Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, United States.
Department of Obstetrics/Gynecology, Maternal-Fetal Medicine, University of Cincinnati, Cincinnati, OH, United States.
Front Immunol. 2024 Jun 4;15:1416162. doi: 10.3389/fimmu.2024.1416162. eCollection 2024.
IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP).
Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation.
IUI induced a robust expression of mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced mRNAs in the AMC and variably decreased elements of IL6 trans-signaling.
These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.
IL6 信号在引发分娩中起着重要作用，IL6 是宫内感染/炎症（IUI）驱动早产（PTL）的既定生物标志物。本研究在人类和非人灵长类动物（NHP）的样本中研究了 IUI 时母胎界面处 IL6 的生物学特性。
招募了胎盘组织学诊断为组织学绒毛膜羊膜炎的孕妇（n=28 例足月，n=43 例 26-36 周妊娠早产）。通过羊膜内注射脂多糖（LPS，n=23）诱导 NHP 的 IUI。使用 Anakinra（人 IL-1 受体拮抗剂，n=13）阻断 IL1 信号，使用抗 TNF 抗体（Adalimumab，n=14）阻断 TNF 信号。这些阻滞剂在 LPS 之前给予。所有动物（包括对照组，n=27，羊膜内注射生理盐水）在 LPS/生理盐水暴露后 16 小时，约在妊娠 80%时分娩。
IUI 在人类（足月和早产）和 NHP 的胎膜（绒毛膜-羊膜-蜕膜组织）中均诱导了 mRNA 的强烈表达。mRNA 表达的主要来源是羊膜间充质细胞（AMC）和蜕膜基质细胞。此外，在 NHP 的 IUI 中，胎膜中的 （一种裂解膜结合型 IL6 受体（IL6R）以释放可溶性形式的蛋白酶）和 mRNA 增加，且 IL6 和可溶性 IL6R 形式的比例，gp130 在羊水中增加，表明 IL6 转导信号的上调。IL1 和 TNF 阻断均抑制了 LPS 诱导的 AMC 中的 mRNAs，并不同程度地降低了 IL6 转导信号的元素。
这些数据表明，通过抑制母胎界面的 IL6 信号，IL1 和 TNF 阻滞剂可能是有用的抗炎药物。
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