Our previous research revealed that steroid receptor coactivators (Src)‐1 and ‐2 serve a critical cooperative role in production of parturition signals, surfactant protein A and platelet‐activating factor, by the developing mouse fetal lung (MFL). To identify the global landscape of genes in MFL affected by Src‐1/‐2 double‐deficiency, we conducted RNA‐seq analysis of lungs from 18.5 days post‐coitum (dpc) Src‐1−/−/‐2−/− (dKO) vs. WT fetuses. One of the genes most highly downregulated (~4.8 fold) in Src‐1/‐2 dKO fetal lungs encodes 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), which catalyzes conversion of inactive 11‐dehydrocorticosterone to the glucocorticoid receptor (GR) ligand, corticosterone. Glucocorticoids were reported to upregulate 11β‐HSD1 expression in various cell types via induction of C/EBP transcription factors. We observed that C/ebpα and C/ebpβ mRNA and protein were markedly reduced in Src‐1/‐2 double‐deficient (Src‐1/‐2d/d) fetal lungs, compared to WT. Moreover, glucocorticoid induction of 11β‐hsd1, C/ebpα and C/ebpβ in cultured MFL epithelial cells was prevented by the SRC family inhibitor, SI‐2. Cytokines also contribute to the induction of 11β‐HSD1. Expression of IL‐1β and TNFα, which dramatically increased toward term in lungs of WT fetuses, was markedly reduced in Src‐1/‐2d/d fetal lungs. Our collective findings suggest that impaired lung development and surfactant synthesis in Src‐1/‐2d/d fetuses are likely caused, in part, by decreased GR and cytokine induction of C/EBP and NF‐κB transcription factors. This results in reduced 11β‐HSD1 expression and glucocorticoid signaling within the fetal lung, causing a break in the glucocorticoid‐induced positive feedforward loop.

中文翻译：

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类固醇受体辅激活因子 (Src) ‐1/‐2 双缺陷胎鼠肺中 11β-羟基类固醇脱氢酶 1 的减少是由糖皮质激素和细胞因子信号传导受损引起的

我们之前的研究表明，类固醇受体共激活剂 (Src)-1 和 2 在发育中的小鼠胎肺 (MFL) 产生分娩信号、表面活性蛋白 A 和血小板激活因子方面发挥着关键的协同作用。为了确定受 Src-1/-2 双缺陷影响的 MFL 基因的全局图谱，我们从性交后 18.5 天 (dpc) Src-1-/-/-2-/- 对肺进行了 RNA-seq 分析(dKO) 与 WT 胎儿。Src-1/-2 dKO 胎儿肺中下调幅度最大的基因之一（~4.8 倍）编码 11β-羟基类固醇脱氢酶 1（11β-HSD1），该酶催化无活性的 11-脱氢皮质酮转化为糖皮质激素受体（GR）配体，皮质酮。据报道，糖皮质激素可通过诱导 C/EBP 转录因子上调各种细胞类型中 11β-HSD1 的表达。我们观察到，与 WT 相比，Src-1/-2 双缺陷 (Src-1/-2d/d) 胎儿肺中的 C/ebpα 和 C/ebpβ mRNA 和蛋白质显着降低。此外，SRC 家族抑制剂 SI-2 阻止了糖皮质激素对培养的 MFL 上皮细胞中 11β-hsd1、C/ebpα 和 C/ebpβ 的诱导。细胞因子也有助于 11β-HSD1 的诱导。IL-1β 和 TNFα 的表达在 WT 胎儿肺中向足月显着增加，而在 Src-1/-2d/d 胎儿肺中显着降低。我们的集体研究结果表明，Src-1/-2d/d 胎儿的肺发育和表面活性剂合成受损可能部分是由于 C/EBP 和 NF-κB 转录因子的 GR 和细胞因子诱导降低所致。这导致胎儿肺内 11β-HSD1 表达和糖皮质激素信号减少，