Lim Ratana, Barker Gillian, Lappas Martha
Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia.
Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Am J Reprod Immunol. 2017 Jul;78(1). doi: 10.1111/aji.12664. Epub 2017 Mar 24.
TNF-α plays a central role in the processes of human labour and delivery. This study sought to determine the role of the adaptor proteins TNFR1-associated death domain protein (TRADD), TNF receptor-associated factor 2 (TRAF2), receptor interacting protein 1 (RIP1) and transforming growth factor beta-activated kinase 1 (TAK1) in TNF-α-induced formation of pro-labour mediators.
Human primary myometrial cells were transfected with siRNA against TRADD (siTRADD), TRAF2 (siTRAF2), RIP1 (siRIP1) or TAK1 (siTAK1), treated with TNF-α, and assayed for pro-inflammatory mediators expression.
siTRADD, siTRAF2, siRIP1 and siTAK1 significantly decreased TNF-α-induced IL-1α, IL-1β, IL-6, IL-8, MCP-1 mRNA expression and release of IL-6, IL-8 and MCP-1; and cyclooxygenase (COX)-2 expression and release of prostaglandin PGF . There was a significant attenuation of TNF-α-induced expression of adhesion molecules ICAM-1 and VCAM-1 mRNA with siTRADD, siTRAF2 or siRIP1. siTRADD and siRIP1 significantly attenuated TNF-α-induced MMP-9 mRNA expression and release and nuclear factor κB (NF-κB) transcriptional activity. There was a significant increase in TNF-α-induced sVCAM-1 release, MMP-9 mRNA expression and NF-κB activity with siTAK1.
TRADD, TRAF2, RIP1 and TAK1 are involved in TNF-α signalling in human myometrium. Further studies are required to determine whether inhibition of these proteins can prevent preterm birth.
肿瘤坏死因子-α（TNF-α）在人类分娩过程中起核心作用。本研究旨在确定衔接蛋白肿瘤坏死因子受体1相关死亡结构域蛋白（TRADD）、肿瘤坏死因子受体相关因子2（TRAF2）、受体相互作用蛋白1（RIP1）和转化生长因子β激活激酶1（TAK1）在TNF-α诱导的促分娩介质形成中的作用。
用针对TRADD（siTRADD）、TRAF2（siTRAF2）、RIP1（siRIP1）或TAK1（siTAK1）的小干扰RNA（siRNA）转染人原代子宫肌层细胞，用TNF-α处理，然后检测促炎介质的表达。
siTRADD、siTRAF2、siRIP1和siTAK1显著降低了TNF-α诱导的白细胞介素-1α（IL-1α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、单核细胞趋化蛋白-1（MCP-1）mRNA表达以及IL-6、IL-8和MCP-1的释放；还降低了环氧化酶（COX）-2的表达以及前列腺素PGF的释放。siTRADD、siTRAF2或siRIP1显著减弱了TNF-α诱导的黏附分子细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）mRNA表达。siTRADD和siRIP1显著减弱了TNF-α诱导的基质金属蛋白酶-9（MMP-9）mRNA表达、释放以及核因子κB（NF-κB）转录活性。siTAK1使TNF-α诱导的可溶性血管细胞黏附分子-1（sVCAM-1）释放、MMP-9 mRNA表达和NF-κB活性显著增加。
TRADD、TRAF2、RIP1和TAK1参与人子宫肌层中的TNF-α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。
