Zhang Zhengguo, Dong Lin, Jia Anna, Chen Xi, Yang Qiuli, Wang Yufei, Wang Yuexin, Liu Ruichen, Cao Yejin, He Ying, Bi Yujing, Liu Guangwei
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Cancers (Basel). 2020 Apr 11;12(4):945. doi: 10.3390/cancers12040945.
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.
糖皮质激素对结肠炎及结肠炎相关癌症的治疗作用尚不清楚。在本研究中，我们调查了糖皮质激素在小鼠急性实验性溃疡性结肠炎和结肠炎相关癌症中的治疗作用及其免疫调节机制。用葡聚糖硫酸钠（DSS）诱导小鼠急性溃疡性结肠炎，并给予不同剂量的地塞米松（Dex）进行治疗。Dex显著加剧了DSS诱导的结肠炎的发病和严重程度，增强了黏膜炎症巨噬细胞和中性粒细胞浸润以及细胞因子的产生。此外，在炎症条件下，糖皮质激素受体（GR）的表达没有明显变化，而雷帕霉素靶蛋白（mTOR）信号在结肠上皮细胞中比在结肠免疫细胞中更高。小鼠肠道上皮细胞而非髓系免疫细胞中mTOR的缺失显著改善了由Dex引起的结肠炎的严重病程，包括体重减轻、临床评分、结肠长度、病理损伤、炎症细胞浸润和促炎细胞因子的产生。这些数据表明，肠道上皮细胞中的mTOR信号，主要是mTORC1，在Dex诱导的急性结肠炎和结肠炎相关癌症的加重中起关键作用。因此，这些证据表明，通过调节先天免疫细胞募集和激活的动态过程，上皮细胞中糖皮质激素诱导的mTOR信号在急性溃疡性结肠炎早期是必需的。
