Notch Signaling in Inflammation-Induced Preterm Labor.
Notch Signaling in Inflammation-Induced Preterm Labor.
复制标题
炎症引起的早产劳动的凹槽信号传导。
DOI：
10.1038/srep15221
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发表时间：
2015-10-16
影响因子：
4.6
通讯作者：
Hirsch E
中科院分区：
文献类型：
--
作者：
Jaiswal MK;Agrawal V;Pamarthy S;Katara GK;Kulshrestha A;Gilman-Sachs A;Beaman KD;Hirsch E
Notch信号在妊娠期先天免疫应答和滋养细胞功能调控中起重要作用。为了确定Notch信号在早产中的作用，我们在早产期间对Notch受体（Notch1-4）、其配体（DLL （delta -样蛋白）-1/3/4）、Jagged 1/2)和Notch诱导转录因子Hes1进行了评估。在妊娠第14.5天通过宫内（IU）注射肽聚糖（PGN）和多肌苷-胞酸（poly(I:C)）开始早产。PGN+poly（I:C）诱导早产时，子宫和胎盘中Notch1、Notch2、Notch4、dl1和Hes1的核定位明显升高。在体外，γ分泌酶抑制剂（GSI） （Notch受体加工抑制剂）显著降低PGN+poly（I:C）诱导的巨噬细胞中M1-和m2相关细胞因子的分泌，以及蜕膜细胞和胎盘细胞中促炎细胞因子（IFN-γ、TNF-α和IL-6）和趋化因子（mmp -1β）的分泌。相反，在PGN+poly（I:C）诱导的早产中，子宫和胎盘中的血管生成因子包括Notch配体Jagged 1/2、DLL-4和VEGF显著降低。注射后48小时，与对照组相比，体内GSI治疗可预防PGN+poly（I:C）诱导的早产55.5%，并显著增加宫内活胎数。综上所述，Notch信号在PGN+poly（I:C）诱导的早产过程中被激活，导致促炎反应上调，抑制Notch信号可改善活胎的宫内存活。
Notch signaling plays an important role in regulation of innate immune responses and trophoblast function during pregnancy. To identify the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligands (DLL (Delta-like protein)-1/3/4), Jagged 1/2) and Notch-induced transcription factor Hes1 were assessed during preterm labor. Preterm labor was initiated on gestation day 14.5 by intrauterine (IU) injection of peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C). Notch1, Notch2, Notch4, DLL-1 and nuclear localization of Hes1 were significantly elevated in uterus and placenta during PGN+poly(I:C)-induced preterm labor. Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch receptor processing) significantly diminished the PGN+poly(I:C)-induced secretion of M1- and M2-associated cytokines in decidual macrophages, and of proinflammatory cytokines (IFN-γ, TNF-α and IL-6) and chemokines (MIP-1β) in decidual and placental cells. Conversely, angiogenesis factors including Notch ligands Jagged 1/2 and DLL-4 and VEGF were significantly reduced in uterus and placenta during PGN+poly(I:C)-induced preterm labor. In vivo GSI treatment prevents PGN+poly(I:C)-induced preterm delivery by 55.5% and increased the number of live fetuses in-utero significantly compared to respective controls 48 hrs after injections. In summary, Notch signaling is activated during PGN+poly(I:C)-induced preterm labor, resulting in upregulation of pro-inflammatory responses, and its inhibition improves in-utero survival of live fetuses.