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TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation.

ABSTRACT: TL1A is a tumor necrosis factor-like molecule that mediates a strong costimulation of T-helper (T(H)) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation.We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine profile in the gut-associated lymphoid tissue (GALT) was measured. Neutralizing anti-TL1A antibodies were injected intraperitoneally into DSS-induced chronic colitis and G protein alphai2(-/-) T-cell transfer colitis models. Severity of colitis was evaluated by body weight, colon length, histology, and cytokine production.DSS-induced chronic colitis was characterized by the infiltration of CD4(+) T cells. TL1A, death receptor 3, interferon (IFN)-gamma, and interleukin (IL)-17 were increased significantly in GALT of DSS-treated mice. TL1A up-regulated both IFN-gamma production from T(H)1 cells and IL-17 production from T(H)17 cells in GALT CD4(+) T cells. Furthermore, IFN-gamma and IL-17 production from CD4(+) T cells, induced by IL-12 and IL-23 respectively, was enhanced synergistically by combination with TL1A. Anti-TL1A antibody prevented chronic colitis and attenuated established colitis by down-regulation of both T(H)1 and T(H)17 activation.Our results reveal that TL1A is an important modulator in the development of chronic mucosal inflammation by enhancing T(H)1 and T(H)17 effector functions. The central role of TL1A represents an attractive, novel therapeutic target for the treatment of Crohn's disease patients.

SUBMITTER: Takedatsu H

PROVIDER: S-EPMC2605110 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation.

Takedatsu Hidetoshi H Michelsen Kathrin S KS Wei Bo B Landers Carol J CJ Thomas Lisa S LS Dhall Deepti D Braun Jonathan J Targan Stephan R SR

Gastroenterology 20080507 2

<h4>Background & aims</h4>TL1A is a tumor necrosis factor-like molecule that mediates a strong costimulation of T-helper (T(H)) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation.<h4>Methods</h4>We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine pro ...[more]

PMID: 18598698

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Project description:Background and aimsRecent 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.MethodsColonic 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.ResultsHigh 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.ConclusionsTL1A 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.

Project description:Abstract Background and Aim TL1A (TNFSF15) is a major Crohn's disease (CD) susceptibility gene, especially in the East Asian population, and is also known to be associated with some clinical phenotypes, such as stricturing and penetrating behavior. This study aims to investigate the association between TL1A genotype and the long?term therapeutic outcomes of infliximab and adalimumab in Japanese CD patients. Methods We investigated 119 biologic?naïve CD patients treated with infliximab or adalimumab. TL1A ?358C/T (rs6478109) was genotyped as a tag single nucleotide polymorphism (SNP) for CD risk or nonrisk haplotype of TL1A (the ?358C allele is a risk allele for CD development). We compared the long?term therapeutic outcomes of anti?tumor necrosis factor (TNF) antibodies between the TL1A ?358C/C group and the C/T+T/T group. Results Sixty?nine cases (58.0%) were homozygous for the risk allele (TL1A ?358C/C group), and 50 cases (42.0%) were heterozygous for the risk allele or homozygous for the protective allele (TL1A ?358C/T+T/T group). No significant differences were found in the cumulative retention rates and the relapse?free survival between the TL1A genotypes. However, the surgery?free survival was significantly lower in the TL1A ?358C/C group than in the C/T+T/T group (log?rank test, P?<?0.05). Multivariate analysis showed that TL1A ?358C/C was identified as an independent risk factor for surgery (hazard ratio, 4.67; 95% confidence interval, 1.39–22.1; P = 0.025). Conclusion An association was found between the TL1A genotype and the therapeutic outcomes of anti?TNF therapy. Our data indicate that the design of customized therapy with anti?TNF antibodies using TL1A genomic information could be effective in the future. In this study, we investigated the association between TL1A genotype and the long?term therapeutic outcomes of infliximab and adalimumab in Crohn's disease (CD) patients. We investigated 119 biologic?naïve CD patients treated with infliximab or adalimumab and found an association between the TL1A genotype and surgery?free survival during anti?tumor necrosis factor (TNF) therapy. The patients whose genotypes are homozygous for the TL1A ?358C (risk allele of CD development) show lower surgery?free survival with anti?TNF treatment.

Project description:TL1A and its functional receptor DR3 are members of the TNF/TNFR superfamilies of proteins. Binding of APC-derived TL1A to lymphocytic DR3 provides co-stimulatory signals for activated lymphocytes. DR3 signaling affects the proliferative activity of and cytokine production by effector lymphocytes, but also critically influences the development and suppressive function of regulatory T-cells. DR3 was also found to be highly expressed by innate lymphoid cells (ILCS), which respond to stimulation by TL1A. Several recent studies with transgenic and knockout mice as well as neutralizing or agonistic antibodies for these two proteins, have clearly shown that TL1A/DR3 are important mediators of several chronic immunological disorders, including Inflammatory Bowel Disease (IBD). TL1A and DR3 are abundantly localized at inflamed intestinal areas of patients with IBD and mice with experimental ileitis or colitis and actively participate in the immunological pathways that underlie mucosal homeostasis and intestinal inflammation. DR3 signaling has demonstrated a dichotomous role in mucosal immunity. On the one hand, during acute mucosal injury it exerts protective functions by ameliorating the severity of acute inflammatory responses and facilitating tissue repair. On the other hand, it critically participates in the pro-inflammatory pathways that underlie chronic inflammatory responses, such as those that take place in IBD. These effects are mediated through modulation of the relative mucosal abundance and function of Th1, Th2, Th17, Th9, and Treg lymphocytes, but also of all types of ILCs. Recently, an important role was demonstrated for TL1A/DR3 as potential mediators of intestinal fibrosis that is associated with the presence of gut inflammation. These accumulating data have raised the possibility that TL1A/DR3 pathways may represent a valid therapeutic target for chronic immunological diseases. Nevertheless, applicability of such a therapeutic approach will greatly rely on the net result of TL1A/DR3 manipulation on the various cell populations that will be affected by this approach.

Dataset Information

TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation.

Publications

TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation.

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