A Non-Infectious Mechanism for Pre-Term Delivery: Free Fetal DNA Sensed by Maternal TLR-9
AS Nugent, S Daly, S Corr, JJ O'Leary, LAJ O'Neill. The Coombe Women and Infants University Hospital, Dublin, Ireland; Trinity College Dublin, Dublin, Ireland
Background: Preterm delivery (PTD) is the largest contributor to the modern day perinatal mortality rates in developed countries. Although much research has gone into the causation of preterm labour, the rate of PTD has remained the same. In this study, we have investigated the potential for fetal DNA, which has been shown to be elevated in maternal blood of women who deliver premature, to cause an inflammatory response.
Design: Purified fetal DNA was used to stimulate Namalwa cells and female peripheral blood mononuclear cells(PBMCs) to measure NFK-B activation by immune blotting. IL-6 concentrations were also measured using ELISA. To test induction of TLR-9, choloroquin and synthetic inhibitory oligodinucleotides were used to block the action of TLR-9. Fetal DNA was then applied to TLR-9 deficient bone marrow derived macrophages. Findings were then applied to an in vivo mouse model.
Results: We show through that purified fetal DNA induces IκB degradation in female peripheral blood mononuclear cells (PBMC). The effect was inhibited by chloroquin and inhibitory oligodinucleotides which block CpG DNA. Fetal DNA induced IL-6 production for PBMC and bone marrow derived macrophages. This effect was not evident in TLR-9 deficient macrophages. When Fetal DNA was injected into mice at increasing concentrations, this was found to have a negative effect on carrying the pregnancy to term.
Conclusions: These results indicate that fetal DNA is an agonist for TLR-9. TLR-9 is present in maternal blood cells and free Fetal DNA is seen in elevated concentrations in mothers who deliver preterm. Fetal DNA induces the production of IL-6 which a key cytokine in the pathway to PTD. Studies in vivo also demonstrate that increasing doses of free Fetal DNA have a negative effect on pregnancy. Taken together, it is possible that Fetal DNA might provoke inflammation seen in PTD via TLR-9.
Category: Gynecologic & Obstetrics
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 127, Tuesday Afternoon