TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice

A Son; T Oshio; Y I Kawamura; T Hagiwara; M Yamazaki; K Inagaki-Ohara; T Okada; P Wu; M Iseki; S Takaki; L C Burkly; T Dohi

doi:10.1038/mi.2013.10

TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice

Mucosal Immunol. 2013 Nov;6(6):1131-42. doi: 10.1038/mi.2013.10. Epub 2013 Mar 6.

Authors

A Son¹, T Oshio, Y I Kawamura, T Hagiwara, M Yamazaki, K Inagaki-Ohara, T Okada, P Wu, M Iseki, S Takaki, L C Burkly, T Dohi

Affiliation

¹ Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.

PMID: 23462911
DOI: 10.1038/mi.2013.10

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cells, Cultured
Chronic Disease
Colitis / chemically induced
Colitis / immunology*
Colon / pathology*
Cytokine TWEAK
Disease Models, Animal
Female
Fibroblasts / immunology*
Fibrosis
Humans
Immunoglobulins / genetics
Immunoglobulins / metabolism
Interleukin-13 / immunology
Interleukin-13 / metabolism*
Mice
Mice, Inbred BALB C
Mice, Knockout
Organ Culture Techniques
Receptors, Cytokine / genetics
Receptors, Cytokine / metabolism
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / immunology
Receptors, Tumor Necrosis Factor / metabolism*
TWEAK Receptor
Th2 Cells / immunology*
Trinitrobenzenesulfonic Acid / administration & dosage
Tumor Necrosis Factors / immunology
Tumor Necrosis Factors / metabolism*

Substances

Cytokine TWEAK
Immunoglobulins
Interleukin-13
Receptors, Cytokine
Receptors, Tumor Necrosis Factor
TNFRSF12A protein, human
TWEAK Receptor
Tnfrsf12a protein, mouse
Tnfsf12 protein, mouse
Tslpr protein, mouse
Tumor Necrosis Factors
Trinitrobenzenesulfonic Acid

Associated data

GEO/GSE36806