Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UPMC Magee-Women's Hospital, Pittsburgh, Pennsylvania.
Am J Perinatol. 2023 Oct;40(14):1585-1589. doi: 10.1055/s-0041-1739354. Epub 2021 Nov 16.
The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation.
We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages.
In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production.
In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB.
· 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..
在 Maternal-Fetal Medicine Unit（MFMU）Network 进行的 17α-羟孕酮己酸酯（17-OHPC）试验中，复发性自发性早产（PTB）的发生率降低了 33%，但 17 年后其作用机制仍难以捉摸。在曾有早产史的孕妇中，白细胞对脂多糖（LPS）刺激的白细胞介素-10（IL-10）反应的稳健性与分娩时的胎龄相关。本研究旨在确定 17-OHPC 浓度与 LPS 刺激反应之间是否存在关系。
我们对 Omega-3 MFMU 试验的数据进行了二次分析，该试验评估了ω-3 脂肪酸补充剂在减少复发性 PTB 中的有效性。我们利用了 Omega-3 试验中 IL-10 和肿瘤坏死因子-α（TNF-α）水平的亚分析中之前描述的数据，这些数据来自外周血单核细胞对 LPS 的刺激。在妊娠 16 至 22 周（基线）和 25 至 28 周（治疗后）时从入组妇女中获得血液。所有妇女均接受了 17-OHPC 治疗，并在 25 至 28 周时测量了血浆 17-OHPC 浓度。我们分析了这些数据以确定 17-OHPC 浓度与细胞因子产生之间是否存在关系。然后，我们进行了一项体外研究，以确定 17-OHPC 是否可以直接改变 THP-1 衍生的巨噬细胞产生的细胞因子。
在临床样本中，我们发现 17-OHPC 血浆浓度与 LPS 刺激的 IL-10 产生量相关。LPS 刺激后 TNF-α的产生与 17-OHPC 浓度无关。在体外研究中，我们证明了 17-OHPC 浓度依赖性地增加了 IL-10 的产生。
在接受 17-OHPC 预防 PTB 的妇女中，我们证明了循环白细胞中血浆 17-OHPC 与 LPS 刺激的 IL-10 产生之间存在关系。我们还证明，在体外，17-OHPC 处理会影响 LPS 刺激的巨噬细胞中 IL-10 的产生。这些发现共同支持 17-OHPC 在预防复发性 PTB 中的免疫调节作用机制。
在有复发性早产风险的妇女的临床样本中，17-OHPC 血浆浓度与 LPS 刺激的 IL-10 水平相关。
17-OHPC 可以调节 LPS 刺激的巨噬细胞对 IL-10 产生的反应，从而增加其产生。
在临床样本或体外均未发现 TNF-α与 17-OHPC 的血浆浓度之间存在关系。
