Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland.
Gut. 2013 Jan;62(1):63-72. doi: 10.1136/gutjnl-2011-300498. Epub 2012 Jan 27.
Epithelial to mesenchymal transition (EMT) seems to play an important role in the pathogenesis of fistulae, a common clinical complication of Crohn's disease (CD). TGFβ and interleukin-13 (IL-13) have been correlated with the onset of EMT-associated organ fibrosis and high levels of TGFβ have been shown in transitional cells (TCs) lining CD fistula tracts. This study investigated whether IL-13 could be involved in the pathogenesis of CD-associated fistulae.
Protein or mRNA levels in HT29 intestinal epithelial cells (IECs) or colonic lamina propria fibroblasts (CLPFs) were studied by western blotting or real-time PCR. CLPFs were isolated from non-inflammatory disease controls or patients with CD with or without fistulae and IL-13 levels were analysed in surgically removed fistula specimens by immunohistochemistry.
TGFβ induced IL-13 secretion in CLPFs from patients with fistulising CD. In fistula specimens high levels of IL-13 were detected in TCs covering fistula tracts. In HT29 IEC monolayers, IL-13 induced SLUG and β6-integrin mRNA, which are associated with cell invasion. HT29 spheroids completely disintegrated when treated with TGFβ for 7 days, whereas IL-13-treated spheroids did not show morphological changes. Here, TGFβ induced mRNA expression of SNAIL1 and IL-13, whereas IL-13 elevated SLUG and β6-integrin mRNA. An anti-IL-13 antibody was able to prevent IL-13-induced SLUG expression in HT29 IECs.
TGFβ induces IL-13 expression and an EMT-like phenotype of IECs, while IL-13 promotes the expression of genes associated with cell invasion. These findings suggest that TGFβ and IL-13 play a synergistic role in the pathogenesis of fistulae and inhibition of IL-13 might represent a novel therapeutic approach for fistula treatment.
上皮-间充质转化（EMT）似乎在克罗恩病（CD）瘘管的发病机制中起重要作用，瘘管是 CD 的一种常见临床并发症。TGFβ 和白细胞介素-13（IL-13）与 EMT 相关的器官纤维化的发生有关，并且在CD 瘘管上皮细胞（TC）中已经显示出高水平的 TGFβ。本研究探讨了 IL-13 是否可能参与 CD 相关瘘管的发病机制。
通过 Western blot 或实时 PCR 研究 HT29 肠上皮细胞（IEC）或结肠固有层成纤维细胞（CLPF）中的蛋白或 mRNA 水平。CLPF 从非炎症性疾病对照或有或没有瘘管的 CD 患者中分离出来，并通过免疫组织化学分析手术切除的瘘管标本中的 IL-13 水平。
TGFβ 诱导来自瘘管性 CD 患者的 CPLF 分泌 IL-13。在瘘管标本中，在覆盖瘘管的 TC 中检测到高水平的 IL-13。在 HT29 IEC 单层中，IL-13 诱导 SLUG 和β6-整合素 mRNA，这与细胞侵袭有关。用 TGFβ 处理 7 天后，HT29 球体完全解体，而用 IL-13 处理的球体没有显示出形态变化。在这里，TGFβ 诱导 SNAIL1 和 IL-13 的 mRNA 表达，而 IL-13 升高 SLUG 和β6-整合素 mRNA。抗 IL-13 抗体能够防止 HT29 IEC 中 IL-13 诱导的 SLUG 表达。
TGFβ 诱导 IEC 中 IL-13 的表达和 EMT 样表型，而 IL-13 促进与细胞侵袭相关的基因的表达。这些发现表明 TGFβ 和 IL-13 在瘘管的发病机制中发挥协同作用，抑制 IL-13 可能代表一种治疗瘘管的新方法。
