Implications for the Pathogenesis and Prediction of Preeclampsia

摘要

First trimester human decidua is composed of decidual cells, CD56^b^r^i^g^h^tCD16^- decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell-derived IFN-@c and either macrophage-derived TNF-@a or IL-1@b synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-@c receptor 1 and 2 mediation via JAK/STAT and NF@kB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell-recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-@cR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56^b^r^i^g^h^tCD16^- pNK cells and intermediate CXCR3 levels on the majority of CD56^d^i^mCD16^+ pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age-matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia.