Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.
Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Reproduction. 2018 Sep;156(3):207-218. doi: 10.1530/REP-18-0140. Epub 2018 Jul 13.
Preterm birth continues to be the leading cause of neonatal mortality and morbidities that can extend into adult life. Few treatment options stem from our incomplete understanding of the mechanisms of human labour and delivery. Activation of the inflammatory response in gestational tissues by inflammation and/or infection leads to the production of pro-inflammatory and pro-labour mediators, thus preterm birth. Interferon regulatory factor 5 (IRF5) has recently emerged as an important pro-inflammatory transcription factor involved in acute and chronic inflammation. The aims of this study were to determine the expression of IRF5 in human myometrium from labouring and non-labouring women, and whether IRF5 is involved in the genesis of pro-inflammatory and pro-labour mediators induced by pro-inflammatory cytokines or toll-like receptor (TLR) ligands. IRF5 mRNA and protein expression was significantly higher in human myometrium after spontaneous term labour, compared to non-labouring tissues. mRNA expression was also significantly higher in primary myometrial cells treated with the pro-inflammatory cytokines IL1B or TNF. In primary myometrial cells, IRF5 knockdown by siRNA (siIRF5) was associated with significantly decreased expression and or secretion of pro-inflammatory cytokines (IL1A, IL6), chemokines (CXCL8, CCL2), adhesion molecules (ICAM1, VCAM1) and contraction-associated proteins , PGF and when in the presence of IL1B, TNF, fsl-1 (TLR2/6 ligand) or flagellin (TLR5 ligand). siIRF5-transfected cells also displayed decreased NF-κB RELA transcriptional activity in the presence of these preterm birth mediators. Our study suggests a novel role for IRF5 in the regulation of the inflammatory response in human myometrium.
早产仍是导致新生儿死亡和发病的主要原因，这些发病可能会延续到成年。由于我们对人类分娩机制的了解不完整，因此很少有治疗选择。炎症和/或感染引起的妊娠组织炎症反应激活会导致促炎和促分娩介质的产生，从而导致早产。干扰素调节因子 5（IRF5）最近已成为涉及急性和慢性炎症的重要促炎转录因子。本研究的目的是确定 IRF5 在分娩和非分娩妇女的人子宫肌中的表达，以及 IRF5 是否参与由促炎细胞因子或 Toll 样受体（TLR）配体诱导的促炎和促分娩介质的产生。与非分娩组织相比，自发性足月分娩后，人子宫肌中的 IRF5 mRNA 和蛋白表达显着升高。用促炎细胞因子 IL1B 或 TNF 处理的原代子宫平滑肌细胞的 mRNA 表达也显着升高。在原代子宫平滑肌细胞中，siRNA（siIRF5）介导的 IRF5 敲低与促炎细胞因子（IL1A、IL6）、趋化因子（CXCL8、CCL2）、粘附分子（ICAM1、VCAM1）和收缩相关蛋白 PGF 和 的表达和/或分泌显着降低，当存在 IL1B、TNF、fsl-1（TLR2/6 配体）或 flagellin（TLR5 配体）时。在这些早产介质存在的情况下，转染 siIRF5 的细胞的 NF-κB RELA 转录活性也降低。我们的研究表明 IRF5 在人子宫肌中炎症反应的调节中具有新的作用。
