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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    • "The DcR3-mediated blockade of LIGHT was shown to reduce T cell activity in vitro and to ameliorate graft-versus-host responses in vivo (Zhang et al., 2001). In addition , the engagement of TL1A, expressed on antigen presenting cells (Bamias et al., 2006), with its signaling receptor DR3, expressed on activated T cells, promotes T cell proliferation (Migone et al., 2002) and appears essential for the development of several inflammatory diseases including Crohn's disease and rheumatoid arthritis (Bull et al., 2008; Meylan et al., 2008; Pappu et al., 2008). Inhibition of TL1A-associated pathways, including the administration of DcR3, has been suggested as a promising approach for the treatment of these autoimmune diseases (Young and Tovey, 2006). "
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    ABSTRACT: Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side-chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as antideterminants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands.
    Structure 02/2011; 19(2):162-71. DOI:10.1016/j.str.2010.12.004 · 6.79 Impact Factor
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    • "TL1A was first reported to be expressed exclusively in human endothelial cells in response to TNFa or IL-1 [1]. Recent reports demonstrated inducible TL1A expression in macrophages [10] [11], T cells [12] [13], monocytes and dendritic cells [14] [15] [16] [17]. TL1A is synthesized as a 28- kDa type II membrane protein with an extracellular domain that contains the TNF homology domain (THD) (Fig. 1A). "
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    ABSTRACT: TL1A, a TNF member implicated in autoimmune diseases, is a transmembrane protein that is processed to release soluble TL1A (TL1A-S). TL1A-S induces a Th1 response, although the functional significance of membrane-bound TL1A (TL1A-M) remains unknown. We generated TL1A-M expression in HEK-293 cells capable of binding DR3-Fc. Co-incubating IL-12/IL-18-primed CD4(+) T cells with HEK-293 cells expressing TL1A-M induced 3-fold increase in IFN-gamma that was blocked by anti-TL1A Ab. These results demonstrate that TL1A-M can bind death domain receptor 3 (DR3) through cell-cell contact to induce downstream IFN-gamma secretion enhancement. Anti-TL1A antibodies designed to treat immune diseases should be verified to block both endogenous TL1A forms.
    FEBS letters 06/2010; 584(11):2376-80. DOI:10.1016/j.febslet.2010.04.030 · 3.34 Impact Factor
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    • "Before this study, TL1A has been reported to be found in serum (Bamias et al., 2008), human umbilical vein endothelial cells (Yang et al., 2004), and myeloid and T-cells (Bamias et al., 2003; Cassatella et al., 2007; Prehn et al., 2007; Meylan et al., 2008). TL1A has been reported to have roles in mucosal immunity (Papadakis et al., 2005), inflammatory bowel disease (Bamias et al., 2006; Takedatsu et al., 2008), inflammatory arthritis (Borysenko et al., 2006; Cassatella et al., 2007; Bull et al., 2008), renal inflammation (Al-Lamki et al., 2008), asthma (Fang et al., 2008; Meylan et al., 2008), and autoimmune encephalitis (Meylan et al., 2008; Pappu et al., 2008). Since the brains of DR3- deficient animals have normal cell numbers and appear devoid of any inflammation or apparent neuropathology, this suggests that cerebral mechanisms exist to dampen neuronal DR3 responsiveness , which is likely to be very threshold or age sensitive. "
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    ABSTRACT: Death receptor 3 is a proinflammatory member of the immunomodulatory tumor necrosis factor receptor superfamily, which has been implicated in several inflammatory diseases such as arthritis and inflammatory bowel disease. Intriguingly however, constitutive DR3 expression has been detected in the brains of mice, rats, and humans, although its neurological function remains unknown. By mapping the normal brain expression pattern of DR3, we found that DR3 is expressed specifically by cells of the neuron lineage in a developmentally regulated and region-specific pattern. Behavioral studies on DR3-deficient (DR3(ko)) mice showed that constitutive neuronal DR3 expression was required for stable motor control function in the aging adult. DR3(ko) mice progressively developed behavioral defects characterized by altered gait, dyskinesia, and hyperactivity, which were associated with elevated dopamine and lower serotonin levels in the striatum. Importantly, retrograde tracing showed that absence of DR3 expression led to the loss of corticostriatal innervation without significant neuronal loss in aged DR3(ko) mice. These studies indicate that DR3 plays a key nonredundant role in the retention of normal motor control function during aging in mice and implicate DR3 in progressive neurological disease.
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