Reproductive Biology Laboratory, Amsterdam Reproduction and Development, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Department of Obstetrics and Gynaecology, Amsterdam Reproduction and Development, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Medicina (Kaunas). 2021 May 21;57(6):515. doi: 10.3390/medicina57060515.
: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. : RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. : Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. : We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.
: 针对涉及子宫静止向明显分娩过渡的分子因素的治疗干预措施并不能显著降低自发性早产的发生率。确定新的合理治疗靶点对于预防新生儿死亡的最常见原因至关重要。基于我们之前的工作表明 Tbx2（T-Box 转录因子 2）是小鼠子宫中孕酮撤退前的一个假定上游调节剂，我们现在研究 TBX2 在人子宫中的作用。：（A）早产人子宫组织样本的 RNA 微阵列分析和（B）体外过表达 TBX2 的子宫细胞，以及随后对（C）Chan 等人和（D）Sharp 等人的两个公开数据集的分析。通过 Luminex 测定法确定 TBX2 过表达对分泌到子宫细胞培养基中的细胞因子/趋化因子的影响。：分析表明，TBX2 在子宫细胞中的过表达导致 TNFα 和干扰素信号的下调。这种下调与先前与人类分娩相关的炎症途径相关的细胞因子和趋化因子的表达减少一致。相比之下，CXCL5（C-X-C 基序趋化因子配体 5）、CCL21 和 IL-6（白细胞介素 6）与分娩有关，似乎不受 TBX2 控制。对四个 mRNA 数据集的联合生物信息学分析确定了一组共同的上游调节剂，这些调节剂受 TBX2 控制，与早产和足月分娩都有关。令人惊讶的是，TBX2 mRNA 水平在早产收缩性子宫中增加。：我们确定了一组共同的上游调节剂，这些调节剂与早产和足月分娩都有关，在分娩时被激活，而被 TBX2 抑制。与在人工早产分娩期间采集的组织相比，在自发性早产剖宫产期间收集的子宫组织中 TBX2 mRNA 表达增加不符合生物信息模型。我们只能通过推测来解释这一点，即 TBX2 在人子宫中的体内活性不仅取决于 TBX2 的表达水平，还取决于 TBX2 活性所需的辅助蛋白的水平。
