Constitutive TL1A (TNFSF15) Expression on Lymphoid or Myeloid Cells Leads to Mild Intestinal Inflammation and Fibrosis

Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2011; 6(1):e16090. DOI: 10.1371/journal.pone.0016090
Source: PubMed


TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohn's disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis.

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Article: Constitutive TL1A (TNFSF15) Expression on Lymphoid or Myeloid Cells Leads to Mild Intestinal Inflammation and Fibrosis

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    • "In addition to be involved in the inflammatory arthritis, TL1A/DR3 has been implicated in the pathogenesis of gut inflammation [8], with polymorphisms of TL1A linked with inflammatory bowel diseases, ulcerative colitis, and Crohn's disease [30]–[32]. In addition, transgenic mice that constitutively express TL1A develop T cell-dependent inflammatory small bowel pathology [33], [34]. Our finding that Atsttrin ameliorated the pathology of DSS-induced colitis (Fig. 5) also supported the concept that TL1A/DR3 pathway plays an important role in the pathogenesis of inflammatory bowel diseases. "
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    • "Its major source is likely to be dendritic cells in mesenteric lymph nodes and small intestinal lamina propria mononuclear cells [25, 32]. 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]. "
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