期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：38
页码：13882-13887
DOI：10.1073/pnas.1411674111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSecreted from viable embryos into the maternal circulation, PreImplantation factor (PIF) has long been implicated in modulating maternal immune tolerance and promoting embryo implantation. Recent evidence also suggests its possible therapeutic use in CNS disorders. However, the molecular signal-transduction pathways driving PIF-mediated effects are unclear. Using murine cell culture combined with a rat hypoxic-ischemic brain injury model, we show that synthetic PIF (sPIF) inhibits microRNA let-7 biogenesis by destabilizing the key microRNA-processing protein, KH-type splicing regulatory protein, in a Toll-like receptor 4-dependent manner. This regulation, together with its induced upregulation of the anti-inflammatory cytokine IL-10, may contribute to sPIF-mediated neuroprotection in vivo and also may underlie PIF's physiological role in maternal immune modulation and embryo implantation. Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.
