%0 Journal Article
%T The Role of TL1A and DR3 in Autoimmune and Inflammatory Diseases
%A Yoshihiro Aiba
%A Minoru Nakamura
%J Mediators of Inflammation
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/258164
%X 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. 1. Characteristics of TL1A and DR3 1.1. TL1A TL1A, also referred to as vascular endothelial growth inhibitor (VEGI)-251, is a member of the tumor necrosis factor superfamily (TNFSF) of ligands, which was identified by Migone et al. in 2002 [1]. Although TL1A was identified as a longer variant of TL1/VEGI, the fourth exon of TL1A encodes the majority of TL1/VEGI, and it has been presumed that the original TL1/VEGI was a cloning artifact. TL1A exhibits approximately 20¨C30% homology to other TNFSF members [1]. Human TL1A consists of 251 amino acids: 35 in the cytoplasmic domain, 24 in the transmembrane region, and 192 in the extracellular domain. There are two potential N-linked glycosylation sites in the TL1A amino acid sequence, specifically Asn residues at amino acids 133 and 229 [1]. TL1A is a type II transmembrane protein. TL1A is initially expressed as a membrane-bound protein and is subsequently released as a soluble protein via ectodomain shedding by a metalloproteinase such as TNF-¦Á converting enzyme (TACE) [2, 3]. TL1A expression is detected on human umbilical vein endothelial cells and synovial fibroblast-like cells and is upregulated by stimulation with proinflammatory cytokines such as TNF-¦Á, IL-1, and PMA, a phorbol ester known to be a potent activator of protein kinase C [1, 4]. TL1A expression has also been confirmed on antigen-presenting cells and lymphocytes that are activated by Toll-like receptor (TLR)
%U http://www.hindawi.com/journals/mi/2013/258164/