Effect and Mechanism of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related Intestinal Fibrosis

Abstract

Background and Aims. Recent evidences reveal that epithelial to mesenchymal transition (EMT) exacerbates the process of intestinal fibrosis. Tumor necrosis factor-like ligand 1A (TL1A) is a member of the tumor necrosis family (TNF), which can take part in the development of colonic inflammation and fibrosis by regulating immune response or inflammatory factors. The purpose of this study was to elucidate the possible contribution of TL1A in onset and progression of intestinal inflammation and fibrosis through EMT. Methods. Colonic specimens were obtained from patients with inflammatory bowel disease (IBD) and control individuals. The expression levels of TL1A and EMT-related markers in intestinal tissues were evaluated. Furthermore, the human colorectal adenocarcinoma cell line, HT-29, was stimulated with TL1A, anti-TL1A antibody, or BMP-7 to assess EMT process. In addition, transgenic mice expressing high levels of TL1A in lymphoid cells were used to further investigate the mechanism of TL1A in intestinal fibrosis. Results. High levels of TL1A expression were detected in the intestinal specimens of patients with ulcerative colitis and Crohn’s disease and were negatively associated with the expression of an epithelial marker (E-cadherin), while it was positively associated with the expression of interstitial markers (FSP1 and α-SMA). Transgenic mice with high expression of TL1A were more sensitive to dextran sodium sulfate and exhibited severe intestinal inflammation and fibrosis. Additionally, the TGF-β1/Smad3 pathway may be involved in TL1A-induced EMT, and the expression of IL-13 and EMT-related transcriptional molecules (e.g., ZEB1 and Snail1) was increased in the intestinal specimens of the transgenic mice. Furthermore, TL1A-induced EMT can be influenced by anti-TL1A antibody or BMP-7 in vitro. Conclusions. TL1A participates in the formation and process of EMT in intestinal fibrosis. This new knowledge enables us to better understand the pathogenesis of intestinal fibrosis and identify new therapeutic targets for its treatment.

Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review

“…Rs10114470 polymorphism is considered to be a loci for IBD susceptibility in Chinese Han population ( Table 2 ) ( 80 ). Furthermore, TL1A gene rs6478109 polymorphism is an independent factor of surgery, which affects the long-term efficacy of anti-TNF antibody therapy ( 72 ). Interestingly, anti-TL1A drug (PF-06480605) improved tissue inflammation and inhibited expression of fibrotic pathways, and reduced intestinal pathogens in UC patients ( 82 ).…”

Intestinal strictures in Crohn’s disease: a 2021 update

“… 23 A study in 2021 found that the expression of TL1A in intestines of CD patients was almost twice as high as that in healthy individuals. 31 The expression of TL1A was negatively associated with E-cadherin expression, whereas positively associated with β-catenin and α-SMA expression, implying that TL1A might be involved in the process of epithelial-to-mesenchymal transition (EMT). 31 Indeed, evidence from both CD patients and a DSS-induced murine model indicated that TL1A could induce EMT through interleukin (IL)-13 and TGF-β1/Smad3 pathway [ Figure 2(c) ].…”

“… 31 The expression of TL1A was negatively associated with E-cadherin expression, whereas positively associated with β-catenin and α-SMA expression, implying that TL1A might be involved in the process of epithelial-to-mesenchymal transition (EMT). 31 Indeed, evidence from both CD patients and a DSS-induced murine model indicated that TL1A could induce EMT through interleukin (IL)-13 and TGF-β1/Smad3 pathway [ Figure 2(c) ]. 31 Another interesting molecule AGR2 was identified via secretome profile of epithelium in ileal CD strictures.…”

“… 31 Indeed, evidence from both CD patients and a DSS-induced murine model indicated that TL1A could induce EMT through interleukin (IL)-13 and TGF-β1/Smad3 pathway [ Figure 2(c) ]. 31 Another interesting molecule AGR2 was identified via secretome profile of epithelium in ileal CD strictures. 24 AGR2 and binding immunoglobulin protein were found to be increasingly expressed in the epithelium, especially under endoplasmic reticulum stress.…”

Dynamic alterations in metabolomics and transcriptomics associated with intestinal fibrosis in a 2,4,6-trinitrobenzene sulfonic acid-induced murine model

“…Some studies have suggested that the abnormal expression of certain genes, such as nucleotide-binding oligomerization domain 2 (NOD2), toll-like receptors-4 (TLR4), and tumor necrosis factor-like ligand 1A (TL1A), might be related to the development of intestinal brosis 5, 7 . These genes play a role in intestinal brogenesis via regulating certain important processes, including epithelial-mesenchymal transition (EMT) initiation and progression, brogenic signal transduction, and macrophage-broblast program [7][8][9] . However, current studies have failed to identify the relationship between the dynamic uctuation of gene expression and colitis-related intestinal brosis.…”