title: TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice.
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.
authors: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
authors: A
authors: A
authors: Son
authors: T
authors: T
authors: Oshio
authors: Y I
authors: YI
authors: Kawamura
authors: T
authors: T
authors: Hagiwara
authors: M
authors: M
authors: Yamazaki
authors: K
authors: K
authors: Inagaki-Ohara
authors: T
authors: T
authors: Okada
authors: P
authors: P
authors: Wu
authors: M
authors: M
authors: Iseki
authors: S
authors: S
authors: Takaki
authors: L C
authors: LC
authors: Burkly
authors: T
authors: T
authors: Dohi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000473:pathology*; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005355:Fibrosis; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000074050:TWEAK Receptor; D018418:Th2 Cells / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D007136:Immunoglobulins; D018793:Interleukin-13; D018121:Receptors, Cytokine; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; C410591:Tslpr protein, mouse; D048069:Tumor Necrosis Factors; D014302:Trinitrobenzenesulfonic Acid