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

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 gamma-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF alpha. 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 gamma-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 naive intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-alpha which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-alpha 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 alpha. IL-13, TNF-alpha, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.