Department of Cell and Molecular Biology, The University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
Biol Open. 2022 Jul 15;11(7). doi: 10.1242/bio.059326. Epub 2022 Jul 25.
The nuclear factor-Kappa B (NF-κB) pathway is a crucial mediator of inflammatory signaling. Aberrant activation of NF-κB is associated with several disorders including preeclampsia (PE). Many regulators of the NF-κB pathway have been identified, including microRNAs (miRNAs). Specifically, miR-517-3p targets mRNA encoding TNFAIP3 Interacting Protein 1 (TNIP1), an inhibitor of NF-κB signaling. Activation of NF-κB increases production of the cytokine TNF superfamily member 15 (TNFSF15), leading to the upregulation of anti-angiogenic soluble vascular endothelial growth factor receptor 1 (sFlt-1). We have previously observed that Cajal bodies (CBs), subnuclear domains, are associated with the chromosome 19 miRNA gene cluster (C19MC), which encodes miR-517-3p. We have also found that coilin, the CB marker protein, is a positive regulator of miRNA biogenesis. Here we report that coilin is a regulator of miR-517-3p, sFlt-1, TNIP1, TNFSF15 and NF-κB activation, and this regulation is influenced by hypoxia. We also report that coilin and CBs are induced in the reduced uterine perfusion pressure (RUPP) rat model of PE. Collectively, the data presented here implicate coilin as a novel regulator of NF-κB activation and sFlt-1 upregulation.
核因子-κB（NF-κB）通路是炎症信号转导的关键介质。NF-κB 的异常激活与包括先兆子痫（PE）在内的几种疾病有关。已经确定了 NF-κB 通路的许多调节剂，包括 microRNAs（miRNAs）。具体而言，miR-517-3p 靶向编码 TNF 超家族成员 15（TNFSF15）的 mRNA，该基因编码 NF-κB 信号的抑制剂 TNFAIP3 相互作用蛋白 1（TNIP1）。NF-κB 的激活增加细胞因子 TNF 超家族成员 15（TNFSF15）的产生，导致抗血管生成可溶性血管内皮生长因子受体 1（sFlt-1）的上调。我们之前观察到 Cajal 体（CBs），亚核域，与染色体 19 miRNA 基因簇（C19MC）相关，该基因簇编码 miR-517-3p。我们还发现 coilin，CB 标记蛋白，是 miRNA 生物发生的正调节剂。在这里，我们报告 coilin 是 miR-517-3p、sFlt-1、TNIP1、TNFSF15 和 NF-κB 激活的调节剂，这种调节受缺氧的影响。我们还报告 coilin 和 CBs 在 PE 的减少子宫灌注压力（RUPP）大鼠模型中诱导。总之，这里提出的数据表明 coilin 是 NF-κB 激活和 sFlt-1 上调的新型调节剂。
