糖皮质激素受体
溃疡性结肠炎
内分泌学
糖皮质激素
内科学
固有层
炎症性肠病
结肠炎
肠粘膜
生物
医学
癌症研究
上皮
病理
疾病
作者
Glauben Landskron,Karen Dubois-Camacho,Octavio Orellana-Serradell,Marjorie De la Fuente,Daniela Parada-Venegas,Mirit Bitrán,David Díaz-Jiménez,Shuāng Táng,John A. Cidlowski,Xiaoling Li,Hector Molina,Carlos González,Daniela Simian,Jaime Lubascher,V Pola,Martín Montecino,Tjasso Blokzijl,Klaas Nico Faber,María-Julieta González,Rodrigo Quera,Marcela A. Hermoso
出处
期刊:Cells
[MDPI AG]
日期:2022-06-12
卷期号:11 (12): 1905-1905
被引量:3
标识
DOI:10.3390/cells11121905
摘要
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.
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