Portal de Periódicos da CAPES

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

2022; Multidisciplinary Digital Publishing Institute; Volume: 11; Issue: 12 Linguagem: Inglês

10.3390/cells11121905

2073-4409

Glauben Landskron, Karen Dubois-Camacho, Octavio Orellana‐Serradell, Marjorie De la Fuente, Daniela Parada-Venegas, Mirit Bitrán, David Díaz-Jiménez, Shuang Tang, John A. Cidlowski, Xiaoling Li, Hector Molina, Carlos González, Daniela Simian, Jaime Lubascher, Víctor Pola, Martı́n Montecino, Tjasso Blokzijl, Klaas Nico Faber, María-Julieta González, Rodrigo Quera, Marcela A. Hermoso,

Immune Cell Function and Interaction

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.