Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice—A Pathway Associated With Ulcerative Colitis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 141; no. 6; pp. 2119 - 2129.e8
• Main Authors: Kawashima, Rei, Kawamura, Yuki I, Oshio, Tomoyuki, Son, Aoi, Yamazaki, Motomi, Hagiwara, Teruki, Okada, Toshihiko, Inagaki–Ohara, Kyoko, Wu, Ping, Szak, Suzanne, Kawamura, Yutaka J, Konishi, Fumio, Miyake, Oki, Yano, Hideaki, Saito, Yukio, Burkly, Linda C, Dohi, Taeko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2011
• Subjects: Animals; Cell Death; Colitis, Ulcerative - genetics; Colitis, Ulcerative - pathology; Cytokine Signaling; Cytokine TWEAK; Diagnostic Marker; Gastroenterology and Hepatology; Gene Expression Regulation - physiology; IBD; Interleukin-13 - metabolism; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Tumor Necrosis Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - physiology; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factors - genetics; TWEAK Receptor; Ulcerative Colitis; knockout; IL; KO; IEC; SPF; TACE; IBD; TNF; Cytokine Signaling; tumor necrosis factor converting enzyme; intestinal epithelial cell; Th; tumor necrosis factor; Ulcerative Colitis; Cell Death; Diagnostic Marker; interleukin; wild-type; WT; T helper; specific pathogen-free
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.08.040

Background & Aims 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.