The Glucocorticoid Receptor in Intestinal Epithelial Cells Alleviates Colitis and Associated Colorectal Cancer in Mice

Abstract

The glucocorticoid receptor in intestinal epithelial cells plays a crucial role in colonic inflammation by regulating gene expression, leukocyte recruitment, and epithelial barrier permeability, and thereby indirectly impacts tumorigenesis in the colon.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.

New Tricks of Our Old Friend the Glucocorticoid Receptor

“…Diving deeper into the mechanistic basis of the aggravated colitis in GR villin mice, Reichardt and colleagues further studied the gene expression profile of IEC isolated from colon. 5 Several chemokines ( Cxcl1 , Cxcl5 , Ccl5 ) that are involved in the pathogenesis of colitis and attract immune cells, such as neutrophils and monocytes, were only upregulated in IEC of DSS-treated GR flox mice, suggesting that GR triggers chemokine induction in IEC during inflammation, a proinflammatory action that has been reported before. 6 In contrast, genes important for the control of the epithelial barrier integrity ( Tnfr2 and Mlck ) or pathogen sensing ( Tlr4 ) were overexpressed in IECs of GR-devoid GR villin mice, but not in functional GR-expressing GR flox mice, indicating GR is required for the repression of these genes.…”

“…Because DSS-induced colitis was exacerbated in GR villin mice, the team of Reichardt further showed that this also influenced tumorigenesis by using the carcinogen azoxymethane. 5 In a DSS/azoxymethane model, both the number and size of the developed tumors was strongly increased in GR villin mice compared with GR flox mice, although not linked to changes in leukocyte infiltration. 5 In an elegant experiment where colitis and tumorigenesis were induced before GR was deleted in IEC, the severity of colitis and the number and size of the developed tumors showed to be comparable in both genotypes.…”

“…In line with the gene expression results, a reduced number of neutrophils, total and inflammatory macrophages, were found in the lamina propria of DSS-treated GR villin mice compared with GR flox mice. 5 This important finding indicates that GR expression in IEC influences recruitment of myeloid cells in the inflamed colon. To link this with the observed aggravated colitis in GR villin mice, a proinflammatory gene expression analysis was performed in lamina propria cells.…”

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , the group of Reichardt took a more direct approach and used both a DSS-induced colitis model and a colitis-associated colorectal cancer model, in which the intestinal epithelial GR was inducibly deleted (GR villin mice), to investigate GR action in IECs. 5 These authors showed that DSS-induced colitis was clearly exacerbated in GR villin mice compared with GR flox mice that still express wild-type GR. More specifically, GR villin mice displayed decreased body weight, worse clinical disease score, reduced colon length, and increased serum interleukin-6 levels compared with GR flox mice.…”

“…Remarkably, chemokine and cytokine expression levels were all strongly upregulated in lamina propria cells of GR villin mice compared with GR flox mice, indicative of hyperactivated lamina propria cells. 5 …”