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.
Highlights
Acute ulcerative colitis is an acute inflammatory disease of the colon and rectum
Acute Experimental Ulcerative Colitis mammalian target of rapamycin (mTOR) signaling has been shown to play an important role in inflammatory bowel disease [44,45,46,47]
Ser240/244 or p-S6 235/236 in intestinal epithelial cells, which was higher than that in intestinal immune cells (Figure 1a,b and Figure S1a). p-S6 is a downstream target of mTOR, and its expression in intestinal epithelial cells was dose-dependent with inflammatory stimulation (Figure S1b)
Summary
Acute ulcerative colitis is an acute inflammatory disease of the colon and rectum. Treatment with effective drugs and deciding upon selective colectomy in a timely fashion. Acute ulcerative colitis is poorly controlled and often develops into chronic colitis and inflammatory-related cancer, even leading to death [3,7,8,9]. The rapid and timely control of acute colitis is an important clinical treatment strategy. Known controlled evidence supports the use of both treatments. The theoretical basis of combination treatment is generally that the combined use of drugs outperforms the effect of either one alone, but the mechanism is still unclear [3,11]. The correct choice of subsequent immunosuppressive drugs is only judged by clinical improvement, but the immunological evidence is still unclear
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