Tumor Necrosis Factor-Alpha, Interleukin-6, and Interleukin-10 Levels are Altered in Preeclampsia: A Systematic Review and Meta-Analysis

Lau, Sandy; Guild, Sarah-Jane; Barrett, Carolyn J.; Chen, Qi; McCowan, Lesley; Jordan, Vanessa; Chamley, Larry

doi:10.1111/aji.12138

Cited by 143 publications

(159 citation statements)

References 98 publications

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“…When we treated HUVECs with esomeprazole ( Figure 4A), there was a significant increase in phosphorylated eNOS (p-eNOS, the active form). Cotreatment of tumor necrosis factor-α (TNF-α; a proinflammatory cytokine that circulates in excess in preeclampsia 28 and likely contributor to endothelial dysfunction 29 ) with esomeprazole and rabeprazole at different doses all induced a nonsignificant increase in p-eNOS protein ( Figure S6A and S6B). These data suggest the PPIs upregulate p-eNOS expression.…”

Section: Proton Pump Inhibitors May Be Promoting Vasodilation By Modumentioning

confidence: 99%

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

et al. 2017

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Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α–induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved.

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Section: Proton Pump Inhibitors May Be Promoting Vasodilation By Modumentioning

confidence: 99%

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

et al. 2017

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“…In addition, Haider and Knöfler [7] reported that TNF-α induces the production of MMP-9 from primary trophoblasts, which may help to maintain pregnancy. Accordingly, alterations of these cytokine levels may be associated with abnormal pregnancy conditions, such as recurrent abortions and preeclampsia [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Cytokines and TLR Ligands on the Production of PlGF and sVEGFR1 in Primary Trophoblasts

Kato

Yamamoto

Chishima³

2016

Gynecol Obstet Invest

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Aim: Cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) play an important role in maintaining pregnancy. Toll-like receptors (TLRs) have also been associated with innate immune responses during pregnancy. Placenta growth factor (PlGF) is one of the angiogenic factors and soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is one of the antiangiogenic factors that regulate PlGF function. To elucidate the effects of cytokines and TLR ligands on the production of angiogenic and antiangiogenic factors in trophoblasts, we examined the production of PlGF and sVEGFR1 from trophoblasts following stimulation with cytokines and TLR ligands. Methods: Villous tissues were obtained from healthy pregnant women who had had an artificial abortion. The trophoblasts were isolated from villous tissues. Subsequently, trophoblasts were treated with TNF-α, IFN-γ and TLR ligands. The levels of PlGF and sVEGFR1 were measured by enzyme-linked immunosorbent assay. The expression of those mRNA was analyzed using quantitative reverse transcription PCR. Results: The production of PlGF in trophoblasts increased by the addition of TNF-α or IFN-γ and decreased by TLR4 ligand. sVEGFR1 levels also increased by following the stimulation with IFN-γ or TLR ligand. Conclusions: Cytokines such as TNF-α and IFN-γ and TLR ligands may contribute to the production of angiogenic and antiangiogenic factors and may affect the placental formation.

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“…During pregnancy, the mother develops Treg specificity for fetal antigens and, similarly, the fetus develops Tregs with specificity for non‐inherited maternal antigens 1, 2, 3. During preeclampsia, there is significant evidence demonstrating markers of maternal immune activation as part of the disease 7. In contrast, investigations of the fetal immune response during preeclampsia are limited with no published studies regarding fetal Treg changes in preeclampsia.…”

Section: Introductionmentioning

confidence: 99%

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Loewendorf

Nguyen

Yesayan

et al. 2015

American J Rep Immunol

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ProblemPreeclampsia affects 3–17% of pregnancies worldwide and has serious consequences for both the mother and the fetus. As maternal–fetal immune tolerance is bidirectional, fetal immunopathology may play a significant role in the pathogenesis of pregnancy disorders. Nevertheless, the impact of preeclampsia on the fetal immune system is unclear.Method of studyIn this case–control study, we examined the phenotype of innate and adaptive immune cells from the cord blood of 3rd trimester babies born to healthy mothers and compared them to cord blood from 3rd trimester babies born to mothers with symptomatic preeclampsia.ResultsThe ratio of CD56hi CD16− non‐activated/regulatory NK cells to CD56lo CD16+ activated/effector NK cells as well as the proportion of CD4+ T cells was significantly decreased in the cord blood of babies born to preeclamptic mothers. The percentage of FoxP3+ Treg, especially the FoxP3lo populations (resting Treg and cytokine Treg), were significantly reduced. Importantly, this reduction in FoxP3+ Treg affected the ratio of CD8+ effector T cells per FoxP3+ Treg in the cord blood of babies born to preeclamptic mothers.ConclusionThese observations indicate that there are significant fetal immune system derangements during preeclampsia.

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Tumor Necrosis Factor-Alpha, Interleukin-6, and Interleukin-10 Levels are Altered in Preeclampsia: A Systematic Review and Meta-Analysis

Abstract: This systematic review and meta-analysis with accompanying summary of non-parametric data shows elevated maternal circulating TNF-α, IL-6, and IL-10 levels in preeclampsia.

Cited by 143 publications

References 98 publications

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

Effects of Cytokines and TLR Ligands on the Production of PlGF and sVEGFR1 in Primary Trophoblasts

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

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