Role of the glucocorticoid receptor in the development of ulcerative colitis and colorectal carcinoma in a murine model

by Eric Phillip Twomey
Doctoral thesis
Date of Examination:2022-08-30
Date of issue:2022-08-29
Advisor:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Alexander Flügel
Persistent Address: http://dx.doi.org/10.53846/goediss-9418

 

 

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Abstract

English

For many decades, glucocorticoids (GCs) have been an essential pillar of the therapy of many inflammatory diseases. The beneficial effects of this class of hormones occur quickly and reliably after administration, although they are accompanied by the risk of various side effects. GCs have also been used successfully in the therapy of ulcerative colitis for many years. Nevertheless, the exact mode of action of their effect on the inflammatory processes in the bowel is still largely unknown. Since GCs trigger most of their effects through binding to the GC receptor (GR), we aimed to elucidate the role of the GR in the gut, especially in intestinal epithelial cells. To reach this objective, we triggered colitis in a mouse model expressing a modified GR whose function was restricted to DNA-binding independent activities, or in mice in which the GR in intestinal epithelial cells was switched off. We hypothesized that under these conditions the disease course was altered. A special focus was laid on the activity of macrophages being a switch point of inflammatory processes. We used clinical parameters to assess the disease course and characterized the molecular processes by investigating cytokine production and gene expression. Immunohistochemical analyses were performed to identify and quantify infiltrating cells. Most importantly, we could show that switching off GR expression in enterocytes worsened the disease course. Both clinically and biochemically, aggravated episodes were observed. Increased gene expression of CCL2 in intestinal epithelial cells could at least be partially accountable for this observation. In the end, we assumed that deletion of the GR also affected colitis-associated colorectal carcinoma in mice. Using the mouse model with a deletion of the GR in intestinal epithelial cells, we could show that more and larger tumors developed under these conditions. In summary, our work demonstrates that the GR expressed in cell of the intestinal tract plays an essential role as an immunoregulatory entity. Hereby, it represents a major factor in the development of both ulcerative colitis and colitis-associated colorectal carcinoma, and thus could serve as a potential target of further therapeutic regimens.
Keywords: ulcerative colitis; glucocorticoid receptor; colorectal carcinoma
 
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