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Bacterial lipopolysaccharide promotes profibrotic activation of intestinal fibroblasts. BJS 2010; 97: 1126-1134.

Published: 28th April 2010

Authors: J. P. Burke, M. F. Cunningham, R. W. G. Watson, N. G. Docherty, J. C. Coffey, P. R. O'Connell et al.

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.

Method

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) β1. Nuclear factor κB (NFκB) pathway activation was assessed by inhibitory κBα (IκBα) degradation and NFκB promoter activity. Fibroblast contractility was measured using a fibroblast‐populated collagen lattice. Smad‐7, a negative regulator of TGF‐β1 signalling, and connective tissue growth factor (CTGF) expression were assessed using reverse transcriptase–polymerase chain reaction and western blot. The NFκB pathway was inhibited by IκBα transfection.

Results

TLR‐4 was present on the surface of intestinal fibroblasts. LPS treatment of fibroblasts induced IκBα degradation, enhanced NFκB promoter activity and increased collagen contraction. Pretreatment with LPS (before TGF‐β1) significantly increased CTGF production relative to treatment with TGF‐β1 alone. LPS reduced whereas TGF‐β1 increased smad‐7 expression. Transfection with an IκBα plasmid enhanced basal smad‐7 expression.

Conclusion

Intestinal fibroblasts express TLR‐4 and respond to LPS by activating NFκB and inducing collagen contraction. LPS acts in concert with TGF‐β1 to induce CTGF. LPS reduces the expression of the TGF‐β1 inhibitor, smad‐7. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

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