27
views
0
recommends
+1 Recommend
2 collections
    0
    shares

      The APC waiver has been extended to also apply to manuscripts submitted until March 31, 2024.

      To submit to the journal, please click here.

      • Record: found
      • Abstract: found
      • Article: found

      Sustained TL1A (TNFSF15) expression on both lymphoid and myeloid cells leads to mild spontaneous intestinal inflammation and fibrosis

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell-dependent ileitis and fibrosis.

          Related collections

          Most cited references38

          • Record: found
          • Abstract: found
          • Article: not found

          TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator.

          DR3 is a death domain-containing receptor that is upregulated during T cell activation and whose overexpression induces apoptosis and NF-kappaB activation in cell lines. Here we show that an endothelial cell-derived TNF-like factor, TL1A, is a ligand for DR3 and decoy receptor TR6/DcR3 and that its expression is inducible by TNF and IL-1alpha. TL1A induces NF-kappaB activation and apoptosis in DR3-expressing cell lines, while TR6-Fc protein antagonizes these signaling events. Interestingly, in T cells, TL1A acts as a costimulator that increases IL-2 responsiveness and secretion of proinflammatory cytokines both in vitro and in vivo. Our data suggest that interaction of TL1A with DR3 promotes T cell expansion during an immune response, whereas TR6 has an opposing effect.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cellular and molecular mechanisms of intestinal fibrosis.

            Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease.

              TL1A is a novel TNF-like factor that acts as a costimulator of IFN-gamma secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn's disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4(+) and CD8(+) lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-gamma production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.
                Bookmark

                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 March 2013
                : 3
                : 1
                : 11-20
                Affiliations
                [ 1 ] F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
                [ 2 ] Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China
                [ 3 ] Center for Inflammatory Bowel Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
                [ 4 ] F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, 8700 Beverly Blvd., Suite 4065, Los Angeles, CA, 90048, USA
                Author notes
                [* ] (310) 423-7724, targans@ 123456cshs.org
                [** ] (310) 423-7724, david.shih@ 123456csmc.edu
                Article
                2
                10.1556/EuJMI.3.2013.1.2
                3638202
                23638306
                8dafac58-250a-4f00-9557-32ef34b2dd03
                History
                : 4 January 2013
                : 13 January 2013

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                fibrosis,mucosal inflammation,transgenic,ileitis

                Comments

                Comment on this article