A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency

Vascular disease in the umbilical placental circulation is associated with fetal growth restriction and adverse outcome. It may be identified antenatally by the study of umbilical artery Doppler flow velocity waveforms. The cause of this vascular disease is unknown. We have previously provided indirect evidence for endothelial cell activation and a proinflammatory cytokine response. Recently, a family of inhibitors of cytokine signaling has been identified, referred to as the suppressors of cytokine signaling (SOCS). Activation of SOCS occurs when cytokines are produced in stimulated cells. We tested the hypothesis that endothelial cell activation was present in umbilical placental vascular disease and was associated with production of proinflammatory cytokines and members of the family of SOCS. Placentas were collected at delivery and microvascular endothelial cells were isolated. We studied 13 normal pregnancies and 10 with umbilical placental vascular disease identified by an abnormal umbilical artery Doppler study. Placental pieces were digested with collagenase and purified by adherence to Dynabeads coated with monoclonal antibody against CD31. The RNA was extracted from isolated endothelial cells. The messenger RNA expression of cytokine production (interleukin-6 and interleukin-8) and the members of SOCS family (CIS, SOCS1, SOCS2, and SOCS3) were assessed by use of semiquantitative reverse transcriptase–polymerase chain reaction. In the microcirculation of the placenta, endothelial cell expression of interleukin-6 messenger RNA (2.50±0.60 vs 1.25±0.26) and interleukin-8 messenger RNA (2.83±0.55 vs 1.58±0.27) was up-regulated in umbilical placental vascular disease in comparison to normal pregnancy. The endothelial cell mRNA expression of SOCS2 (3.36±0.77 vs 1.76±0.29) and SOCS3 (2.77±0.60 vs 1.48±0.26) was enhanced in placental vascular disease. There was no significant difference in expression of CIS and SOCS1 in microvessel endothelial cells. We have demonstrated that microvessel endothelium of the fetal placental vasculature produces both the proinflammatory cytokines (interleukin-6 and interleukin-8) and members of SOCS family (SOCS2 and SOCS3) in umbilical placental vascular disease. This cytokine production may play a key role in the interaction of endothelial cells of the placenta villi with neighboring cells. The up-regulation of SOCS2 and SOCS3 indicates these are the major negative regulators in umbilical placental microvessel endothelial cell activation pathways. By its occurrence, this also confirms the presence of a proinflammatory cytokine response.