Activation of NF-κB in Placentas of Women with Preeclampsia

Vaughan, John E.; Walsh, Scott W.

doi:10.3109/10641955.2011.642436

Cited by 116 publications

(97 citation statements)

References 37 publications

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“…We demonstrate that CTBs treated with poly I:C as well as placentas from P-PIC mice have elevated levels of NF-κBp50 whereas P-PIC TLR3 KO placentas exhibit no change in expression of NF-κBp50 or HIF-1α. NF-κB levels were also increased in placentas of PE women compared to normotensive women as detected by immunohistochemistry [47]. Taken together our data suggests that both of these transcription factors are up-regulated following TLR3 activation and that their interplay contributes to miR-210 transcriptional up-regulation.…”

Section: Discussionsupporting

confidence: 66%

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

et al. 2013

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Several clinical studies have reported increased placental miR-210 expression in women with PE compared to normotensive women, but whether miR-210 plays a role in the etiology of PE is unknown. We reported that activation of TLR3 produces the PE-like symptoms of hypertension, endothelial dysfunction, and proteinuria in mice only when pregnant, but whether TLR3 activation in pregnant mice and human cytotrophoblasts (CTBs) increases miR-210 and modulates its targets related to inflammation are unknown. Placental miR-210 levels were increased significantly in pregnant mice treated with the TLR3 agonist poly I:C (P-PIC). Both HIF-1α and NF-κBp50, known to bind the miR-210 promoter and induce its expression, were also increased significantly in placentas of P-PIC mice. Target identification algorithms and gene ontology predicted STAT6 as an inflammation-related target of miR-210 and STAT6 was decreased significantly in placentas of P-PIC mice. IL-4, which is regulated by STAT6 and increases during normotensive pregnancy, failed to increase in serum of P-PIC mice. P-PIC TLR3 KO mice did not develop hypertension and placental HIF-1α, NF-κBp50, miR-210, STAT6, and IL-4 levels were unchanged. To determine the placental etiology, treatment of human CTBs with poly I:C significantly increased HIF-1α, NF-κBp50, and miR-210 levels and decreased STAT6 and IL-4 levels. Overexpression of miR-210 in CTBs decreased STAT6 and IL-4 while inhibition of miR-210 increased STAT6 and IL-4. These findings demonstrate that TLR3 activation induces placental miR-210 via HIF-1α and NF-κBp50 leading to decreased STAT6 and IL-4 levels and this may contribute to the development of PE.

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Section: Discussionsupporting

confidence: 66%

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

et al. 2013

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“…Indeed, activation of NF-κB in placentas and leukocytes of women with preeclampsia has been reported. 20-21 We also found that activation of the MAPK pathways, specifically p38 kinase, is essential for sFlt-1 production from PMAs. Others have investigated the MAPK pathways in placentas taken from women with preeclampsia.…”

Section: Commentmentioning

confidence: 63%

Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia

Major¹,

Campbell²,

Silver³

et al. 2014

American Journal of Obstetrics and Gynecology

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Objective Soluble fms-like tyrosine kinase (sFlt-1) is an important mediator in the pathogenesis of preeclampsia. We sought to determine if platelet-monocyte aggregates (PMAs) produced sFlt-1 and if PMAs contributed to sFlt-1 production in preeclampsia. Study Design Case-control study of sFlt-1 release from PMAs using blood samples from women with preeclampsia matched by gestational age to pregnant controls. A third group of nonpregnant, reproductive-age women comprised an additional control group. Experiments were also performed using blood from non-pregnant women to elucidate if inducing PMAs could stimulate sFlt-1 production, and if so, to determine the necessary receptors and pathways. Results Women with preeclampsia had increased total Flt-1 concentrations in platelets and monocytes at baseline compared to pregnant controls (25 vs. 10 pg/ml, p=0.0003). sFlt-1 production was elicited from monocytes incubated with thrombin-activated platelets from non-pregnant women. sFlt-1 production was regulated at the transcriptional level by p38 and NF-κB dependent pathways. Conclusion Activated platelets in preeclampsia bind monocytes to generate sFlt-1. PMAs are a previously unrecognized source of sFlt-1 that may contribute to endothelial dysfunction and systemic inflammation commonly observed in preeclampsia.

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“…On the other hand, survivin is one of the genes repressed at the transcriptional level by p53 [48,49]. In preeclamptic placentas, NF-κB, IGF-1 and STAT3 are up-regulated [50–52], which cannot explain the decrease in the survivin gene. Intriguingly, p53 is increased in preeclampsia [20].…”

Section: Discussionmentioning

confidence: 99%

Function of Survivin in Trophoblastic Cells of the Placenta

et al. 2013

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BackgroundPreeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide and its pathogenesis is not totally understood. As a member of the chromosomal passenger complex and an inhibitor of apoptosis, survivin is a well-characterized oncoprotein. Its roles in trophoblastic cells remain to be defined.MethodsThe placental samples from 16 preeclampsia patients and 16 well-matched controls were included in this study. Real-time PCR, immunohistochemistry and Western blot analysis were carried out with placental tissues. Primary trophoblastic cells from term placentas were isolated for Western blot analysis. Cell proliferation, cell cycle analysis and immunofluorescence staining were performed in trophoblastic cell lines BeWo, JAR and HTR-8/SVneo.ResultsThe survivin gene is reduced but the protein amount is hardly changed in preeclamptic placentas, compared to control placentas. Upon stress, survivin in trophoblastic cells is phosphorylated on its residue serine 20 by protein kinase A and becomes stabilized, accompanied by increased heat shock protein 90. Depletion of survivin induces chromosome misalignment, abnormal centrosome integrity, and reduced localization and activity of Aurora B at the centromeres/kinetochores in trophoblastic metaphase cells.ConclusionsOur data indicate that survivin plays pivotal roles in cell survival and proliferation of trophoblastic cells. Further investigations are required to define the function of survivin in each cell type of the placenta in the context of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion.

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Activation of NF-κB in Placentas of Women with Preeclampsia

Cited by 116 publications

References 37 publications

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

TLR3-Induced Placental miR-210 Down-Regulates the STAT6/Interleukin-4 Pathway

Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia

Function of Survivin in Trophoblastic Cells of the Placenta

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