroblasts isolated from strictures in Crohn's disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn's stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.en_GB
dc.language.isoengen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.meshAged, 80 and overen_GB
dc.subject.meshAntigens, CD/metabolism/*physiologyen_GB
dc.subject.meshBlotting, Westernen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshCrohn Disease/metabolismen_GB
dc.subject.meshFibroblasts/*metabolismen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMicroscopy, Confocalen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshReceptors, Cell Surface/metabolism/*physiologyen_GB
dc.subject.meshTransforming Growth Factor beta1/*metabolismen_GB
dc.titleEndoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.en_GB
dc.contributor.departmentDepartment of Surgery, St Vincent's University Hospital, Dublin, Ireland.en_GB
dc.identifier.journalThe British journal of surgeryen_GB
dc.description.provinceLeinster-

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