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: 9.67). 06/2006; 103(22):8441-6. DOI: 10.1073/pnas.0510903103
Source: PubMed


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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    • "IL-2 is produced by T-cells in direct response to TCR stimulation, whereas IL-15 is produced by APCs and different tissue-specific cell types. One of our initial findings was that re-stimulation of effector T-cells using TL1A was only possible if the level of IL-2 during growth was kept low (20 U/mL instead of 100 U/mL normally used), corresponding to the observation made by Bamias et al. in 2006, that IFN-γ release mediated by TL1A was higher in cells stimulated with low levels of anti-CD3 [30]. This setting could reflect conditions in chronic inflammation tissue such as joints in RA or psoriatic lesions. "
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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 08/2014; 9(8):e105627. DOI:10.1371/journal.pone.0105627 · 3.23 Impact Factor
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    • "Mice with constitutive TL1A expression in antigen-presenting cells and T cells show intestinal inflammation and colonic fibrosis with a high percentage of T cells that are positive for CCR9 and CCR10, both of which are gut-homing chemokines in T cells [34]. As with TL1A, DR3 expression is increased in DSS-induced chronic colitis mice, and its transmembrane splicing variant is increased in correlation with inflammation in chronic ileitis mice, TNFΔARE mice, and SAMP1/Yit Fc mice [25, 32]. Administration of blocking anti-TL1A monoclonal antibodies inhibits DSS-induced colonic inflammation in mice [32], and DR3-deficient mice are protected from intestinal inflammation even after colitis induction [27]. "
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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.
    Mediators of Inflammation 12/2013; 2013:258164. DOI:10.1155/2013/258164 · 3.24 Impact Factor
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    • "TL1A, which represented a ligand for the death domain receptor 3 (DR3), was involved in clinical and experimental intestinal inflammation [16, 29]. TL1A induced Th17 immune response in cooperation with IL-23 in the CD pathogenesis [30]. "
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    ABSTRACT: Interleukin-23/T-helper 17 (IL-23/Th17) pathway plays a key role in the pathogenesis of inflammatory bowel disease (IBD), but little is known about its expression in Chinese population. In this study, we investigated the mRNA and protein levels of IL-12p40, tumor necrosis factor-like cytokine 1A (TL1A), Janus kinase 2 (JAK2), and IL-23R both locally and systemically in Chinese IBD patients. Our results indicated that the mRNA levels of IL-12p40 and TL1A were increased in ulcerative colitis (UC) patients. Furthermore, serum IL-12p40 and TL1A levels were higher in active UC patients, especially in patients with disease course less than 1.25 years or initial onset. No correlation was found between the genotype and serum levels of IL-12p40 or TL1A in UC patients. Additionally, the mRNA and protein expression of JAK2 and IL-23R were increased in UC and Crohn's disease (CD) patients. Taken together, our results provided evidence that IL-23/Th17 pathway genes may represent important biomarkers of active stage of IBD and serve as novel therapeutic targets for IBD in Chinese population.
    Mediators of Inflammation 12/2013; 2013(11):425915. DOI:10.1155/2013/425915 · 3.24 Impact Factor
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