LAUSR

lcerative colitis is the most common form of inUflammatory bowel disease (IBD) and a major risk factor for the development of colorectal cancer. Synthetic glucocorticoids are essential drugs in combatting inflammatory diseases and mediate their anti-inflammatory actions by binding the glucocorticoid receptor (GR). Despite its clinical importance, prolonged glucocorticoid treatment is hampered by the emergence of glucocorticoid resistance and detrimental side effects. Therefore, it is crucial to optimize glucocorticoid use in IBD, which requires an improved understanding of the glucocorticoid action in IBD. Because GR is ubiquitously expressed, glucocorticoids can affect different cell types in the colon, including immune cells and intestinal epithelial cells (IECs). Using a dextran sulfate sodium (DSS)-induced colitis model, GR deletion in myeloid cells was shown to inhibit the resolution (but not the acute) phase of the disease, which was accompanied by increased infiltration of macrophages and proinflammatory cytokine expression in the colon. Yet, for ulcerative colitis the role of GR in IECs has remained largely unresolved. Earlier work showed that GR deletion in IECs coincided with transient upregulation of proinflammatory chemokines and cytokines in basal conditions, but an inflammatory or tumorigenic context was not considered. 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 mice), to investigate GR action in IECs. These authors showed that DSS-induced colitis was clearly exacerbated in GR mice compared with GR mice that still express wild-type GR. More specifically, GR mice displayed decreased body weight, worse clinical disease score, reduced colon length, and increased serum interleukin-6 levels compared with GR mice. This is further supported by their findings that compared with GR mice, GR mice showed both aggravated DSS-induced tissue damage, and an even further compromised epithelial barrier integrity. Diving deeper into the mechanistic basis of the aggravated colitis in GR mice, Reichardt and colleagues further studied the gene expression profile of IEC isolated from colon. 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 mice, suggesting that GR triggers chemokine induction in IEC during inflammation, a proinflammatory action that has been reported before. In contrast, genes important for the control of the epithelial barrier integrity (Tnfr2 and Mlck) or pathogen sensing