Lappas Martha
Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Reprod Biol. 2017 Dec;17(4):333-340. doi: 10.1016/j.repbio.2017.09.006. Epub 2017 Oct 6.
Interleukin (IL)-1β plays a central role in the processes of human labour and delivery. The adaptor proteins involved in the IL-1β signalling pathway in human myometrium are not known. This study sought to determine the role of the adaptor proteins myeloid differentiation primary response 88 (MyD88), tumour necrosis factor receptor-associated factor 6 (TRAF6), IL-1 receptor-associated kinase 4 (IRAK4) and transforming growth factor beta-activated kinase 1 (TAK1) in IL-1β-induced formation of pro-inflammatory and pro-labour mediators in human myometrium. Human primary myometrial cells were transfected with siRNA against MyD88 (siMYD88), TRAF6 (siTRAF6), IRAK4 (siIRAK4) or TAK1 (siTAK1), treated with IL-1β, and assayed for the mRNA expression and or secretion of pro-inflammatory and pro-labour mediators. Transfection of primary myometrial cells with siMYD88, siTRAF6, siIRAK4 and siTAK1 significantly decreased IL-1β-induced IL-1α, IL-6, growth-regulated alpha protein (GRO-α), IL-8, monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and cyclooxygenase (COX)-2 mRNA expression and release of IL-6, GRO-α, IL-8, MCP-1, ICAM-1 and prostaglandin PGF. The expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase (MMP)-9 was significantly lower with siMYD88 and siTRAF6. Finally, IL-1β-induced nuclear factor κB (NF-κB) transcriptional activity was significantly attenuated by transfection with siMyD88, siTRAF6 and siIRAK4; there was no effect of siTAK1 transfection on NF-κB transcriptional activity. Collectively, these findings suggest that MyD88, TRAF6, IRAK4 and TAK1 are involved in IL-1β signalling in human myometrium. Further studies are required to determine if inhibition of these proteins can prevent preterm birth.
白细胞介素（IL）-1β在人类分娩过程中起核心作用。目前尚不清楚参与人子宫肌层中IL-1β信号通路的衔接蛋白。本研究旨在确定衔接蛋白髓样分化初级反应88（MyD88）、肿瘤坏死因子受体相关因子6（TRAF6）、IL-1受体相关激酶4（IRAK4）和转化生长因子β激活激酶1（TAK1）在IL-1β诱导人子宫肌层中促炎和促分娩介质形成中的作用。用针对MyD88（siMYD88）、TRAF6（siTRAF6）、IRAK4（siIRAK4）或TAK1（siTAK1）的小干扰RNA（siRNA）转染人原代子宫肌层细胞，用IL-1β处理，然后检测促炎和促分娩介质的mRNA表达及分泌情况。用siMYD88、siTRAF6、siIRAK4和siTAK1转染原代子宫肌层细胞可显著降低IL-1β诱导的IL-1α、IL-6、生长调节α蛋白（GRO-α）、IL-8、单核细胞趋化蛋白（MCP）-1、细胞间黏附分子（ICAM）-1和环氧化酶（COX）-2的mRNA表达以及IL-6、GRO-α、IL-8、MCP-1、ICAM-1和前列腺素PGF的释放。siMYD88和siTRAF6处理后，细胞外基质重塑酶基质金属蛋白酶（MMP）-9的表达和分泌显著降低。最后，用siMyD88、siTRAF6和siIRAK4转染可显著减弱IL-1β诱导的核因子κB（NF-κB）转录活性；siTAK1转染对NF-κB转录活性无影响。总的来说，这些发现表明MyD88、TRAF6、IRAK4和TAK1参与人子宫肌层中的IL-1β信号传导。需要进一步研究以确定抑制这些蛋白是否能预防早产。
