Glucocorticoids Promote the Onset of Acute Experimental Colitis and Cancer by Upregulating mTOR Signaling in Intestinal Epithelial Cells

Abstract

The therapeutic effects of glucocorticoids on colitis and colitis-associated cancer are unclear. In this study, we investigated the therapeutic roles of glucocorticoids in acute experimental ulcerative colitis and colitis-associated cancer in mice and their immunoregulatory mechanisms. Murine acute ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with dexamethasone (Dex) at different doses. Dex significantly exacerbated the onset and severity of DSS-induced colitis and potentiated mucosal inflammatory macrophage and neutrophil infiltration, as well as cytokine production. Furthermore, under inflammatory conditions, the expression of the glucocorticoid receptor (GR) did not change significantly, while mammalian target of rapamycin (mTOR) signaling was higher in colonic epithelial cells than in colonic immune cells. The deletion of mTOR in intestinal epithelial cells, but not that in myeloid immune cells, in mice significantly ameliorated the severe course of colitis caused by Dex, including weight loss, clinical score, colon length, pathological damage, inflammatory cell infiltration and pro-inflammatory cytokine production. These data suggest that mTOR signaling in intestinal epithelial cells, mainly mTORC1, plays a critical role in the Dex-induced exacerbation of acute colitis and colitis-associated cancer. Thus, these pieces of evidence indicate that glucocorticoid-induced mTOR signaling in epithelial cells is required in the early stages of acute ulcerative colitis by modulating the dynamics of innate immune cell recruitment and activation.

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

“…In contrast to the beneficial effects of GCs in IBD patients, dexamethasone treatment of acute colitis aggravated clinical symptoms rather than ameliorating them, a phenomenon which is not yet understood. 9 , 10 , 11 Based on this observation, the analysis of GR knockout mice currently appears to be the preferred strategy to explore GC activities in experimental colitis.…”

The therapeutic potential and deleterious effect of glucocorticoids on AOM/DSS-induced colorectal cancer in mice

“…Recently, there was study demonstrating that DEX accelerated the onset and severity of colitis and colitisassociated cancer mediated by mTOR signaling pathway, in which mice were treated with DEX (2.5 mg/kg) at the beginning of DSS drinking [46]. Besides, another study concluded that corticosterone, which was given in feeding solution (50 mg/L) one week after DSS administration, could inhibit the in ammation but promoted the development of AOM/DSS-induced colon cancer by activating NF-κB and COX-2 [16].…”

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

“…The addition of an HDACi entinostat (ENT) to AZA further enhances the regulation of the immune microenvironment. Triple or quadruple treatment of AZA and ENT plus immunotherapy anti-PD-1 and anti-CTLA-4 exhibited highly effective tumor elimination [8,[159][160][161][162]. Adjuvant epigenetic therapy with AZA and ENT blocks the migration of MDSCs by downregulating CCR2 and CXCR2, which leads to the differentiation of MDSCs into macrophages and disturbance of pMN [161,163,164].…”