Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu, China.
Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu, China.
Cell Immunol. 2018 Dec;334:1-10. doi: 10.1016/j.cellimm.2018.08.009. Epub 2018 Aug 18.
The nuclear receptor Small Heterodimer Partner (SHP) is a transcriptional target and inhibitor of Liver Receptor Homolog 1 (LRH-1), the transcriptional regulator of intestinal glucocorticoid (GC) synthesis. The role of SHP in the regulation of intestinal GC synthesis and its impact on T cell-mediated anti-viral immune responses in the intestinal mucosa are currently not understood. Lymphocytic choriomeningitis virus (LCMV) infection promoted intestinal GC synthesis, which was enhanced in SHP-deficient mice. Intestinal GC suppressed the expansion and altered the activation of virus-specific T cells. In contrast, deletion of LRH-1 reduced intestinal GC synthesis and accelerated the expansion of cytotoxic T cells post LCMV infection. These findings show that virus-induced intestinal GC synthesis is controlled by LRH-1 and SHP, and that local steroidogenesis contributes to the maintenance of intestinal immune homeostasis. Thus, LRH-1-regulated intestinal GC synthesis could represent an interesting therapeutic target in the treatment of inflammatory disorders.
核受体 Small Heterodimer Partner（SHP）是肠内糖皮质激素（GC）合成的转录调控因子肝受体同源物 1（LRH-1）的转录靶标和抑制剂。目前尚不清楚 SHP 在调节肠道 GC 合成及其对肠道黏膜中 T 细胞介导的抗病毒免疫反应的影响。淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染促进了肠道 GC 的合成，而 SHP 缺陷小鼠中的这种合成增强了。肠道 GC 抑制了病毒特异性 T 细胞的扩增并改变了其激活。相比之下，LRH-1 的缺失减少了肠道 GC 的合成，并加速了 LCMV 感染后细胞毒性 T 细胞的扩增。这些发现表明，病毒诱导的肠道 GC 合成受 LRH-1 和 SHP 控制，局部类固醇生成有助于维持肠道免疫稳态。因此，LRH-1 调节的肠道 GC 合成可能成为治疗炎症性疾病的一个有趣的治疗靶点。
