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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice
1Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
Abstract:
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a TNF superfamily member, induces damage of the epithelial cells (ECs) and production of inflammatory mediaters through its receptor Fn14 in a model of acute colitis. In our current study of chronic colitis induced by repeated rectal injection of a hapten, we found that inflammation, fibrosis, and T helper 2 (Th2)-type immunity were significantly reduced in Fn14 gene knockout (KO) mice when compared with wild-type (WT) control mice. Expression of thymic stromal lymphopoietin (TSLP) was lower in Fn14 KO colon ECs than in WT ECs. TWEAK potentiates the induction of TSLP by interleukin-13 (IL-13) in colon explants from WT but not in Fn14 KO tissue. TSLP receptor KO mice exhibit milder chronic colitis, similar to that in Fn14 KO mice. TWEAK and IL-13 synergistically promote fibroblast proliferation. Thus we propose an IL-13-TWEAK/Fn14-TSLP axis as a key mechanism underlying chronic colitis with fibrosis.
Insights
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signaling via Fn14 exacerbates chronic colitis and fibrosis. Blocking this pathway reduces inflammation and Th2 immunity, suggesting a therapeutic target for inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are implicated in epithelial cell damage and inflammation in acute colitis.
- Chronic colitis models often involve complex immune responses and tissue remodeling, including fibrosis.
Purpose of the Study:
- To investigate the role of the TWEAK/Fn14 axis in chronic colitis with fibrosis.
- To elucidate the involvement of thymic stromal lymphopoietin (TSLP) and T helper 2 (Th2) immunity in this model.
Main Methods:
- Induction of chronic colitis in wild-type (WT) and Fn14 gene knockout (KO) mice via rectal hapten injection.
- Assessment of inflammation, fibrosis, Th2-type immunity, and gene/protein expression (TSLP, IL-13).
- Functional studies using colon explants and TSLP receptor KO mice.
Main Results:
- Fn14 KO mice exhibited significantly reduced inflammation, fibrosis, and Th2 immunity compared to WT mice.
- TSLP expression was lower in Fn14 KO colon epithelial cells; TWEAK potentiated IL-13-induced TSLP production in WT but not Fn14 KO tissues.
- TSLP receptor KO mice showed milder chronic colitis, and TWEAK/IL-13 synergistically promoted fibroblast proliferation.
Conclusions:
- The IL-13-TWEAK/Fn14-TSLP axis is a critical mechanism driving chronic colitis with fibrosis.
- Targeting this axis may offer a therapeutic strategy for inflammatory bowel disease characterized by fibrosis.
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