Department of Laboratory Medicine, Nantong Women and Children Health Care Hospital, Nantong, Jiangsu 226018, P.R. China.
Department of Obstetrics, Nantong Women and Children Health Care Hospital, Nantong, Jiangsu 226018, P.R. China.
Mol Med Rep. 2017 Nov;16(5):6368-6375. doi: 10.3892/mmr.2017.7348. Epub 2017 Aug 24.
Abnormal immune response resulting from disordered T helper (Th)1/Th2 and Th17/regulatory T cells (Treg) cytokine expression has been demonstrated to serve an important role in the pathogenesis of preeclampsia (PE). However, the role of transcription factors regulating Th cell differentiation contributing to PE remain unclear. To determine whether a decrease in the expression of the T cell lineage transcription factor T‑bet can restore immune balance and alleviate the systemic inflammatory response present in PE, 30 patients diagnosed with PE were assessed and compared with healthy pregnant controls. The expression of the transcription factors T‑bet and retinoic acid receptor‑related orphan receptor (ROR)γt were increased in the peripheral blood mononuclear cells of PE patients compared with controls, consistent with the presence of abnormally high T‑bet:GATA3 and RORγt:forkhead box (FOX) P3 ratios. The present study additionally identified a high‑efficiency, specific small interfering (si)RNA that can downregulate RORγt and T‑bet mRNA levels and inhibit protein expression. This effective siRNA was transfected into activated CD4+ T cells derived from patients with PE to observe the changes to transcription factor expression and attempt to elucidate the regulatory mechanism of T cell subsets. It was identified that knockdown of RORγt induced increased expression of FOXP3 and that the ratios of RORγt:FOXP3 and interleukin (IL)‑17A:IL‑10 were subsequently decreased. The results suggested that siRNA‑mediated knockdown of T‑bet regulated the immune balance of Th17/Tregs via changes to RORγt and FOXP3. When siRNA against RORγt and T‑bet were used in combination, a stronger ability to regulate immune balance was observed. These results imply that Th1‑ and Th17‑type immunity is dominant in PE and that the siRNA‑mediated knockdown of certain Th1 and Th17 cell transcription factors may be an effective therapeutic target for promoting immune balance in CD4+ T cell subgroups and ameliorating local and generalized inflammation in PE.
异常的免疫应答是导致先兆子痫（PE）发病机制的主要原因之一，其与辅助性 T 细胞（Th）1/Th2 和 Th17/调节性 T 细胞（Treg）细胞因子表达紊乱有关。然而，调节 Th 细胞分化的转录因子在 PE 中的作用仍不清楚。为了确定 T 细胞谱系转录因子 T 细胞激活蛋白（T-bet）表达减少是否可以恢复免疫平衡并减轻 PE 中存在的全身炎症反应，评估了 30 例被诊断为 PE 的患者，并与健康孕妇对照组进行了比较。与对照组相比，PE 患者外周血单个核细胞中 T-bet 和维甲酸受体相关孤儿受体（ROR）γt 的表达增加，这与异常高的 T-bet：GATA3 和 RORγt：叉头框（FOX）P3 比值一致。本研究还鉴定了一种高效、特异性的小干扰（si）RNA，可下调 RORγt 和 T-bet mRNA 水平并抑制蛋白表达。将该有效的 siRNA 转染至源自 PE 患者的活化 CD4+T 细胞中，以观察转录因子表达的变化，并尝试阐明 T 细胞亚群的调节机制。结果表明，敲低 RORγt 诱导 FOXP3 表达增加，并且 RORγt：FOXP3 和白细胞介素（IL）-17A：IL-10 的比值随后降低。结果表明，siRNA 介导的 T-bet 敲低通过改变 RORγt 和 FOXP3 调节 Th17/Treg 的免疫平衡。当使用针对 RORγt 和 T-bet 的 siRNA 联合使用时，观察到更强的调节免疫平衡的能力。这些结果表明，PE 中存在 Th1 和 Th17 型免疫应答，并且针对某些 Th1 和 Th17 细胞转录因子的 siRNA 介导的敲低可能是促进 CD4+T 细胞亚群免疫平衡和改善 PE 局部和全身炎症的有效治疗靶点。
