Abstract
Increased neutrophil–endothelial binding and inflammatory responses are significant pathophysiological events in the maternal vascular system in preeclampsia, a hypertensive disorder in human pregnancy. Interleukin 6 (IL-6) and its soluble receptors (soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)) are critical inflammatory mediators. During pregnancy, maternal IL-6 and sgp130 levels were increased, but sIL-6R levels were decreased, in women with preeclampsia compared to normotensive pregnant women. However, little is known about differences in IL-6, sIL-6R, and sgp130 production by neutrophils and endothelial cells between normal pregnancy and preeclampsia. To study this, we isolated neutrophils and cultured human umbilical vein endothelial cells (HUVECs) from normal and preeclamptic pregnancies. Production of IL-6, sIL-6R, and sgp130 was measured. The role of placental factor(s)-mediated neutrophil production of IL-6, sIL-6R, and sgp130 was also determined by pretreating neutrophils with placental conditioned medium generated from placental villous cultures. We found that IL-6 and sgp130 were mainly produced by endothelial cells, while sIL-6R was mainly produced by neutrophils. Endothelial cells from preeclampsia produced significantly more IL-6 and sgp130, and neutrophils from preeclampsia produced significantly less sIL-6R than normal pregnancy cells. Interestingly, production of IL-6, sIL-6R, and sgp130 were time-dependently increased when neutrophils and endothelial cells were co-cultured. We also found that neutrophils from normal pregnancies produced more IL-6, but less sIL-6R, after being primed by preeclamptic-placental conditioned medium. These results demonstrated that neutrophils and endothelial cells have different capacities in producing IL-6, sIL-6R, and sgp130 between normal pregnancy and preeclampsia. These results also provide evidence that the placenta plays a role in inducing neutrophil activation in preeclampsia.
Highlights
In the vascular system, endothelial cells and circulating neutrophils are major components of the systemic response to inflammation
We found that increased Interleukin 6 (IL-6) and sgp130 levels are associated with reduced suppressor of cytokine signaling-3 (SOCS-3) expression in both maternal vessel endothelium and circulating neutrophils in preeclampsia [11]
We first determined IL-6, soluble IL-6R (sIL-6R), and sgp130 production by neutrophils and endothelial cells derived from normal pregnant subjects
Summary
Endothelial cells and circulating neutrophils are major components of the systemic response to inflammation. An excessive inflammatory phenotype is a central pathophysiological event in the vascular system in preeclampsia [1], a hypertensive, and multi-system disorder unique to human pregnancy. Preeclampsia is characterized by maternal hypertension and proteinuria after 20 weeks of gestation. Maternal levels of inflammatory mediators, such as inflammatory cytokines interleukin 6 (IL-6), IL-8, and tumor necrosis factor-α (TNFα) [2,3,4], and endothelial adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1 (VCAM-1), and P-selectin [5,6] are elevated. Neutrophil adhesion molecules CD11b, CD64, and L-selectin are significantly increased in women with 4.0/).
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