Department of Obstetrics and Gynaecology, Coombe Women & Infants University Hospital, Dublin 8, Ireland.
J Immunol. 2012 Jun 1;188(11):5706-12. doi: 10.4049/jimmunol.1103454. Epub 2012 Apr 27.
Preterm birth, the major cause of neonatal mortality in developed countries, is associated with intrauterine infections and inflammation, although the exact mechanisms underlying this event are unclear. In this study, we show that circulating fetal DNA, which is elevated in pregnancies complicated by preterm labor or preeclampsia, triggers an inflammatory reaction that results in spontaneous preterm birth. Fetal DNA activates NF-κB, shown by IκBα degradation in human PBMCs resulting in production of proinflammatory IL-6. We show that fetal resorption and preterm birth are rapidly induced in mice after i.p. injection of CpG or fetal DNA (300 μg/dam) on gestational day 10-14. In contrast, TLR9(-/-) mice were protected from these effects. Furthermore, this effect was blocked by oral administration of the TLR9 inhibitor chloroquine. Our data therefore provide a novel mechanism for preterm birth and preeclampsia, highlighting TLR9 as a potential therapeutic target for these common disorders of pregnancy.
早产是发达国家新生儿死亡的主要原因，与宫内感染和炎症有关，但这一事件的确切机制尚不清楚。在这项研究中，我们表明，循环胎儿 DNA 在由早产或先兆子痫引起的妊娠中升高，引发炎症反应，导致自发性早产。胎儿 DNA 激活 NF-κB，导致人 PBMCs 中 IκBα 降解，从而产生促炎细胞因子 IL-6。我们表明，在妊娠第 10-14 天经腹腔注射 CpG 或胎儿 DNA（300μg/只）后，小鼠会迅速发生胎儿吸收和早产。相比之下，TLR9(-/-) 小鼠则免受这些影响。此外，TLR9 抑制剂氯喹的口服给药可阻断这种作用。因此，我们的数据为早产和子痫前期提供了一种新的机制，强调 TLR9 是这些常见妊娠疾病的潜在治疗靶点。
