The Glucocorticoid Receptor in Intestinal Epithelial Cells Alleviates Colitis and Associated Colorectal Cancer in Mice.
Cell Mol Gastroenterol Hepatol
; 11(5): 1505-1518, 2021.
Article
em En
| MEDLINE
| ID: mdl-33316454
ABSTRACT
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 GRvillin 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 GRvillin mice, leading to a reduced recruitment and a hyperactivation of leukocytes in the lamina propria of the colon. Importantly, the exaggerated inflammatory response in GRvillin 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Glucocorticoides
/
Colite
/
Carcinogênese
/
Neoplasias Associadas a Colite
/
Inflamação
/
Mucosa Intestinal
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article