title: Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis.
abstract: OBJECTIVE
  TWEAK, a member of the tumor necrosis factor (TNF) superfamily, promotes intestinal epithelial cell injury and signals through the receptor Fn14 following irradiation-induced tissue damage and during development of colitis in mice. Interleukin (IL)-13, an effector of tissue damage in similar models, has been associated with the pathogenesis of ulcerative colitis (UC). We investigated interactions between TWEAK and IL-13 following mucosal damage in mice.
  
  
  METHODS
  We compared patterns of gene expression in intestinal tissues from wild-type and TWEAK knockout mice following γ-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF-α. Levels of messenger RNA for IL-13, TWEAK, and Fn14 were measured in mucosal samples from patients with UC.
  
  
  RESULTS
  Based on gene expression analysis, TWEAK mediates γ-irradiation-induced epithelial cell cycle arrest and apoptosis. However, TWEAK alone did not induce damage or apoptosis of primary intestinal epithelial cells. On the other hand, exogenous IL-13 activated caspase-3 in naïve intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-α which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-α required IL-13, TWEAK, and Fn14. In mucosa from patients with UC, messenger RNA levels of IL-13, TWEAK, and Fn14 increased with level of disease severity.
  
  
  CONCLUSIONS
  IL-13-induced damage of intestinal epithelial cells requires TWEAK, its receptor (Fn14), and TNF-α. IL-13, TNF-α, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.
authors: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, Tokyo, Japan.
authors: Rei
authors: R
authors: Kawashima
authors: Yuki I
authors: YI
authors: Kawamura
authors: Tomoyuki
authors: T
authors: Oshio
authors: Aoi
authors: A
authors: Son
authors: Motomi
authors: M
authors: Yamazaki
authors: Teruki
authors: T
authors: Hagiwara
authors: Toshihiko
authors: T
authors: Okada
authors: Kyoko
authors: K
authors: Inagaki-Ohara
authors: Ping
authors: P
authors: Wu
authors: Suzanne
authors: S
authors: Szak
authors: Yutaka J
authors: YJ
authors: Kawamura
authors: Fumio
authors: F
authors: Konishi
authors: Oki
authors: O
authors: Miyake
authors: Hideaki
authors: H
authors: Yano
authors: Yukio
authors: Y
authors: Saito
authors: Linda C
authors: LC
authors: Burkly
authors: Taeko
authors: T
authors: Dohi
mesh_terms: D000818:Animals; D016923:Cell Death; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology*; D000074049:Cytokine TWEAK; D005786:Gene Expression Regulation / Q000502:physiology*; D018793:Interleukin-13 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000074050:TWEAK Receptor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000235:genetics*
chemical_list: D000074049:Cytokine TWEAK; D018793:Interleukin-13; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors