Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.
Biol Reprod. 2019 Jun 1;100(6):1617-1629. doi: 10.1093/biolre/ioz041.
Untimely activation of the inflammatory response by sterile or infective insults in uterine tissues can result in preterm birth. Pro-inflammatory cytokines and pathogenic activation of toll-like receptors (TLRs) initiate a biochemical cascade of events leading to myometrial activation and contractility, cervical dilatation, and rupture of the chorioamniotic membranes. GIT2 is a signaling protein known to play a role in innate and adaptive immunity; however, its role in the inflammatory pathways of human labor is not known. In this article, we report that GIT2 expression is lower in human myometrium and fetal membranes with term labor, and in preterm amnion with histological chorioamnionitis. GIT2 knockdown by siRNA in primary myometrial and amnion cells exhibited reduced expression of pro-inflammatory cytokines and chemokines in response to inflammatory challenge by cytokines or TLR ligands. In addition, the pro-inflammatory cytokines IL1B and TNF could not induce the expression of extracellular matrix degrading enzymes in GIT2-deficient amnion cells. Myometrial activation in response to pro-inflammatory cytokines was also significantly suppressed in GIT2-deficient cells as evidenced by decreased prostaglandin release and expression of contraction-associated proteins. Further to this, collagen gel assays demonstrated that TNF had a reduced ability to induce myometrial contractility in situ in GIT2-deficient myometrial cells compared to control-transfected cells. In summary, the loss of GIT2 diminishes the effects inflammatory mediators have in promoting myometrial contraction and fetal membrane rupture in vitro, suggesting that GIT2 could be a possible target for preterm birth therapies.
无菌或感染性损伤导致的子宫组织炎症反应的过早激活，可能导致早产。促炎细胞因子和 Toll 样受体 (TLR) 的致病性激活，引发一系列生化事件，导致子宫肌层激活和收缩、宫颈扩张以及绒毛膜羊膜破裂。GIT2 是一种已知在先天和适应性免疫中发挥作用的信号蛋白，但它在人类分娩的炎症途径中的作用尚不清楚。在本文中，我们报告 GIT2 的表达在足月分娩的人子宫肌层和胎膜中较低，在有组织学绒毛膜羊膜炎的早产羊膜中也较低。用 siRNA 敲低原代子宫肌层和羊膜细胞中的 GIT2 表达，可降低促炎细胞因子和趋化因子的表达，对细胞因子或 TLR 配体的炎症刺激作出反应。此外，GIT2 缺陷型羊膜细胞中，促炎细胞因子 IL1B 和 TNF 不能诱导细胞外基质降解酶的表达。用促炎细胞因子刺激子宫肌层，在 GIT2 缺陷型细胞中也明显受到抑制，表现为前列腺素释放减少和收缩相关蛋白表达减少。进一步的，胶原凝胶试验表明，与对照转染细胞相比，TNF 在 GIT2 缺陷型子宫肌层细胞中诱导原位子宫肌层收缩的能力降低。总之，GIT2 的缺失减少了炎症介质在体外促进子宫肌层收缩和胎膜破裂的作用，表明 GIT2 可能是治疗早产的一个潜在靶点。
