The role of the Glucocorticoid Receptor in intestinal inflammation and tumorigenesis in a murine model of colitis and colitis-associated colorectal cancer

by Chiara Muzzi
Doctoral thesis
Date of Examination:2022-07-25
Date of issue:2022-08-12
Advisor:Dr. Sybille Reichardt
Referee:Prof. Dr. Lutz Walter
Referee:Prof. Dr. Matthias Dobbelstein
Persistent Address: http://dx.doi.org/10.53846/goediss-9400

 

 

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Abstract

English

Ulcerative colitis (UC) is a life-threatening disease with constantly increasing incidence. Glucocorticoids (GCs) are one of the first choices for the treatment of this disease thanks to their anti-inflammatory action and their low costs. However, they are associated with adverse effects. GCs exert their function by binding to the GC receptor (GR), which is ubiquitously expressed and can impact gene transcription by different mechanisms. To obtain new insights into the mechanism of GCs in the context of UC, we chemically induced colitis in a mouse strain with impaired GR DNA-binding (GRdim). Here we found that disease symptoms were reduced compared to littermate controls, and that expression of pro-inflammatory genes was downregulated. We also observed a differential expression of genes associated with colon permeability in untreated GRdim mice, which presumably confers a protective effect during colitis. When we induced colitis-associated colon cancer by additionally injecting a cancerogenic agent, we observed a lower number of tumors in GRdim mice. Impaired GR DNA-binding activity thus seems to be beneficial in colitis and cancer progression, indicating that more selective GR agonists could improve UC treatment. Intestinal epithelial cells (IECs) are essential in maintaining gut homeostasis and play a crucial role in the pathogenesis of UC, but the function of the GR in this cell type has not been investigated yet. To study this issue, we used mice carrying an inducible deletion of the GR in IECs (GRvillin) and subjected them to the same chemically induced UC model. Epithelial permeability in the colon and the expression of pro-inflammatory genes in IECs were increased in GRvillin mice. Recruitment of immune cells into the lamina propria was compromised in mutant mice, presumably leading to an impaired clearance of pathogens. In contrast, the infiltrating cells were hyperactivated in GRvillin mice leading to a perpetuation of inflammation. Taken together, a lack of the GR in IECs aggravates colitis. These data underscore the importance of GC action in IECs in controlling colonic inflammation and raise the question if a drug administered to directly target them might be an option for improved treatment of UC.
Keywords: inflammatory bowel disease; ulcerative colitis; glucocorticoids; glucocorticoids receptor; colitis-associated colorectal cancer
Schlagwörter: ulcerative colitis; inflammatory bowel disease; glucocorticoids; glucocorticoids receptor; colitis-associated colorectal cancer
 
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