BACKGROUND AND AIM: Although the mechanisms underlying the formation of intestinal fibrostrictures in Crohn's disease (CD) are not fully understood, activation of fibroblasts and excessive collagen deposition are supposed to contribute to the development of such complications. Here, we investigated the role of cadherin-11 (CDH-11), a fibroblast-derived protein that induces collagen production in various organs, in intestinal fibrosis. METHODS: CDH-11 expression was evaluated in inflammatory (I) and fibrostricturing (FS) CD mucosal samples, ulcerative colitis (UC) mucosal samples and ileal and colonic control samples by real-time PCR, Western blotting and immunohistochemistry. CDH-11 expression was evaluated in normal and CD intestinal fibroblasts stimulated with inflammatory/fibrogenic cytokines. FS CD fibroblasts were cultured either with a specific CDH-11 antisense oligonucleotide (AS) or activating CDH-11 fusion protein and activation of RhoA/ROCK and TGF-β pathways and collagen production were evaluated by Western blotting. Finally, we assessed the susceptibility of CDH-11-knockout (KO) mice to colitis-induced intestinal fibrosis. RESULTS: CDH-11 RNA and protein expression was increased in both CD and UC as compared to controls. In CD, the greater expression of CDH-11 was seen in FS samples. Stimulation of fibroblasts with TNF-α, interleukin (IL)-6, IFN-γ, IL-13 and IL-1β enhanced CDH-11 expression. Knockdown of CDH-11 in FS CD fibroblasts impaired RhoA/ROCK/TGF-β signalling and reduced collagen synthesis, while activation of CDH-11 increased collagen secretion. CDH-11 KO mice were largely protected from intestinal fibrosis. CONCLUSIONS: Data show that CDH-11 expression is up-regulated in IBD and suggest a role for this protein in the control of intestinal fibrosis.

Franzè, E., Monteleone, I., Laudisi, F., Rizzo, A., Dinallo, V., Di Fusco, D., et al. (2019). Cadherin-11 is a Regulator of Intestinal Fibrosis. JOURNAL OF CROHN'S AND COLITIS [10.1093/ecco-jcc/jjz147].

Cadherin-11 is a Regulator of Intestinal Fibrosis

Monteleone, Ivan
Membro del Collaboration Group
;
Rizzo, Angelamaria
Membro del Collaboration Group
;
Dinallo, Vincenzo
Membro del Collaboration Group
;
Colantoni, Alfredo
Membro del Collaboration Group
;
Ortenzi, Angela
Membro del Collaboration Group
;
Di Carlo, Sara
Membro del Collaboration Group
;
Sica, Giuseppe S
Membro del Collaboration Group
;
Monteleone, Giovanni
2019-01-01

Abstract

BACKGROUND AND AIM: Although the mechanisms underlying the formation of intestinal fibrostrictures in Crohn's disease (CD) are not fully understood, activation of fibroblasts and excessive collagen deposition are supposed to contribute to the development of such complications. Here, we investigated the role of cadherin-11 (CDH-11), a fibroblast-derived protein that induces collagen production in various organs, in intestinal fibrosis. METHODS: CDH-11 expression was evaluated in inflammatory (I) and fibrostricturing (FS) CD mucosal samples, ulcerative colitis (UC) mucosal samples and ileal and colonic control samples by real-time PCR, Western blotting and immunohistochemistry. CDH-11 expression was evaluated in normal and CD intestinal fibroblasts stimulated with inflammatory/fibrogenic cytokines. FS CD fibroblasts were cultured either with a specific CDH-11 antisense oligonucleotide (AS) or activating CDH-11 fusion protein and activation of RhoA/ROCK and TGF-β pathways and collagen production were evaluated by Western blotting. Finally, we assessed the susceptibility of CDH-11-knockout (KO) mice to colitis-induced intestinal fibrosis. RESULTS: CDH-11 RNA and protein expression was increased in both CD and UC as compared to controls. In CD, the greater expression of CDH-11 was seen in FS samples. Stimulation of fibroblasts with TNF-α, interleukin (IL)-6, IFN-γ, IL-13 and IL-1β enhanced CDH-11 expression. Knockdown of CDH-11 in FS CD fibroblasts impaired RhoA/ROCK/TGF-β signalling and reduced collagen synthesis, while activation of CDH-11 increased collagen secretion. CDH-11 KO mice were largely protected from intestinal fibrosis. CONCLUSIONS: Data show that CDH-11 expression is up-regulated in IBD and suggest a role for this protein in the control of intestinal fibrosis.
2019
Online ahead of print
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/12 - GASTROENTEROLOGIA
English
Con Impact Factor ISI
CDH-11; IBD; RhoA/ROCK pathway; TGF-β pathway
Franzè, E., Monteleone, I., Laudisi, F., Rizzo, A., Dinallo, V., Di Fusco, D., et al. (2019). Cadherin-11 is a Regulator of Intestinal Fibrosis. JOURNAL OF CROHN'S AND COLITIS [10.1093/ecco-jcc/jjz147].
Franzè, E; Monteleone, I; Laudisi, F; Rizzo, A; Dinallo, V; Di Fusco, D; Colantoni, A; Ortenzi, A; Giuffrida, P; Di Carlo, S; Sica, Gs; Di Sabatino, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/224867
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