Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis.
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.
Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
David Q
DQ
Shih
Robert
R
Barrett
Xiaolan
X
Zhang
Nicole
N
Yeager
Hon Wai
HW
Koon
Piangwarin
P
Phaosawasdi
Yahui
Y
Song
Brian
B
Ko
Michelle H
MH
Wong
Kathrin S
KS
Michelsen
Gislaine
G
Martins
Charalabos
C
Pothoulakis
Stephan R
SR
Targan
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D005355:Fibrosis / Q000209:etiology / Q000276:immunology; D015870:Gene Expression; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics*; D015854:Up-Regulation
C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
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