Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-α: Implications in preeclampsia (PE).
There is a consensus that factors released by the placenta to maternal circulation, including TNF-α, play a key role in activating the maternal endothelium in pregnancies with preeclampsia (PE). Dual perfusion preserves the structural organization of the placenta to a greater degree than other in vitro systems and has been used by our group and others to examine placental pathophysiology associated with PE. The objective of this study was to use the dual perfusion model to test whether TNF-α released by the placenta to maternal perfusate affects pro-inflammatory cytokine secretion by, and activation of, endothelial cells, thereby furthering our understanding of placental and endothelial dysfunction in PE.



We used maternal perfusate, two endothelial cell lines (HUVECs and HEECs), and a TNF-α blocking antibody to test whether placental-derived TNF-α plays a significant role in altering the expression and secretion of pro-inflammatory cytokines in endothelial cells as well as the expression of activation markers in this cell type.



The presence of maternal perfusate significantly enhanced IL-6, IL-8, and MCP-1 secretion, levels of their mRNA, as well as mRNA levels of markers of endothelial activation (E-selectin, ICAM-1, and VCAM-1). The addition of a TNF-α blocking antibody significantly inhibited the maternal perfusate-mediated enhancement of cytokine secretion by, and expression of activation markers, in both HUVECs and HEECs.



These results demonstrate that TNF-α significantly contributed to endothelial cell pro-inflammatory cytokine secretion and activation suggesting that blocking TNF-α action may mitigate the effects of maternal endothelial dysfunction in PE.
Obstetrics, Gynecology, & Reproductive Sciences, Yale School of Medicine, United States.
Jeff
J
Shaw
Obstetrics, Gynecology, & Reproductive Sciences, Yale School of Medicine, United States.
Zhonghua
Z
Tang
Department of Obstetrics & Gynecology, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Henning
H
Schneider
OB/GYN, Institute of Clinical Sciences, Lund University, Lund, Sweden; Department of Clinical Pharmacology, University Medicine, Greifswald, Germany.
Karen
K
Saljé
OB/GYN, Institute of Clinical Sciences, Lund University, Lund, Sweden.
Stefan R
SR
Hansson
Obstetrics, Gynecology, & Reproductive Sciences, Yale School of Medicine, United States. Electronic address: seth.guller@yale.edu.
Seth
S
Guller
D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D019040:E-Selectin; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
Endothelium; Inflammation; Placental secretion; Preeclampsia; TNF-α