Center for Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China.
BMC Med. 2024 Oct 8;22(1):432. doi: 10.1186/s12916-024-03650-2.
Parturition is an inflammation process. Exaggerated inflammatory reactions in infection lead to preterm birth. Although nuclear factor kappa B (NF-κB) has been recognized as a classical transcription factor mediating inflammatory reactions, those mediated by NF-κB per se are relatively short-lived. Therefore, there may be other transcription factors involved to sustain NF-κB-initiated inflammatory reactions in gestational tissues in infection-induced preterm birth.
Cebpd-deficient mice were generated to investigate the role of CCAAT enhancer-binding protein δ (C/EBPδ) in lipopolysaccharide (LPS)-induced preterm birth, and the contribution of fetal and maternal C/EBPδ was further dissected by transferring Cebpd or WT embryos to Cebpd or WT dams. The effects of C/EBPδ pertinent to parturition were investigated in mouse and human myometrial and amnion cells. The interplay between C/EBPδ and NF-κB was examined in cultured human amnion fibroblasts.
The mouse study showed that LPS-induced preterm birth was delayed by Cebpd deficiency in either the fetus or the dam, with further delay being observed in conceptions where both the dam and the fetus were deficient in Cebpd. Mouse and human studies showed that the abundance of C/EBPδ was significantly increased in the myometrium and fetal membranes in infection-induced preterm birth. Furthermore, C/EBPδ participated in LPS-induced upregulation of pro-inflammatory cytokines as well as genes pertinent to myometrial contractility and fetal membrane activation in the myometrium and amnion respectively. A mechanistic study in human amnion fibroblasts showed that C/EBPδ, upon induction by NF-κB, could serve as a supplementary transcription factor to NF-κB to sustain the expression of genes pertinent to parturition.
C/EBPδ is a transcription factor to sustain the expression of gene initiated by NF-κB in the myometrium and fetal membranes in infection-induced preterm birth. Targeting C/EBPδ may be of therapeutic value in the treatment of infection-induced preterm birth.
分娩是一个炎症过程。感染中过度的炎症反应会导致早产。虽然核因子-κB（NF-κB）已被认为是介导炎症反应的经典转录因子，但 NF-κB 本身介导的炎症反应持续时间相对较短。因此，在感染引起的早产中，妊娠组织中可能存在其他转录因子来维持 NF-κB 引发的炎症反应。
生成 Cebpd 缺陷小鼠以研究 CCAAT 增强子结合蛋白δ（C/EBPδ）在脂多糖（LPS）诱导的早产中的作用，并通过将 Cebpd 或 WT 胚胎转移到 Cebpd 或 WT 母鼠中来进一步剖析胎儿和母体 C/EBPδ 的作用。在小鼠和人子宫肌层和羊膜细胞中研究了 C/EBPδ 与分娩的关系。在培养的人羊膜成纤维细胞中研究了 C/EBPδ 与 NF-κB 的相互作用。
小鼠研究表明，无论是胎儿还是母体 Cebpd 缺陷，LPS 诱导的早产都会延迟，而当母体和胎儿都缺乏 Cebpd 时，延迟更为明显。小鼠和人类研究表明，感染诱导的早产中，子宫肌层和胎儿膜中 C/EBPδ 的丰度显著增加。此外，C/EBPδ 参与 LPS 诱导的促炎细胞因子以及与子宫肌层和羊膜中的子宫肌层收缩性和胎儿膜激活相关的基因的上调。在人羊膜成纤维细胞中的一项机制研究表明，C/EBPδ 在 NF-κB 诱导后，可作为 NF-κB 的补充转录因子，维持与分娩相关基因的表达。
C/EBPδ 是一种转录因子，可在感染诱导的早产中维持 NF-κB 启动的子宫肌层和胎儿膜中基因的表达。靶向 C/EBPδ 可能对治疗感染诱导的早产具有治疗价值。
