Bacterial lipopolysaccharide promotes profibrotic activation of intestinal fibroblasts.
Affiliation
Department of Surgery, St Vincent's University Hospital, Dublin, Ireland.Issue Date
2012-02-01T10:28:56ZMeSH
AgedAged, 80 and over
Cells, Cultured
Colonic Neoplasms/metabolism
Connective Tissue Growth Factor/biosynthesis
Fibroblasts/*drug effects/metabolism
Humans
I-kappa B Kinase/metabolism
Lipopolysaccharides/*pharmacology
Middle Aged
NF-kappa B/metabolism
Smad7 Protein/metabolism
Toll-Like Receptor 4/*metabolism
Transforming Growth Factor beta1/*pharmacology
Wound Healing/*physiology
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Br J Surg. 2010 Jul;97(7):1126-34.Journal
The British journal of surgeryDOI
10.1002/bjs.7045PubMed ID
20632282Abstract
BACKGROUND: Fibroblasts play a critical role in intestinal wound healing. Lipopolysaccharide (LPS) is a cell wall component of commensal gut bacteria. The effects of LPS on intestinal fibroblast activation were characterized. METHODS: Expression of the LPS receptor, toll-like receptor (TLR) 4, was assessed in cultured primary human intestinal fibroblasts using flow cytometry and confocal microscopy. Fibroblasts were treated with LPS and/or transforming growth factor (TGF) beta1. Nuclear factor kappaB (NFkappaB) pathway activation was assessed by inhibitory kappaBalpha (IkappaBalpha) degradation and NFkappaB promoter activity. Fibroblast contractility was measured using a fibroblast-populated collagen lattice. Smad-7, a negative regulator of TGF-beta1 signalling, and connective tissue growth factor (CTGF) expression were assessed using reverse transcriptase-polymerase chain reaction and western blot. The NFkappaB pathway was inhibited by IkappaBalpha transfection. RESULTS: TLR-4 was present on the surface of intestinal fibroblasts. LPS treatment of fibroblasts induced IkappaBalpha degradation, enhanced NFkappaB promoter activity and increased collagen contraction. Pretreatment with LPS (before TGF-beta1) significantly increased CTGF production relative to treatment with TGF-beta1 alone. LPS reduced whereas TGF-beta1 increased smad-7 expression. Transfection with an IkappaBalpha plasmid enhanced basal smad-7 expression. CONCLUSION: Intestinal fibroblasts express TLR-4 and respond to LPS by activating NFkappaB and inducing collagen contraction. LPS acts in concert with TGF-beta1 to induce CTGF. LPS reduces the expression of the TGF-beta1 inhibitor, smad-7.Language
engISSN
1365-2168 (Electronic)0007-1323 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1002/bjs.7045
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