Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis are devastating chronic immunopathologies of the intestinal mucosa, which are frequently treated by immunosuppressive glucocorticoids. Endogenous glucocorticoids are not only produced by the adrenal glands, but also by the intestinal epithelium. Local glucocorticoid synthesis critically contributes to the immune homeostasis of the intestinal mucosa. As defective intestinal glucocorticoid synthesis has been associated with the development of IBD, we investigated the expression of steroidogenic enzymes and the key transcriptional regulator Liver Receptor Homolog-1 (LRH-1/NR5A2) in ileal and colonic biopsies human pediatric IBD and control patients. Furthermore, the induction of steroidogenic enzymes and their transcriptional regulation by LRH-1 was investigated in a mouse model of experimental colitis. These analyses revealed that colitis-induced expression of steroidogenic enzymes in the murine colon is dependent on the presence of LRH-1, as intestinal deletion of LRH-1 strongly reduced their colitis-induced expression. Similarly, a strong correlation between the expression of LRH-1 and different steroidogenic enzymes was seen in intestinal biopsies of human pediatric patients. Importantly, reduced expression of hydroxysteroid dehydrogenase 11B1 (HSD11B1) was observed in IBD patients compared to control patients, suggesting that defective local reactivation of glucocorticoids could contribute to the pathogenesis of IBD.

中文翻译：

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小儿炎症性肠病患者的肠道糖皮质激素合成酶。

诸如克罗恩氏病和溃疡性结肠炎之类的炎症性肠病（IBD）是破坏性的肠粘膜慢性免疫病变，通常通过免疫抑制糖皮质激素治疗。内源性糖皮质激素不仅由肾上腺产生，而且由肠上皮产生。局部糖皮质激素的合成对肠道粘膜的免疫稳态起关键作用。由于肠道糖皮质激素的合成缺陷与IBD的发展有关，我们研究了在小儿IBD和对照患者的回肠和结肠活检中类固醇生成酶和关键转录调节因子肝受体Homolog-1（LRH-1 / NR5A2）的表达。此外，在实验性结肠炎的小鼠模型中研究了LRH-1对类固醇生成酶的诱导及其转录调控。这些分析表明，结肠炎诱导的鼠结肠中类固醇生成酶的表达取决于LRH-1的存在，因为肠道中LRH-1的缺失强烈降低了结肠炎诱导的表达。同样，在小儿患者的肠活检中，LRH-1的表达与不同的类固醇生成酶之间也存在很强的相关性。重要的是，与对照患者相比，在IBD患者中观察到羟类固醇脱氢酶11B1（HSD11B1）的表达降低，这表明糖皮质激素局部失活可能与IBD的发病有关。这些分析表明，结肠炎诱导的鼠结肠中类固醇生成酶的表达取决于LRH-1的存在，因为肠道中LRH-1的缺失强烈降低了结肠炎诱导的表达。同样，在小儿患者的肠活检中，LRH-1的表达与不同的类固醇生成酶之间也存在很强的相关性。重要的是，与对照患者相比，在IBD患者中观察到羟类固醇脱氢酶11B1（HSD11B1）的表达降低，这表明糖皮质激素的局部失活可能是IBD发病的原因。这些分析表明，结肠炎诱导的鼠结肠中类固醇生成酶的表达取决于LRH-1的存在，因为肠道中LRH-1的缺失强烈降低了结肠炎诱导的表达。同样，在小儿患者的肠活检中，LRH-1的表达与不同的类固醇生成酶之间也存在很强的相关性。重要的是，与对照患者相比，在IBD患者中观察到羟类固醇脱氢酶11B1（HSD11B1）的表达降低，这表明糖皮质激素局部失活可能与IBD的发病有关。在小儿患者的肠道活检中，LRH-1的表达与不同的类固醇生成酶之间存在很强的相关性。重要的是，与对照患者相比，在IBD患者中观察到羟类固醇脱氢酶11B1（HSD11B1）的表达降低，这表明糖皮质激素局部失活可能与IBD的发病有关。在小儿患者的肠道活检中，LRH-1的表达与不同的类固醇生成酶之间存在很强的相关性。重要的是，与对照患者相比，在IBD患者中观察到羟类固醇脱氢酶11B1（HSD11B1）的表达降低，这表明糖皮质激素局部失活可能与IBD的发病有关。