Abstract 039: Normalization of Uterine Interleukin (IL)-15 in the BPH/5 Preeclamptic Mouse Improves Decidual Natural Killer Cell Activation at the Maternal-Fetal Interface

Abstract

Preeclampsia (PE) is a hypertensive disease that affects up to 10% of pregnancies worldwide. Although a leading cause of maternal and fetal morbidity/mortality, the cause is unknown. Inadequate remodeling of decidual vessels and reduced placental perfusion are hallmarks of PE. Decidual Natural Killer cells (dNKs) are critical in this process. Early in pregnancy, dNKs are activated by uterine IL-15 to promote angiogenesis at the maternal-fetal interface. Activated dNKs produce IFN-γ to facilitate vasodilation of decidual vessels. In the BPH/5 mouse model that spontaneously develops late gestation hypertension, proteinuria and placentopathies, we have demonstrated an early pregnancy reduction in dNK activation and IFN-γ mRNA at the maternal-fetal interface. We functionally linked uterine IL-15 overexpression to dNK loss in C57 mice. Here we tested the hypothesis that uterine IL-15 in BPH/5 mice contributes to dNK dysregulation at the maternal-fetal interface prior to placenta formation. BPH/5 e7.5 implantation sites show a 5-fold increase in IL-15 protein vs C57 (.7±.07vs.35±.17, n=4, p<.05). We have shown that Cox2 inhibition early in BPH/5 pregnancy improves fetoplacental development. Cox2-derived products influence expression of the pro-inflammatory cytokine, IL-15. To address if Cox2 inhibition alters IL-15 in BPH/5 implantation sites, celecoxib (a selective Cox2 inhibitor) was administered at e6.5 (10mg/kg orally). This normalized IL-15 in BPH/5 e7.5 implantation sites compared to C57 veh-treated (n=4, p<.05). Flow cytometry confirmed a 2-fold increase in DBA+/CD122+ (dNK) cell numbers in BPH/5 e7.5 implantation sites from celecoxib vs veh-treated mice (16.6 vs 7.95). Moreover, the dNKs from e7.5 BPH/5 celecoxib-treated implantation sites had a 2-fold increase in IFNγ mean fluorescent intensity vs BPH/5 veh-treated. This demonstrates that uterine IL-15 overexpression in BPH/5 contributes to dNK loss and that normalization improves dNK activation by increasing their expression of IFNγ at the maternal-fetal interface. This highlights the significance of uterine inflammation in dNK regulation and suggests that aberrations in these cellular processes in early pregnancy may contribute to the placentopathies seen in PE pregnancies.