Abstract
Intestinal fibrotic stricture is a major complication of Crohn's disease (CD) and epithelial-to-mesenchymal transition (EMT) is considered as an important contributor to the formation of intestinal fibrosis by increasing extracellular matrix (ECM) proteins. Curcumin, a compound derived from rhizomes of Curcuma, has been demonstrated with a potent antifibrotic effect. However, its effect on intestinal fibrosis and the potential mechanism is not completely understood. Here we found that curcumin pretreatment significantly represses TGF-β1-induced Smad pathway and decreases its downstream α-smooth muscle actin (α-SMA) gene expression in intestinal epithelial cells (IEC-6); in contrast, curcumin increases expression of E-cadherin and peroxisome proliferator-activated receptor γ (PPARγ) in IEC-6. Moreover, curcumin promotes nuclear translocation of PPARγ and the inhibitory effect of curcumin on EMT could be reversed by PPARγ antagonist GW9662. Consistently, in the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of PPARγ and E-cadherin and decreasing the expression of α-SMA, FN, and CTGF in colon tissue. Collectively, these results indicated that curcumin is able to prevent EMT progress in intestinal fibrosis by PPARγ-mediated repression of TGF-β1/Smad pathway.
Highlights
Intestinal stricture is a common complication in Crohn’s disease (CD) [1]
In the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of peroxisome proliferator-activated receptor γ (PPARγ) and E-cadherin and decreasing the expression of α-smooth muscle actin (α-SMA), FN, and connective tissue growth factor (CTGF) in colon tissue
It has been proved that fibroblasts can transform from nonmesenchymal cells to mesenchymal cells [4], leading to occurrence of epithelial-to-mesenchymal transition (EMT) which is a key process in organ fibrosis
Summary
Intestinal stricture is a common complication in Crohn’s disease (CD) [1]. Over one-third of patients with CD require surgery to relieve obstruction due to fibrotic strictures [2]. As a consequence of chronic, transmural inflammation, intestinal fibrosis in CD is mainly characterized by overproduction and deposition of extracellular matrix (ECM) [3]. ECM-producing cells are mainly derived from mesenchymal cells such as fibroblasts, myofibroblasts, and smooth muscle cells. It has been proved that fibroblasts can transform from nonmesenchymal cells to mesenchymal cells [4], leading to occurrence of epithelial-to-mesenchymal transition (EMT) which is a key process in organ fibrosis. EMT, a phenotypic transition of epithelial cell, is a complex and dynamic phenomenon that is accompanied by a loss of the epithelial cell hallmarks such as E-cadherin and an acquisition of the mesenchymal characterized proteins including α-smooth muscle actin (α-SMA), fibronectin (FN), and connective tissue growth factor (CTGF) [5]. It is widely believed that EMT can induce the production of ECM and promote the formation of the intestinal fibrosis through direct and indirect mechanisms [6]
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