Article

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis.

Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2006; 103(22):8441-6. DOI: 10.1073/pnas.0510903103
Source: PubMed

ABSTRACT TL1A is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-gamma and may, therefore, participate in the development of T helper-1-type effector responses. In this study, we investigated whether interactions between TL1A and DR3 are involved in the pathogenesis of chronic murine ileitis. We demonstrate that alternative splicing of DR3 mRNA takes place during the activation of lymphocytes, which results in up-regulation of the complete/transmembrane (tm) form of DR3. Using two immunogenetically distinct animal models of Crohn's disease, we demonstrate that induction of intestinal inflammation is associated with significant up-regulation of TL1A and tm DR3 in the inflamed mucosa. In addition, within isolated lamina propria mononuclear cells from mice with inflammation, TL1A is primarily expressed on CD11c(high) dendritic cells. We also report that TL1A acts preferentially on memory CD4(+)/CD45RB(lo) murine lymphocytes by significantly inducing their proliferation, whereas it does not affect the proliferation of the naïve CD4(+)/CD45RB(hi) T helper cell subpopulation. Finally, we demonstrate that TL1A synergizes with both the cytokine-dependent IL-12/IL-18 pathway and with low-dose stimulation of the T cell receptor to significantly induce the secretion of IFN-gamma via an IL-18-independent pathway. Our results raise the possibility that interaction(s) between TL1A expressed on antigen-presenting cells and tm DR3 on lymphocytes may be of particular importance for the pathogenesis of chronic inflammatory conditions that depend on IFN-gamma secretion, including inflammatory bowel disease. Blockade of the TL1A/DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.

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    ABSTRACT: TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.
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    ABSTRACT: Elevated levels of the cytokine TL1A is associated with several autoimmune diseases e.g. rheumatoid arthritis and inflammatory bowel disease. However, the exact role of TL1A remains elusive. In this study, we investigated the function of TL1A in a pro-inflammatory setting. We show that TL1A together with IL-12, IL-15 and IL-18 increases expression of the co-stimulatory molecules CD154 (CD40 ligand) and CD134 (OX40) on previously activated CD4+ T cells. This indicates that TL1A functions as a co-stimulatory molecule, decreasing the activation threshold of T-cells. We have previously shown that TL1A co-stimulation strongly induces IL-6 in human healthy leukocytes. Interestingly, the cytokine-activated effector T-cells did not produce IL-6 in response to TL1A, indicating distinct effects of TL1A on different cell populations. We further show that this co-stimulation increases the expression of CD25 (IL-2Rα) and CD11a (α-chain of LFA-1) on CD4 T-cells, likely governing increased IL-2/IL-15 sensitivity and cell-cell contact. Along with this, TL1A co-stimulation caused a specific induction of IL-22 and GM-CSF from the activated T-cells. These results substantially contribute to the explanation of TL1A's role in inflammation. Our results suggest that TL1A should be considered as a target for immunotherapeutic treatment of rheumatoid arthritis and inflammatory bowel disease.
    PLoS ONE 01/2014; 9(8):e105627. · 3.53 Impact Factor
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    ABSTRACT: Objectives: To investigate the role of Death Receptor 3 (DR3) and its ligand TNF-like protein 1A (TL1A) in early stages of inflammatory arthritis.Methods: C57BL/6 mice genetically deficient in the DR3 gene (DR3KO) and their DR3WT littermates were subjected to antigen-induced arthritis (AIA) by priming and intra-articular injection of methylated BSA. Joints were sectioned and analyzed histochemically for damage to cartilage and expression of DR3, TL1A, Ly6G (a marker for neutrophils), the gelatinase matrix metallopeptidase 9 (MMP-9), the aggrecanase a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and the neutrophil chemoattractant CXCL1. In vitro production of MMP-9 was measured from cultures of fibroblasts, macrophages and neutrophils following addition of TL1A and other pro-inflammatory stimuli.Results: DR3 expression was upregulated in the joint following induction of AIA in DR3WT mice. DR3KO mice were protected from cartilage damage compared to DR3WT mice, even at early timepoints prior to the main accumulation of effector T cells in the joint. Early protection from AIA in vivo correlated with reduced levels of MMP-9. In vitro, neutrophils were found to be major producers of MMP-9, while in vivo neutrophil numbers were reduced in DR3KO joints. However, TL1A neither induced MMP-9 release, nor affected survival of, neutrophils. Instead, reduced levels of CXCL1 were recorded in DR3KO joints.Conclusions: DR3 drives early cartilage destruction in the AIA model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint leading to enhanced local production of cartilage destroying enzymes. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 06/2014;

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