Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice-A Pathway Associated With Ulcerative Colitis
Interleukin-13 Damages Intestinal Mucosa via TWEAK and Fn14 in Mice-A Pathway Associated With Ulcerative Colitis
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DOI：
10.1053/j.gastro.2011.08.040
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发表时间：
2011-12-01
期刊：
影响因子：
29.4
通讯作者：
Dohi, Taeko
中科院分区：
文献类型：
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作者：
Kawashima, Rei;Kawamura, Yuki I.;Dohi, Taeko
背景与目的：TWEAK是肿瘤坏死因子（TNF）超家族的一员，在小鼠中辐射诱导的组织损伤后和结肠炎发展期间促进肠上皮细胞损伤并通过受体Fn 14发出信号。白细胞介素（IL）-13，在类似的模型中的组织损伤的效应器，已与溃疡性结肠炎（UC）的发病机制。我们研究了TWEAK和IL-13在小鼠粘膜损伤后的相互作用。方法：我们比较了γ射线照射后野生型和TWEAK基因敲除小鼠肠组织中基因表达的模式。来自这些小鼠的肠外植体用于检测由IL-13和TNF α诱导的细胞损伤。在UC患者的粘膜样本中测量IL-13、TWEAK和Fn 14的信使RNA水平。结果：基于基因表达分析，TWEAK介导γ射线诱导的上皮细胞周期阻滞和凋亡。然而，单独的TWEAK不诱导原代肠上皮细胞的损伤或凋亡。另一方面，外源性IL-13激活幼稚肠外植体中的caspase-3;该过程需要TWEAK、Fn 14和内源性TNF-α的分泌，其由ADAM 17介导。相反，外源性TNF-α激活caspase需要IL-13、TWEAK和Fn 14。在UC患者的粘膜中，IL-13、TWEAK和Fn 14的信使RNA水平随着疾病严重程度的增加而增加。结论：IL-13诱导的肠上皮细胞损伤需要TWEAK及其受体（Fn 14）和TNF α。IL-13、TNF-α、TWEAK和Fn 14可使UC患者的肠道炎症持续存在并加重。
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.