Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate mode of colitis
Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate mode of colitis
复制标题
DOI：
10.1172/jci28121
复制
发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Wu, Gary D.
中科院分区：
文献类型：
--
作者：
McVay, Laila D.;Keilbaugh, Sue A.;Wu, Gary D.
虽然炎症性肠病（IBD）是遗传易感个体对共生肠道细菌的免疫反应失调的结果，但细菌导致IBD发展的机制尚不清楚。有趣的是，肠杯状细胞的缺失可以保护肠道免受损伤，这表明这种上皮细胞谱系可能产生加剧IBD的分子。我们之前报道过抵抗素样分子β （RELM β，也称为FIZZ2）是一种肠道杯状细胞特异性蛋白，在细菌定植后被诱导，然后在肠和结肠中表达，这是肠中最常涉及IBD的肠道区域。本研究表明，在小鼠结肠损伤的葡聚糖硫酸钠（DSS）模型中，破坏该基因可降低结肠炎的严重程度。虽然RELM β不改变结肠上皮细胞增殖或屏障功能，但我们发现重组蛋白激活巨噬细胞产生tnf - α。无论是体外还是体内。SAMP1/Fc IBD模型的回肠末端也强烈诱导RELM β表达。这些结果提示了一个模型，即DSS导致上皮屏障功能的丧失导致位于管腔的RELM β激活先天粘膜反应，支持该蛋白是杯状细胞、共生菌和IBD发病机制之间的联系的假设。
Although inflammatory bowel disease (IBD) is the result of a dysregulated immune response to commensal gut bacteria in genetically predisposed individuals, the mechanism(s) by which bacteria lead to the development of IBD are unknown. Interestingly, deletion of intestinal goblet cells protects against intestinal injury, suggesting that this epithelial cell lineage may produce molecules that exacerbate IBD. We previously reported that resistin-like molecule beta (RELM beta; also known as FIZZ2) is an intestinal goblet cell-specific protein that is induced upon bacterial colonization whereupon it is expressed in the ileum and colon, regions of the gut most often involved in IBD. Herein, we show that disruption of this gene reduces the severity of colitis in the dextran sodium sulfate (DSS) model of murine colonic injury. Although RELM beta does not alter colonic epithelial proliferation or barrier function, we show that recombinant protein activates macrophages to produce TNF-alpha. both in vitro and in vivo. RELM beta expression is also strongly induced in the terminal ileum of the SAMP1/Fc model of IBD. These results suggest a model whereby the loss of epithelial barrier function by DSS results in the activation of the innate mucosal response by RELM beta located in the lumen, supporting the hypothesis that this protein is a link among goblet cells, commensal bacteria, and the pathogenesis of IBD.