• Irene Marafini, Ivan Monteleone, Vincenzo Dinallo, Davide Di Fusco, Veronica De Simone, Federica Laudisi, Massimo Claudio Fantini, Antonio Di Sabatino, Francesco Pallone, and Giovanni Monteleone.
• Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
• J Crohns Colitis. 2017 May 1; 11 (5): 603-609.

Background And AimsThe chemokine CCL20 is over-produced in epithelium of Crohn's disease [CD] patients and contributes to recruiting immune cells to inflamed gut. Tumour necrosis factor-α [TNF-α] is a powerful inducer of CCL20 in intestinal epithelial cells. In CD, high levels of Smad7 block the activity of transforming growth factor-β1 [TGF-β1], a negative regulator of TNF signalling. We investigated whether intestinal epithelial cell-derived CCL20 is negatively regulated by TGF-β1 and whether Smad7 knock-down reduces CCL20 in CD.MethodsCCL20 was evaluated in NCM460, a normal colonic epithelial cell line, stimulated with TGF-β1 and TNF-α, and in Smad7 over-expressing NCM460 cells. CCL20 and Smad7 expression were assessed in sections of CD intestinal specimens by immunochemistry, and in CD colonic explants treated with mongersen, a Smad7 antisense oligonucleotide. CCL20 was examined in serum samples taken from 95 of 166 active CD patients receiving mongersen or placebo for 2 weeks and participating in a phase II, multicentre, double-blind, placebo-controlled study.ResultsCCL20 expression was increased by TNF-α, and this effect was inhibited by TGF-β1 in NCM460 cells, but not in Smad7 over-expressing NCM460 cells. In CD, epithelium CCL20 and Smad7 co-localised, and treatment of CD explants with mongersen reduced CCL20 production. During follow-up, in responders to mongersen, serum CCL20 levels significantly decreased, whereas patients without response/remission to mongersen and placebo patients did not have change in CCL20.ConclusionsTGF-β1 reduces intestinal epithelial cell-derived CCL20 production, an effect abrogated by Smad7. CD patients responding to mongersen demonstrated a reduction in serum CCL20.Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

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