Ozmen Asli, Guzeloglu-Kayisli Ozlem, Tabak Selcuk, Guo Xiaofang, Semerci Nihan, Nwabuobi Chinedu, Larsen Kellie, Wells Ali, Uyar Asli, Arlier Sefa, Wickramage Ishani, Alhasan Hasan, Totary-Jain Hana, Schatz Frederick, Odibo Anthony O, Lockwood Charles J, Kayisli Umit A
Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, United States.
Front Cell Dev Biol. 2022 Jun 28;10:898088. doi: 10.3389/fcell.2022.898088. eCollection 2022.
Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 () as the only gene affected by both IL-6 plus IL-11 vs. control or IL-6 or IL-11 treatment of primary human cytotrophoblast cultures. immunostaining was specific to EVTs among other trophoblast types in the first and third trimester placental specimens, and significantly lower levels were observed in EVT from PE vs. GA-matched control placentae ( = 0.006). Induction of primary trophoblastic stem cell cultures toward EVT linage increased mRNA levels by 7.8-fold ( = 0.004). silencing in HTR8/SVneo cultures, a first trimester EVT cell line, inhibited invasion, proliferation, expression of (a cell migration receptor) and filamentous actin while increasing expression of (a receptor for hemi-desmosomal adhesion). Moreover, silencing further enhanced levels of IL-1β-induced pro-inflammatory cytokines (, and ) in HTR8/SVneo cells. Collectively, these results indicate that acts as a critical regulator of EVT morphology and function and that diminished expression is associated with PE, potentially mediating reduced interstitial trophoblast invasion and enhancing local inflammation at the maternal-fetal interface. Thus, agents inducing expression may provide a novel therapeutic approach in PE.
在几种白细胞介素（IL）-6家族成员中，由于IL-6受体（IL-6R）和IL-11受体缺乏细胞内信号结构域，只有IL-6和IL-11需要gp130蛋白同二聚体进行细胞内信号传导。我们之前报道过，与孕周（GA）匹配的对照组相比，子痫前期（PE）患者母胎界面处蜕膜IL-6和IL-11水平升高，相邻间质滋养层细胞中膜周IL-6免疫染色显著增强。这使我们推测，这些细胞因子与gp130的竞争性结合会损害绒毛外滋养层（EVT）的分化、增殖和/或侵袭。通过全基因组微阵列分析，本研究发现，在原代人细胞滋养层培养物中，干扰素刺激基因15（）的抑制是受IL-6加IL-11与对照组或IL-6或IL-11处理影响的唯一基因。在孕早期和孕晚期胎盘标本的其他滋养层类型中，免疫染色对EVT具有特异性，与GA匹配的对照胎盘的EVT相比，PE患者的EVT中水平显著降低（ = 0.006）。原代滋养层干细胞培养物向EVT谱系的诱导使mRNA水平增加了7.8倍（ = 0.004）。在孕早期EVT细胞系HTR8/SVneo培养物中沉默，可抑制侵袭、增殖、（一种细胞迁移受体）和丝状肌动蛋白的表达，同时增加（半桥粒黏附受体）的表达。此外，沉默进一步增强了HTR8/SVneo细胞中IL-1β诱导的促炎细胞因子（、和）的水平。总体而言，这些结果表明，作为EVT形态和功能的关键调节因子，其表达降低与PE相关，可能介导间质滋养层侵袭减少并增强母胎界面处的局部炎症。因此，诱导表达的药物可能为PE提供一种新的治疗方法。
