Barnea Eytan R, Hayrabedyan Soren, Todorova Krassimira, Almogi-Hazan Osnat, Or Reuven, Guingab Joy, McElhinney James, Fernandez Nelson, Barder Timothy
The Society for the Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ, USA; BioIncept LLC, Cherry Hill, NJ, USA.
Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Immunobiology. 2016 Jul;221(7):778-93. doi: 10.1016/j.imbio.2016.02.004. Epub 2016 Feb 23.
Secreted by viable embryos, PIF is expressed by the placenta and found in maternal circulation. It promotes implantation and trophoblast invasion, achieving systemic immune homeostasis. Synthetic PIF successfully transposes endogenous PIF features to non-pregnant immune and transplant models. PIF affects innate and activated PBMC cytokines and genes expression. We report that PIF targets similar proteins in CD14+, CD4+ and CD8+ cells instigating integrated immune regulation. PIF-affinity chromatography followed by mass-spectrometry, pathway and heatmap analysis reveals that SET-apoptosis inhibitor, vimentin, myosin-9 and calmodulin are pivotal for immune regulation. PIF acts on macrophages down-stream of LPS (lipopolysaccharide-bacterial antigen) CD14/TLR4/MD2 complex, targeting myosin-9, thymosin-α1 and 14-3-3eta. PIF mainly targets platelet aggregation in CD4+, and skeletal proteins in CD8+ cells. Pathway analysis demonstrates that PIF targets and regulates SET, tubulin, actin-b, and S100 genes expression. PIF targets systemic immunity and has a short circulating half-life. Collectively, PIF targets identified; protective, immune regulatory and cytoskeleton proteins reveal mechanisms involved in the observed efficacy against immune disorders.
PIF由存活胚胎分泌，在胎盘中表达并存在于母体循环中。它促进着床和滋养层细胞侵袭，实现全身免疫稳态。合成PIF成功地将内源性PIF的特性转移到非妊娠免疫和移植模型中。PIF影响天然和活化的外周血单个核细胞（PBMC）的细胞因子及基因表达。我们报告PIF作用于CD14 +、CD4 +和CD8 +细胞中的相似蛋白，从而激发整合免疫调节。通过PIF亲和层析，随后进行质谱分析、通路分析和热图分析发现，SET凋亡抑制剂、波形蛋白、肌球蛋白-9和钙调蛋白对免疫调节至关重要。PIF作用于脂多糖（细菌抗原）CD14/TLR4/MD2复合物下游的巨噬细胞，靶向肌球蛋白-9、胸腺素-α1和14-3-3η。PIF主要作用于CD4 +细胞中的血小板聚集以及CD8 +细胞中的骨架蛋白。通路分析表明，PIF靶向并调节SET、微管蛋白、肌动蛋白-b和S100基因的表达。PIF作用于全身免疫系统，且循环半衰期较短。总体而言，已确定PIF的作用靶点；其靶向的保护性、免疫调节性和细胞骨架蛋白揭示了其对免疫紊乱所观察到的疗效涉及的机制。
