Lu Yi, Zhou Qiong, Lu Jiang-Wen, Wang Wang-Sheng, Sun Kang
Center for Reproductive Medicine, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
Am J Reprod Immunol. 2019 Aug;82(2):e13150. doi: 10.1111/aji.13150. Epub 2019 Jun 18.
Cortisol, which is regenerated from biologically inactive cortisone by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human fetal membranes, may play an important role in human parturition. Recently, we have demonstrated that human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute-phase protein of inflammation, and SAA1 may be engaged in multiple actions associated with human parturition. It remains to be determined whether SAA1 can interact with cortisol in the regulation of 11β-HSD1 in the fetal membranes.
In the current study, we examined the regulation of 11β-HSD1 expression by SAA1, and the interaction between SAA1 and cortisol in the regulation of 11β-HSD1 expression in primary human amnion fibroblasts and amnion tissue.
Either SAA1 or cortisol induced 11β-HSD1 expression in a concentration-dependent manner. Combination of SAA1 and cortisol synergistically enhanced 11β-HSD1 expression. Mechanism studies revealed that SAA1 and cortisol induced the phosphorylation of the transcription factor STAT3 in a sequential order with the induction by SAA1 preceding the induction by cortisol. Furthermore, the induction of 11β-HSD1 expression by either SAA1 or cortisol or combination of SAA1 and cortisol was blocked by STAT3 inhibition with its antagonist S3I-201 or siRNA-mediated knockdown.
This study has demonstrated that SAA1 and cortisol can reinforce each other in the induction of 11β-HSD1 expression through sequential phosphorylation of STAT3. The synergistic enhancement of 11β-HSD1 expression by SAA1 and cortisol may lead to excessive cortisol accumulation in the fetal membranes at parturition.
在人胎膜中，11β-羟基类固醇脱氢酶1型（11β-HSD1）可将无生物活性的可的松转化为皮质醇，皮质醇可能在人类分娩过程中发挥重要作用。最近，我们已经证明人胎膜能够从头合成血清淀粉样蛋白A1（SAA1），一种炎症急性期蛋白，并且SAA1可能参与了与人类分娩相关的多种作用。SAA1在胎膜中11β-HSD1的调节过程中是否能与皮质醇相互作用仍有待确定。
在本研究中，我们检测了SAA1对11β-HSD1表达的调节作用，以及在原代人羊膜成纤维细胞和羊膜组织中，SAA1与皮质醇在11β-HSD1表达调节中的相互作用。
SAA1和皮质醇均以浓度依赖的方式诱导11β-HSD1表达。SAA1与皮质醇联合使用可协同增强11β-HSD1表达。机制研究表明，SAA1和皮质醇按顺序诱导转录因子STAT3磷酸化，SAA1的诱导作用先于皮质醇。此外，用其拮抗剂S3I-201抑制STAT3或通过siRNA介导的敲低来抑制STAT3，均可阻断SAA1、皮质醇或SAA1与皮质醇联合使用对11β-HSD1表达的诱导作用。
本研究表明，SAA1和皮质醇可通过STAT3的顺序磷酸化在诱导11β-HSD1表达方面相互增强。SAA1和皮质醇对11β-HSD1表达的协同增强作用可能导致分娩时胎膜中皮质醇过度积累。
