Background & Aims

Inflammatory bowel disease is commonly treated by administration of glucocorticoids. While the importance of intestinal epithelial cells for the pathogenesis of this disorder is widely accepted, their role as target cells for glucocorticoids has not been explored. To address this issue, we induced colonic inflammation in GR^villin mice, which carry an inducible deletion of the glucocorticoid receptor in intestinal epithelial cells.

Methods

Colitis and colitis-associated colorectal cancer were induced by administration of dextran sulfate sodium and azoxymethane in mice. Clinical parameters, epithelial permeability and tumor development were monitored during disease progression. Colon tissue, lamina propria cells and intestinal epithelial cells were examined by gene expression analyses, flow cytometry, histopathology, and immunohistochemistry.

Results

The absence of the intestinal epithelial glucocorticoid receptor aggravated clinical symptoms and tissue damage, and compromised epithelial barrier integrity during colitis. Gene expression of chemokines, pattern recognition receptors and molecules controlling epithelial permeability was dysregulated in intestinal epithelial cells of GR^villin mice, leading to a reduced recruitment and a hyperactivation of leukocytes in the lamina propria of the colon. Importantly, the exaggerated inflammatory response in GR^villin mice also enhanced associated tumorigenesis, resulting in a higher number and larger size of tumors in the colon.

Conclusions

Our results reveal an important role of intestinal epithelial cells as targets of glucocorticoid action in inflammatory bowel disease and suggest that the efficacy with which colitis is kept at bay directly affects the progression of colorectal cancer.

中文翻译：

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肠上皮细胞中的糖皮质激素受体可减轻小鼠的结肠炎和相关的结肠直肠癌

背景与目标

炎症性肠病通常通过给予糖皮质激素来治疗。虽然肠上皮细胞对这种疾病发病机制的重要性已被广泛接受，但尚未探索它们作为糖皮质激素靶细胞的作用。^{为了解决这个问题，我们在 GR绒毛蛋白}小鼠中诱导了结肠炎症，其在肠上皮细胞中携带可诱导的糖皮质激素受体缺失。

方法

通过在小鼠中施用葡聚糖硫酸钠和偶氮甲烷诱导结肠炎和结肠炎相关的结肠直肠癌。在疾病进展期间监测临床参数、上皮通透性和肿瘤发展。通过基因表达分析、流式细胞术、组织病理学和免疫组织化学检查结肠组织、固有层细胞和肠上皮细胞。

结果

肠上皮糖皮质激素受体的缺失加重了临床症状和组织损伤，并在结肠炎期间损害了上皮屏障的完整性。趋化因子、模式识别受体和控制上皮通透性的分子的基因表达在 GR ^vilin小鼠的肠上皮细胞中失调，导致结肠固有层中白细胞的募集减少和过度活化。重要的是，GR ^villin小鼠中过度的炎症反应也增强了相关的肿瘤发生，导致结肠中肿瘤的数量和尺寸更大。

结论

我们的研究结果揭示了肠上皮细胞作为糖皮质激素作用靶点在炎症性肠病中的重要作用，并表明抑制结肠炎的功效直接影响结直肠癌的进展。