CCL20 Is Negatively Regulated by TGF-β1 in Intestinal Epithelial Cells and Reduced in Crohn's Disease Patients With a Successful Response to Mongersen, a Smad7 Antisense Oligonucleotide. (25th October 2016)

• Record Type: Journal Article
• Authors: Marafini, Irene; Monteleone, Ivan; Dinallo, Vincenzo; Di Fusco, Davide; De Simone, Veronica; Laudisi, Federica; Fantini, Massimo Claudio; Di Sabatino, Antonio; Pallone, Francesco; Monteleone, Giovanni
• Is Part Of: Journal of Crohn's and colitis. Volume 11:Number 5(2017:May)
• Page Start: 603
• Page End: 609
• Publication Date: 2016-10-25
• Subjects: IBD -- Mip-3α -- TGF-β; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjw191
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: The 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. Methods: CCL20 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. Results: CCL20 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. Conclusions: TGF-β1 reduces intestinal epithelial cell-derived CCL20 production, an effect abrogated by Smad7. CD patients responding to mongersen demonstrated a reduction in serum CCL20.