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

Abstract

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.

Cloning, Expression, and Functional Characterization of TL1A-Ig

“…Therefore, a comparison with the functional effects of the natural ligand, TL1A, is necessary. Consistent with the effects elicited by 4C12, transgenic overexpression of TL1A resulted in increased numbers of Tregs, but TL1A-transgenic overexpression also led to modulation of CD4 + Tconv responses, intestinal goblet cell hyperplasia, and intestinal inflammation (14,(41)(42)(43), indicating important regulatory functions of TL1A, especially in the intestinal mucosa.…”

TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses

“…The administration of exogenous TL1A aggravates CIA, whereas TL1A-neutralizing Ab reduces the severity of CIA (5,23). Transgenic overexpression of TL1A worsens dextran sodium sulfate-induced colitis and causes intestinal mucosal inflammation (9,20,21,48). Several mechanistic aspects of these disease models corroborate each other.…”

“…In mice with transgenic TL1A expression or mice administered with exogenous recombinant TL1A, the immune/inflammation responses were aggravated but not ameliorated (5,9,21,48). In all the studies using either TL1A or DR3 KO mice models or TL1A neutralizing Abs (3,15,(23)(24)(25), the immune responses were abated.…”

“…We have demonstrated that the administration of recombinant TL1A to mice with collagen-induced arthritis (CIA) aggravates the disease (5). Furthermore, overexpression of TL1A in transgenic mice results in spontaneous inflammatory bowel disease as well as increased number of Th cells (9,20,21). In contrast, DR3 gene knockout (KO) mice have reduced disease severity of allergic lung inflammation and Ag-induced arthritis and present less effective antiviral and antibacterial immune responses (15,(22)(23)(24)(25).…”

Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

“…[100][101][102] In mice, constitutive TL1A overexpression causes spontaneous ileitis with increased collagen deposition. 103,104 Under colitogenic conditions induced by chronic dextran sulfate sodium (DSS) treatment or adoptive T-cell transfer, increased inflammation, fibrosis, and fibrostenotic lesions in the gut are seen. 105 These results support the role of TL1A in induction of intestinal inflammation and suggest its contribution to fibrogenesis in the gut.…”