title: TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynaecology, Coombe Women & Infants University Hospital, Dublin 8, Ireland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scharfe-Nugent
authors.forename: Sinéad C
authors.initials: SC
authors.lastname: Corr
authors.forename: Susan B
authors.initials: SB
authors.lastname: Carpenter
authors.forename: Louise
authors.initials: L
authors.lastname: Keogh
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Cara
authors.initials: C
authors.lastname: Martin
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Sean
authors.initials: S
authors.lastname: Daly
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Leary
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000097:blood / Q000235:genetics*; D005260:Female; D005313:Fetal Death / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects / Q000097:blood / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011225:Pre-Eclampsia / Q000453:epidemiology*; D011247:Pregnancy; D047928:Premature Birth / Q000453:epidemiology*; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA