Fetal plasma stimulates endothelial cell production of cytokines and the family of suppressor of cytokine signaling in umbilical placental vascular disease.
OBJECTIVE
We have shown that fetal plasma from pregnancies with placental vascular disease that were identified by an abnormal umbilical artery Doppler study causes endothelial cell activation. We investigated the hypothesis that this would be associated with endothelial cell production of cytokines and their natural regulators, the suppressor of cytokine signaling family. Activation of suppressor of cytokine signaling at the time of cytokine release confirms the fact that cytokine production is occurring in a stimulated cell.


METHODS
Aliquots from a common culture of human umbilical vein endothelial cells were incubated with fetal plasma from normal pregnancy (n = 29 pregnancies), from umbilical placental vascular disease defined by abnormal umbilical artery Doppler waveforms (n = 38 pregnancies), and from preeclampsia with normal umbilical artery Doppler scans (n = 10 pregnancies). The expression of messenger RNA for the cytokines interleukin-6 and interleukin-8 and the members of suppressor of cytokine signaling family (cytokine-inducible SH2-containing protein, suppressor of cytokine signaling 1, 2, and 3) were assessed by reverse transcriptase-polymerase chain reaction.


RESULTS
Endothelial cell expression of interleukin-6 messenger RNA (1.94 +/- 0.24 vs 1.31 +/- 0.16) and interleukin-8 messenger RNA (2.62 +/- 0.33 vs 1.64 +/- 0.22) were enhanced in response to incubation with fetal plasma from placental vascular disease in comparison to incubation with fetal plasma from normal pregnancy. The messenger RNA expression of suppressor of cytokine signaling-2 (2.03 +/- 0.23 vs 1.37 +/- 0.16) was up-regulated significantly in placental vascular disease. Differences for cytokine-inducible SH2-containing protein, suppressor of cytokine signaling-1, and suppressor of cytokine signaling-3 were not significant. The expression of cytokines and the suppressor of cytokine signaling family did not differ from normal in the group with maternal preeclampsia and a normal umbilical study. Interestingly, in the umbilical placental vascular disease group, the results were similar in the subgroups, with or without preeclampsia in the mother.


CONCLUSIONS
We have shown that factors that cause endothelial cell injury are present in the fetal circulation in umbilical placental vascular disease. This study is the first report of cytokine production and release and activation of the suppressor of cytokine signaling family by endothelial cells in response to fetal plasma in placental vascular disease. The role of all members of the suppressor of cytokine signaling family in this process must be investigated further. The fact that both the agonist (cytokines) and the antagonist (suppressor of cytokine signaling-2) are produced points to a significant role of endothelial cells in this disease.
Wang
Xin
X
Department of Obstetrics and Gynaecology, University of Sydney at Westmead Hospital, NSW, Australia.
Athayde
Neil
N
Trudinger
Brian
B
D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005312:Fetal Blood / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D010922:Placenta Diseases / Q000378:metabolism*; D011247:Pregnancy; D011256:Pregnancy Outcome; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014470:Umbilical Cord
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors