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

Abstract

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.

Colitis Induces Sex-Specific Intestinal Transcriptomic Responses in Mice

“…Several nuclear receptors were specifically downregulated in males (Vdr, Lrh1/Nr5a2, Mr/Nr3c2, Rev-erbβ/Nr1d2, Car/Nr1i3, Esrrg, Lxrα/Nr1h3) and have indeed been demonstrated to regulate key protective functions relating to colitis or CRC. This includes, for example, adherens junctions important for intestinal permeability (Vdr [ 23 ]), intestinal cortisol production (Lrh1 [ 24 ]), tumor-suppressive functions (Nr3c2 [ 25 ]), and suppression of CRC aggressiveness (Esrrg [ 26 ]). Importantly, Lxrα has been reported to inhibit proliferation of CRC cells and its overexpression to result in fewer and smaller intestinal tumors [ 27 ].…”

Pictolysin-III, a Hemorrhagic Type-III Metalloproteinase Isolated from Bothrops pictus (Serpentes: Viperidae) Venom, Reduces Mitochondrial Respiration and Induces Cytokine Secretion in Epithelial and Stromal Cell Lines

“…Briefly, a supernatant of cells exposed to treatments was incubated with a mixture of anti-cytokine capture antibodies-conjugated beads and PE-conjugated detector antibodies for 3 h at room temperature in the dark, subsequently washed with 1× wash buffer, and centrifuged at 200× g for 5 min at room temperature. Data was acquired using a FACS CantoTM II flow cytometer (BD) and analyzed using BD Cytometric Bead Array software (Version 1.4) (BD) as described [ 50 ].…”

Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research

“…In order to better predict when patients become resistant to glucocorticoid therapy and to be able to switch to a more effective therapy in time, validated biomarkers are necessary. In an elaborate study encompassing experiments on human patient samples, a mouse model, organoids and cell cultures, Landskron et al [ 12 ] investigated the relationship between glucocorticoid responsiveness and the induction of local cortisol production in the intestines of ulcerative colitis patients. They found increased cytoplasmic levels of the transcription factor LRH-1—which is known to be involved in intestinal steroidogenesis—in the intestinal cells of steroid-dependent and steroid-refractory patients, providing a possible explanation for the decreased local cortisol production in these patients.…”