1Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
Sci Signal. 2014 Feb 25;7(314):ra20. doi: 10.1126/scisignal.2004786.
Intestinal crypt epithelial cells synthesize glucocorticoids, steroid hormones that protect against inflammatory bowel disease. To investigate how intestinal glucocorticoids are regulated during chronic inflammation, we induced chronic colitis in mice by exposing them to the chemical dextran sulfate sodium (DSS). We found that intestinal glucocorticoid secretion and expression of the genes Cyp11a1 and Cyp11b1 (which encode enzymes that synthesize glucocorticoids) were initially stimulated, but declined during the chronic phase, whereas tumor necrosis factor (TNF) and inflammatory cytokines secreted by T helper type 1 (TH1) and TH17 cells continuously increased in abundance in the inflamed colon. This suggested that inadequate intestinal glucocorticoid synthesis is a feature of chronic intestinal inflammation. We screened for cytokines that regulated intestinal glucocorticoid synthesis and found that TNF suppressed corticosterone secretion and Cyp11a1 and Cyp11b1 expression in an intestinal crypt epithelial cell line. TNF suppressed steroidogenesis by activating the transcription factors c-Jun and nuclear factor κB (NF-κB), which both interacted with the transcription factor NR5A2 and repressed Cyp11a1 reporter activity. This repression was relieved by expression of a dominant-negative form of c-Jun amino-terminal kinase 1 (JNK1), inhibitor of NF-κB, or by a JNK inhibitor. Furthermore, the dominant-negative TNF inhibitor XPro1595 inhibited c-Jun and NF-κB activation in mice, restored intestinal Cyp11a1 and Cyp11b1 expression, reduced colonic cell death, and rescued chronic colitis caused by DSS. Thus, during chronic colitis, TNF suppresses intestinal steroidogenic gene expression by inhibiting the activity of NR5A2, thus decreasing glucocorticoid synthesis and sustaining chronic inflammation.
肠隐窝上皮细胞合成糖皮质激素，这是一种保护免受炎症性肠病的类固醇激素。为了研究慢性炎症期间肠道糖皮质激素是如何调节的，我们通过暴露于化学物质葡聚糖硫酸钠（DSS）来诱导小鼠慢性结肠炎。我们发现，肠道糖皮质激素的分泌和 Cyp11a1 和 Cyp11b1（编码合成糖皮质激素的酶）的基因表达最初受到刺激，但在慢性期下降，而肿瘤坏死因子（TNF）和辅助性 T 细胞 1（TH1）和 TH17 细胞分泌的炎症细胞因子在发炎的结肠中不断增加。这表明肠道糖皮质激素合成不足是慢性肠道炎症的特征。我们筛选了调节肠道糖皮质激素合成的细胞因子，发现 TNF 通过激活转录因子 c-Jun 和核因子 κB（NF-κB）来抑制皮质酮的分泌和 Cyp11a1 和 Cyp11b1 的表达，这两种转录因子都与转录因子 NR5A2 相互作用并抑制 Cyp11a1 报告基因活性。表达 c-Jun 氨基末端激酶 1（JNK1）的显性负形式、NF-κB 的抑制剂或 JNK 抑制剂可缓解这种抑制。此外，显性负 TNF 抑制剂 XPro1595 抑制了小鼠中 c-Jun 和 NF-κB 的激活，恢复了肠道 Cyp11a1 和 Cyp11b1 的表达，减少了结肠细胞死亡，并挽救了由 DSS 引起的慢性结肠炎。因此，在慢性结肠炎中，TNF 通过抑制 NR5A2 的活性抑制肠道甾体生成基因的表达，从而减少糖皮质激素的合成并维持慢性炎症。
