interleukin-8 and Pre-Eclampsia

Pre-eclampsia (PE) is a pregnancy complication associated with maternal and fetal morbidity and mortality. Among the potential pathogenesis discussed, inflammation is considered an essential initiator of PE. Previous studies have compared the levels of various inflammatory biomarkers that indicate the existence of PE; however, the relative levels of pro-inflammatory and anti-inflammatory biomarkers and their dynamic changes during PE progression remain unclear. This knowledge is essential to explain the occurrence and progression of the disease.. We aimed to identify the relationship between inflammatory status and PE using inflammatory biomarkers as indicators. We also discussed the underlying mechanism by which inflammatory imbalance contributes to PE by comparing the relative levels of pro-inflammatory and anti-inflammatory biomarkers. Furthermore, we identified additional risk factors for PE.. We reviewed PubMed, Embase, and the Cochrane Library for articles published until 15. Thirteen articles that investigated 2,549 participants were included in this meta-analysis. Patients with PE had significantly higher levels of C-reactive protein (CRP), interleukin (IL)-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) than the controls. CRP and pro-inflammatory cytokine levels were higher than those of anti-inflammatory cytokines. Patients with gestational age > 34 weeks had significantly higher IL-6 and TNF levels. Patients with higher systolic blood pressure had significantly higher IL-8, IL-10, and CRP levels.. Inflammatory imbalance is an independent risk factor for PE development. Impairment of the anti-inflammatory system is a crucial initiating factor for PE development. Failed autoregulation, manifested as prolonged exposure to pro-inflammatory cytokines, leads to PE progression. Higher levels of inflammatory biomarkers suggest more severe symptoms, and pregnant women after 34 weeks of gestation are more susceptible to PE.

Topics: Biomarkers; C-Reactive Protein; Cytokines; Female; Humans; Infant; Interleukin-10; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Interleukin-6 (IL-6) is an acknowledged inflammatory cytokine with a pleiotropic action, mediating innate and adaptive immunity and multiple physiological processes, including protective and regenerative ones. IL-8 is a pro-inflammatory CXC chemokine with a primary function in attracting and activating neutrophils, but also implicated in a variety of other cellular processes. These two ILs are abundantly expressed at the feto-maternal interface over the course of a pregnancy and have been shown to participate in numerous pregnancy-related events. In this review, we summarize the literature data regarding their role in healthy and pathological pregnancies. The general information related to IL-6 and IL-8 functions is followed by an overview of their overall expression in cycling endometrium and at the feto-maternal interface. Further, we provide an overview of their involvement in pregnancy establishment and parturition. Finally, the implication of IL-6 and IL-8 in pregnancy-associated pathological conditions, such as pregnancy loss, preeclampsia, gestational diabetes mellitus and infection/inflammation is discussed.

Topics: Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Parturition; Pre-Eclampsia; Pregnancy

It is possible that in fetal growth restriction without pre-eclampsia endothelial cell activation does not occur. This might be either because there is no release of 'factor X' or because of maternal resistance to its effects. To test this hypothesis, we took blood samples from 26 women with pre-eclampsia (without fetal growth restriction), 13 women with fetal growth restriction (without pre-eclampsia) and 24 normal pregnant controls, and measured the circulating levels of three markers of endothelial cell activation (soluble VCAM, ICAM and E-selectin) and three cytokines [tumour necrosis factor-a (TNF-alpha), interleukin-6 (IL-6) and -8 (IL-8)]. The levels of the markers of endothelial cell activation were raised in both pre-eclampsia and fetal growth restriction pregnancies compared with controls; however, the levels of TNF-alpha, IL-6 and IL-8 were significantly raised in pregnancies complicated by pre-eclampsia, but not in fetal growth restriction, compared with controls. These data show that endothelial cell activation is common to both pre-eclampsia and fetal growth restriction, but that the circulating levels of cytokines are elevated only in pre-eclampsia. Thus, it seems likely that endothelial cell activation is a consequence of a failure of trophoblast invasion and that a further step is required, possibly involving cytokine release, for the expression of the full clinical picture of pre-eclampsia.

Topics: Adult; Blood Pressure; Body Mass Index; E-Selectin; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Pilot Projects; Pre-Eclampsia; Pregnancy; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

To explore the ATF2 expression of preeclampsia patients and investigate whether the level of ATF2 expression impacted the low-dose aspirin treatment of preeclampsia patients.. Preeclampsia is a severe pregnancy-related hypertension disorder and refers to hypertension.. This study was designed to explore the activating transcription factor 2 (ATF2) expression of preeclampsia patients and investigate whether the level of ATF2 expression impacted the low-dose aspirin treatment of preeclampsia patients.. Firstly, we collected the plasma of normal and preeclampsia pregnancies and quantified the expressions of ATF2 by ELISA. Then we quantified the expression of the three downstream target genes of ATF2 (IL-8, IL-6 and MMP-2). Finally, we collected and quantified the interventional and observational group plasma. All data were compared by t-test (p<0.05).. ATF2 and its target genes (IL-6, IL-8 and MMP-2) were upregulated in preeclampsia patients. In addition, ATF2 and its target genes were downregulated in the interventional group (LDA-treated group).. Our results indicated that LDA could inhibit ATF2 expression in preeclampsia. It suggests that ATF2 may be a potential target of LDA in the prevention of preeclampsia.

Topics: Activating Transcription Factor 2; Aspirin; Female; Humans; Hypertension; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 2; Pre-Eclampsia; Pregnancy

Promotion of a healthy pregnancy is dependent on a coordinated immune response that minimizes inflammation at the maternal-fetal interface. Few studies investigated the effect of fetal sex on proinflammatory biomarkers during pregnancy and whether maternal race could impact this association. We aimed to examine whether fetal sex could, independently of maternal race/ethnicity and the condition of pregnancy (normal vs. complicated), impact inflammatory markers (C-reactive protein [CRP] and interleukin-8 [IL-8] levels) in early and late pregnancy.. This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART, N = 816). Maternal serum CRP and IL-8 levels were measured in early and late pregnancy (10-18 and 32-38 weeks of gestation, respectively). Five hundred and twenty-eight out of 816 pregnant women who participated in the trial had available CRP and IL-8 measurements at both study time points. We examined the association of fetal sex with early and late CRP and IL-8 levels and their paired sample difference. We further investigated whether maternal race/ethnicity, pregnancy complications (i.e., preeclampsia and gestational diabetes), and early pregnancy body mass index (BMI) could affect the association between these two biomarkers and fetal sex adjusting for potential confounders. For this purpose, we used generalized linear and logistic regression models on log-normalized early and late CRP and IL-8 levels as well as their split at median to form high and low groups.. Women pregnant with male fetuses (266/528 = 56.5%) had higher CRP levels in early to mid-pregnancy (β = .18: 95% confidence interval [CI]: CI = 0.03-0.32; p = .02). Twenty-seven percent (143/528) of the study subjects were Hispanic. Hispanic African American [AA] women and women of races other than White and AA had higher levels of CRP at early to mid-pregnancy compared with White women (β = .57; 95% CI: 0.17-0.97; p < .01 and β = .27; 95% CI: 0.05-0.48; p = .02, respectively). IL-8 levels were not associated with fetal sex in early and late pregnancy (p's > .05). Other factors such as gestational diabetes and early pregnancy BMI were associated with higher CRP levels and higher CRP and IL-8 levels, respectively. Dichotomizing log-normalized cytokine levels at the median in a sensitivity analysis, women with male fetuses had lower odds of high (above-median) IL-8 levels at early pregnancy. Also, women with races other than AA and White carrying male fetuses had higher odds of having high (above-median) late-pregnancy CRP and early-pregnancy IL-8 levels (adjusted odds ratio [aOR] = 3.80, 95% CI: 0.24-1.23; p = .02 and aOR = 3.57; 95% CI: 0.23-1.03; p = .02, respectively). Of the pregnancy complications, women with gestational diabetes mellitus had a higher paired difference of early and late pregnancy CRP levels (β = .38; 95% CI: 0.09-0.68; p = .01), but no difference in IL-8 levels (p's > .05). No associations between the inflammatory markers and preeclampsia were found.. Fetal sex is associated with CRP in early pregnancy and an association with IL-8 in early pregnancy is implied. Our study further indicates that maternal race/ethnicity could be a contributing factor in the relationship between fetal sex and inflammatory responses during pregnancy. However, the specificity and level of the contribution might vary by type of cytokine, pregnancy stage, and other confounding factors such as BMI that may impact these associations.

Topics: Biomarkers; C-Reactive Protein; Cytokines; Diabetes, Gestational; Ethnicity; Female; Humans; Interleukin-8; Male; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Obesity and preeclampsia both involve a pathological inflammatory response, which may be how obesity increases preeclampsia risk. Previous studies have failed to assess robust measurements of inflammatory markers across gestation, specifically in overweight/ obese women in the context of preeclampsia.. We measured 20 inflammatory markers in plasma via multiplex assay (ThermoFisher Inflammation 20 plex Human ProcartaPlex Panel) across the three trimesters of pregnancy in an existing cohort of overweight and obese women who developed preeclampsia (n = 37) and without preeclampsia (n = 74). Mann-Whitney U tests examined differences in inflammatory marker concentrations between cases and controls. Repeated measures ANOVA tests were used to explore differences in inflammatory marker concentrations over time within cases and controls.. Pro-inflammatory markers (IL-1α, IL-1β, IL-6, IFN-α, IFN-γ, GM-CSF, IL-12p70, IL-17α, TNF-α, IL-8) and anti-inflammatory markers (IL-4, IL-10, IL-13) were higher in the first and second trimester in participants who later developed preeclampsia compared to those who did not (p < .05). Only TNF-α and IL-8 remained elevated in the third trimester. Inflammatory markers did not change across pregnancy in preeclampsia cases but did increase across pregnancy in controls.. Our findings diverge from prior studies, predominantly of non-obese women, that report lower circulating concentrations of anti-inflammatory cytokines in preeclampsia versus normotensive pregnancy, particularly by late pregnancy. We posit that women with overweight and obesity who develop preeclampsia entered pregnancy with a heightened pro-inflammatory state likely related to obesity, which increased risk for preeclampsia. Further studies are needed to investigate if inflammatory maker profiles differ between obese and non-obese women.

Topics: Female; Humans; Interleukin-8; Obesity; Overweight; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

Topics: Chemokine CXCL10; Chorionic Gonadotropin; Chorionic Gonadotropin, beta Subunit, Human; Female; Fetal Growth Retardation; Humans; Interleukin-8; Mitochondria; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

Pre-eclampsia (PE) is a major cause of maternal and perinatal death. Previous research has indicated the role of histone deacetylase 2 (HDAC2) in the pathogenesis of PE but the relevant molecular mechanisms are unknown. However, there is hitherto little information concerning the molecular mechanism behind HDAC2 in PE. Herein, we hypothesized that HDAC2 promotes trophoblast cell proliferation and this requires the involvement of microRNA-183 (miR-183), forkhead box protein A1 (FOXA1), and interleukin 8 (IL-8). We collected placental specimens from 30 PE affected and 30 normal pregnant women. HDAC2 and FOXA1 were poorly expressed while miR-183 and IL-8 were highly expressed in placental tissues in PE. In vitro, HDAC2 overexpression enhanced the proliferation, migration, and invasion of human trophoblast cells HTR-8/SVNEO. HDAC2 inhibited the expression of miR-183 by diminishing H4 acetylation in the miR-183 promoter region. miR-183 inhibition by its specific inhibitor increased the expression of FOXA1 and thus enhanced HTR-8/SVNEO cell proliferation, migration, and invasion. FOXA1, a transcriptional factor, enhanced HTR-8/SVNEO cell proliferation, migration, and invasion by inhibiting the transcription of IL-8. We also observed HDAC2 knockdown was lost upon FOXA1 overexpression, suggesting that HDAC2 could promote HTR-8/SVNEO proliferation, migration, and invasion through the miR-183/FOXA1/IL-8 pathway. In summary, the results highlighted the role of the HDAC2/miR-183/FOXA1/IL-8 pathway in PE pathogenesis and thus suggest a novel molecular target for PE.

Topics: Acetylation; Adult; Case-Control Studies; Cell Line; Cell Movement; Cell Proliferation; Female; Hepatocyte Nuclear Factor 3-alpha; Histone Deacetylase 2; Humans; Interleukin-8; MicroRNAs; Pre-Eclampsia; Pregnancy; Promoter Regions, Genetic; Signal Transduction; Trophoblasts

Revaluation of the association of the STOX1 (STORKHEAD_BOX1 PROTEIN 1) transcription factor mutation (Y153H, C allele) with the early utero-vascular origins of placental pathology is warranted. To investigate if placental STOX1 Y153H genotype affects utero-vascular remodeling-compromised in both preterm birth and preeclampsia-we utilized extravillous trophoblast (EVT) explant and placental decidual coculture models, transfection of STOX1 wild-type and mutant plasmids into EVT-like trophoblast cell lines, and a cohort of 75 placentas from obstetric pathologies. Primary EVT and HTR8/SVneo cells carrying STOX1 Y153H secreted lower levels of IL (interleukin) 6, and IL-8, and higher CXCL16 (chemokine [C-X-C motif] ligand 16) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) than wild-type EVT and Swan71 cells. Media from wild-type EVT or Swan71 cells transfected with wild-type STOX1 stimulated: endothelial chemokine expression, angiogenesis, and decidual natural killer cell and monocyte migration. In contrast, Y153H EVT conditioned medium, Swan71 transfected with the Y153H plasmid, or HTR8/SVneo media had no effect. Genotyping of placental decidual cocultures demonstrated association of the placental STOX1 CC allele with failed vascular remodeling. Decidual GG NODAL R165H increased in failed cocultures carrying the placental CC alleles of STOX1. Multivariate analysis of the placental cohort showed that the STOX1 C allele correlated with premature birth, with or without severe early-onset preeclampsia, and small for gestational age babies. In conclusion, placental STOX1 Y153H is a precipitating factor in preterm birth and placental preeclampsia due to defects in early utero-placental development.

Topics: Adolescent; Adult; Alleles; Carrier Proteins; Cell Line; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Premature Birth; Trophoblasts; Young Adult

The pathogenesis of pre-eclampsia (PE) is associated with significant maternal and neonatal complications, an increased inflammatory response, placental hypoxia, and endothelial dysfunction, coupled with differential exosomal release profiles with immune modulation effects. Hence, this study evaluated the impact of circulating exosomes derived from early and late-onset pre-eclamptic pregnancies on inflammatory cytokine secretion by BeWo cells.. Exosomes were isolated from plasma obtained from early-onset pre-eclamptic (EOPE; n = 15), late-onset pre-eclamptic (LOPE; n = 15), and gestational age-matched normotensive pregnancies (N ≤ 33 weeks; n = 15 and N ≥ 34 weeks; n = 15). Human BeWo cells were treated with characterized and quantified exosomes (100 μg/mL exosomal protein per pregnant group) for 24 h. The immunoassay method was used to measure the concentration of IL-8, IL-10, leptin, and HIF-α.. Exosome administration from women with EOPE and LOPE increased IL-8 and decreased IL-10 expression in BeWo cells.. Cumulatively, our data demonstrated that circulating exosomes from the placenta and activated immune cells potentially influence inflammatory cytokine production in pre-eclamptic pregnancies.

Topics: Adult; Cell Line, Tumor; Culture Media, Conditioned; Exosomes; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-10; Interleukin-8; Leptin; Pre-Eclampsia; Pregnancy; Young Adult

This study aimed to identify significantly altered long non-coding RNAs (lncRNAs), microRNAs (miRNAs), mRNAs, pathways in preeclampsia (PE), and to investigate their targeted relationships and biological functions.GSE96985 from Gene Expression Omnibus database was extracted, involving 3 PE and 4 normal tissues. After the differential expression analysis of miRNAs, lncRNAs, and mRNAs using the limma package, protein-protein interaction (PPI) network and module analyses were performed for differentially expressed mRNAs (dif-mRNAs). Combined with the miRanda and miRWalk tools, a regulatory relationship between dif-miRNAs and dif-mRNAs/lncRNAs (dif-mRNAs/dif-lncRNAs) was predicted. Finally, mRNA-miRNA-lncRNA regulatory network construction was performed using Cytoscape software.A total of 511 dif-mRNAs were screened in PE. The top 5 nodes in the PPI networks included up-regulated complement component 3 (C3), C-X-C motif chemokine ligand 8 (CXCL8), and fibronectin 1 (FN1). Three significant network modules were identified for dif-mRNAs. C3 and CXCL8 were identified in module A, and FN1 was identified in module C. A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) was down-regulated by the miR-210-3p. Therefore, lnc-CTD-2383M3.1 functions as a competing endogenous RNA in ADAMTS6 expression regulation by competitively binding to miR-210-3p during the regulation process of PE.C3, CXCL8, FN1, and ADAMTS6 might be involved in the development of PE. The lnc-CTD-2383M3.1-miR-210-3p-ADAMTS6 axis might be a potential regulatory mechanism in PE.

Topics: ADAMTS Proteins; Biomarkers; Complement C3; Datasets as Topic; Down-Regulation; Female; Fibronectins; Gene Expression Profiling; Gene Regulatory Networks; Humans; Interleukin-8; MicroRNAs; Pre-Eclampsia; Pregnancy; RNA, Long Noncoding; RNA, Messenger; Up-Regulation

The impact of pregnancy hypertension in the offspring endothelia remains unknown. We evaluated the transcriptional expression of four genes that participate in the process of endothelial dysfunction using umbilical vein endothelial cell cultures (HUVEC) from healthy pregnant women (PW) and those with hypertensive disorders (HD). The cytochrome P450 1A1 (CYP1A1), gluthathione S-transferase subtype T1 (GSTT1), interleukin 6 (IL-6) and 8 (IL-8) mRNA and IL-6 protein levels were assessed. IL-6 and IL-8 transcripts were significantly reduced in HUVEC obtained from HD women. Our results suggest that a hypertensive environment in utero modifies the transcriptional expression of key inflammatory molecules in the newborn.

Topics: Adult; Case-Control Studies; Cytochrome P-450 CYP1A1; Endothelium, Vascular; Female; Glutathione Transferase; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Transcription, Genetic; Umbilical Veins; Young Adult

Preeclampsia (PE) is a systemic inflammatory disease, and its effect on human milk immune components is poorly understood.. To investigate whether PE affects human milk cytokine levels.. This was a prospective observational study involving mothers diagnosed with PE and with singleton pregnancy with no fetal malformation. The following cases were excluded: diabetes, chorioamnionitis, use of illicit drugs and alcohol, mastitis and congenital infection. In total, 228 mothers were studied and divided into two groups matched by gestational age: PE (n = 114) and normotensive (control, n = 114). Colostrum was collected from 24-72 hours postpartum, and mature milk was collected at the end of the first month. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, and TNF-α) were measured using flow cytometry. A generalized linear model with a gamma distribution was used to analyze the differences between groups versus time interaction.. The mean gestational age was 36 weeks. Increased IL-1 and IL-6 levels and reduced IL-12 levels in the colostrum were detected in PE, while in the mature milk, the IL-6 and IL-8 levels were lower than those of the control group.. PE is associated with increased levels of inflammatory cytokines in colostrum and decreased levels in mature milk.

Topics: Adult; Case-Control Studies; Colostrum; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Milk, Human; Pre-Eclampsia; Pregnancy; Prospective Studies; Tumor Necrosis Factor-alpha; Young Adult

To evaluate the placental and decidual gene expression and maternal and umbilical serum concentrations of tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1), along with the proinflammatory/anti-inflammatory cytokine ratios in women with preeclampsia (PE) vs. women with normal pregnancy (NP), and to analyze PE classified as early- (EO) and late-onset (LO).. This cross-sectional study was performed with 50 women with PE (EO n = 30, LO n = 20) and 50 women with NP. Tissue gene expression levels were measured by real-time RT-PCR. Cytokines and adhesion molecules serum concentrations were measured by immunoassays.. In PE, placental expression of IL-10 and IL-1RA was lower, while placental IL-8/IL-1RA ratio and maternal concentrations of VCAM-1 were higher vs. NP. In EO, placental expression of IL-10 was lower, while placental IL-8/IL-10 and IL-8/IL-1RA ratios were higher than LO and NP. Maternal concentrations of IL-6 were higher in LO than EO and NP. Throughout PE, maternal VCAM-1 concentrations were higher vs. NP. No significant differences were observed in the decidual expression and umbilical concentrations of the markers between the groups.. PE associates with a proinflammatory placental state; however, EO associates with a proinflammatory placental state, while LO associates with systemic maternal inflammation. Both subtypes associated with maternal endothelial dysfunction.

Topics: Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Cytokines; Decidua; Endothelium; Female; Fetal Blood; Gene Expression; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Young Adult

Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood.. Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation.. Our findings suggest that elevated decidual TGFb1 supresses the activation of specific subsets of dNK which in turn contributes to the uteroplacental pathology associated with the onset of preeclampsia.

Topics: Cells, Cultured; Culture Media, Conditioned; Decidua; Down-Regulation; Female; Flow Cytometry; Humans; Interferon-gamma; Interleukin-8; Killer Cells, Natural; Lysosomal-Associated Membrane Protein 1; Pre-Eclampsia; Pregnancy; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Adaptor Proteins, Signal Transducing; Adult; Biomarkers; CD4 Lymphocyte Count; Chemokine CCL2; Female; Humans; Incidence; Interleukin-10; Interleukin-8; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Prognosis; Prospective Studies; Risk Factors; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha; Young Adult

Hyperglycemia increases the risk of preeclampsia. Hyperglycemia induces a placental trophoblast inflammatory (IL-1β, IL-6, IL-8), antiangiogenic (sFlt-1, sEndoglin), and anti-migratory profile. The IL-1β response is mediated via inflammasome activation by the damage-associated molecular pattern (DAMP), uric acid. The objective of this study was to determine the role of high-mobility group box-1 (HMGB1), a DAMP that activates Toll-like receptor 4 (TLR4), in human first trimester trophoblast responses to hyperglycemia. The trophoblast response to excess glucose under different oxygen tensions was also investigated.. The human first trimester trophoblast cell line (Sw.71) was exposed to glucose mimicking normoglycemia (5 mmol/L) and hyperglycemia (10 mmol/L), either alone or with the TLR4 antagonist, LPS-RS; or the HMGB1 inhibitor, glycyrrhizin. Cells were also treated with glucose under hyperoxic (21% O. Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4. The IL-1β and sFlt-1/PlGF response was TLR4-mediated, but HMGB1-independent, suggesting another DAMP may be involved. Hyperoxia rather than normoxia or hypoxia was a major driver of trophoblast dysfunction in response to excess glucose.. The findings from this study indicate a novel mechanism by which hyperglycemia may impact trophoblast function, early placentation, and ultimately, pregnancy outcome.

Topics: Alarmins; Cell Line; Cell Movement; Female; Glycyrrhizic Acid; HMGB1 Protein; Humans; Hyperglycemia; Inflammation; Interleukin-1beta; Interleukin-8; Pre-Eclampsia; Pregnancy; Risk; Signal Transduction; Toll-Like Receptor 4; Trophoblasts; Vascular Endothelial Growth Factor Receptor-1

Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8.. Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum.. We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1.. This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia.

Topics: Adult; Biomarkers; Female; Gestational Age; Giant Cells; HMGB1 Protein; Humans; Immunohistochemistry; Inflammation; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 4

To study the production of pro-inflammatory (IL-1β, IL- 2, IL-6, IL-8) and anti-inflammatory (IL-4, IL-10) cytokines in pregnancy complicated by preeclampsia in the third trimester. Institution: University Clinic of Gynecology and Obstetrics, Skopje, Republic of Macedonia.. Fifty women with pregnancies complicated by preeclampsia in the third trimester and 50 women with physiological pregnancy. Levels of IL-1β, IL-2, IL-6, IL-8, IL-4, and IL-10 were measured by using a solid-phase enzyme immunoassay. Statistical data processing was done using the application program SPSS for Windows 13.0. To describe the distribution of analyzed variables, descriptive methods (mean, median, minim and max) were used .. In pregnancies complicated by preeclampsia, there are increased levels of proinflammatory cytokines and a change in the behaviour of opposing pools. Most pronounced changes in the levels of proinflammatory cytokines were observed in mild preeclampsia. In severe preeclampsia there was reduction of the concentration of anti-inflammatory cytokines IL-4 and IL-10.. The use of assessment cytokine profile monitoring of health status of women with preeclampsia is expedient.

Topics: Adult; Case-Control Studies; Cytokines; Female; Humans; Interleukin-10; Interleukin-1beta; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Severity of Illness Index

We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia.. Preeclamptic pregnancies feature hypertension, proteinuria, and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies.. We performed whole-genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By reverse transcriptase-polymerase chain reaction, we confirmed this finding in early-onset (<34 gestational week, n=26) and late-onset (≥34 gestational week, n=24) samples from preeclamptic women, compared with healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry, and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared with controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naive and activated macrophages lacking CD74 showed a shift toward a proinflammatory signature with an increased secretion of tumor necrosis factor-α, chemokine (C-C motif) ligand 5, and monocyte chemotactic protein-1, when cocultured with trophoblasts compared with control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα, and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas, and impaired spiral artery remodeling with fetal growth restriction.. CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation toward a proinflammatory signature and a disturbed crosstalk with trophoblasts.

Topics: Animals; Antigens, Differentiation, B-Lymphocyte; Case-Control Studies; Cell Adhesion Molecules; Cells, Cultured; Chemokine CXCL5; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Down-Regulation; Female; Histocompatibility Antigens Class II; Humans; Interleukin-8; Macrophages; Mice; Mice, Inbred C57BL; Pre-Eclampsia; Pregnancy; Syndecan-2; Trophoblasts; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

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.

Topics: Cell Line; Chemokine CCL2; E-Selectin; Endothelial Cells; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

To determine whether miR-203 mediates endothelial inflammatory response in preeclampsia.. Maternal vessel miR-203 expression was assessed by in situ hybridization. Suppressor of cytokine signaling-3 (SOCS-3) and ICAM expression was determined by immunostaining. Subcutaneous fat tissue sections from normal and preeclamptic pregnant women were used. miR-203-induced inflammatory response was evaluated by the measurements of IL-6, IL-8, ICAM, and VCAM expression and production and neutrophil adhesion in the endothelial cells (EC) transfected with miR-203 precursor, pre-miR-203. SOCS3 expression was also determined.. Up-regulation of miR-203 and ICAM expression and down-regulation of SOCS-3 expression were demonstrated in maternal vessel endothelium in preeclampsia. Overexpression of miR-203 resulted in down-regulation of SOCS-3 expression and increases in the production of IL-6, IL-8, ICAM, and VCAM and neutrophil adhesion in ECs.. As miR-203 is an inflammatory microRNA, increased miR-203 production/expression in ECs could diminish an anti-inflammatory activity and increase the endothelial inflammatory response in preeclampsia.

Topics: Adult; Base Sequence; Case-Control Studies; Cell Adhesion; Female; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; MicroRNAs; Neutrophils; Pre-Eclampsia; Pregnancy; Primary Cell Culture; Signal Transduction; Subcutaneous Fat; Suppressor of Cytokine Signaling 3 Protein; Transfection; Vascular Cell Adhesion Molecule-1

Preeclampsia (PE) is one of the leading causes of maternal and perinatal mortality and morbidity. One of the main hallmarks observed in PE is impaired inflammation state. In the current study, we found that miR-125b was deregulated in placental tissues and plasma derived from PE patients, which suggest a potential association between this miRNA and the pathogenesis of PE. Overexpression of miR-125b significantly reduced SGPL1 expression, and luciferase assays confirmed that SGPL1 is a direct target of miR-125b. We also found that miR-125b enhanced IL-8 production by directly targeting sphingosine-1-phosphate lyase 1 (SGPL1), and this effect could be reversed by SGPL1 overexpression. In placentas derived from PE patients, a negative correlation of miR-125b and SGPL1 was observed, and IL-8 was validated to be increased in the circulation of PE patients. Our data demonstrated a critical role of miR-125b in IL-8 production and the development of PE.

Topics: 3' Untranslated Regions; Adult; Aldehyde-Lyases; Base Sequence; Blotting, Western; Cell Line; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Interleukin-8; MicroRNAs; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Nucleic Acid; Young Adult

Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls.. Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age.. In first trimester samples, IL-12 was associated with preeclampsia (p=0.0255). IFN-gamma (p=0.0063), IL1-beta (p=0.0006), IL5 (p=0.0422) and TNFr (p=0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p=0.0180) and term preeclampsia (p=0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p=0.0288).. Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Chemokine CCL5; Cytokines; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-1beta; Interleukin-4; Interleukin-5; Interleukin-6; Interleukin-8; Lymphotoxin-alpha; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Preeclampsia (PE) is a common pregnancy-specific disorder associated with significant maternal and fetal morbidity and mortality worldwide.The present study was performed to investigate the role of a CXC chemokine interleukin-8 (IL-8), in the pathogenesis of PE. IL-8 expression levels were assessed in placental and serum samples from 160 pregnant women with PE (N = 68 severe, 92 mild) and 140 healthy donors.Results from enzyme-linked immunosorbent assay showed that the concentration of serum IL-8 in PE patients (180.27 ± 5.81 ng/L) was significantly higher than that in healthy controls (41.57 ± 5.67 ng/L). Patients with severe PE had even higher serum IL-8 levels. Similar messenger RNA and protein expression patterns of IL-8 in placental tissues were confirmed by quantitative real-time polymerase chain reaction and immunohistochemical assay (N = 30 each in the mild PE, severe PE, and control groups). In addition, single nucleotide polymorphisms of IL-8 gene were detected with polymerase chain reaction-restricted fragment length polymorphism/SSP. The frequency of IL-8-251A allele was significantly higher than that in controls (58.4% vs 48.9%, P < 0.05). The occurrence frequency of haplotype -353A/-251A/+678T (AAT) in PE subjects was 27.2% as compared to 21.9% in the control participants (P < 0.05).Our study reveals that IL-8 expression is positively associated with the severity of PE. Presence of haplotype AAT in pregnant women appears to be a risk factor for PE.

Topics: Adult; Alleles; Case-Control Studies; Female; Gene Expression; Haplotypes; Humans; Interleukin-8; Placenta; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; RNA, Messenger; Young Adult

To find out whether there is a correlation between the extent of platelet activation and inflammation and the severity of preeclampsia (PE) in the third trimester of pregnancy.. Forty-one women with PE (n = 23 severe, n = 18 mild) and 80 normotensive pregnant (NP) women were included in the study. Their blood samples were obtained and interleukin (IL)-8 and IL-10 levels measured by an enzyme-linked immunosorbent assay. Basal CD61 and CD62P expressions on CD41-positive platelets were analyzed with the use of flow-cytometry. Platelet aggregation was induced by adenosine diphosphate and determined by aggregometry.. CD62P expression was increased in severely preeclamptic women, and the platelet aggregation was decreased in both mildly and severely preeclamptic women in comparison with NP women. However, CD61 expression was similar among the groups. An enhanced inflammatory response was seen in severely preeclamptic women demonstrated by increased levels of IL-8 and decreased levels of IL-10. However, the intensity of platelet activation did not correlate directly with the change in plasma levels of IL-8 and IL-10 in preeclamptic women.. Platelets may have a role in the inflammatory response in PE. However, the severity of inflammation is found to be independent from the intensity of platelet activation in preeclamptic women. This seems to be related to mechanisms causing alterations of cytokine levels such as IL-8 and IL-10, rather than platelet activation.

Topics: Adult; Blood Platelets; Blood Pressure; Case-Control Studies; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-8; Platelet Activation; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Severity of Illness Index

Mesenchymal stem cells (MSCs) possess the ability to modulate the immune response, and their abnormalities are related to several diseases. We previously reported that miR-30a expression significantly increased in the maternal-fetal interface during preeclampsia (PE), but the effects of miR-30a on the immunoregulatory characteristics of MSCs are unclear. In this study, we determined that miR-30a over-expression inhibited the IL-1β-elicited activation of the nuclear factor κB (NF-κB) and JNK signaling pathways and the production of IL-6, cyclooxygenase 2 (COX2) and IL-8 by targeting transforming growth factor-β-activated kinase 1 binding protein 3 (TAB3) in MSCs. Moreover, the over-expression of miR-30a also impaired MSCs' anti-inflammatory effects on macrophages. These data demonstrated that miR-30a in MSCs may participate in the immune dysregulation of the maternal-fetal interface during PE.

Topics: Adaptor Proteins, Signal Transducing; Base Sequence; Cell Cycle; Cyclooxygenase 2; Female; Humans; Immune Tolerance; Interleukin-1beta; Interleukin-6; Interleukin-8; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Macrophages; MAP Kinase Kinase 4; Mesenchymal Stem Cells; MicroRNAs; NF-kappa B; Pre-Eclampsia; Pregnancy; Signal Transduction; Umbilical Cord; Up-Regulation

Regulatory T cells (T(regs); CD4+CD25(high)Foxp3+) are critical in maintaining immune tolerance during pregnancy and uterine vascularization. In this study, we show that, in Mexican women with different preeclamptic severity levels, the number of T(regs) and the subset of CD4+CD25(high)Foxp3+ are decreased compared with those of normotensive pregnant women (NP). Moreover, a systemic inflammatory state is a pivotal feature in the pathogenesis of this disorder and could be related to hypertension and endothelial dysfunction. Likewise, we observed elevated levels of IL-6, TNF-α, and IL-8 in the serum of severe preeclamptic patients (SPE); no differences were found in the IL-1β and IL-10 levels compared with those of NP patients. An analysis of chemokines in the preeclamptic serum samples showed high levels of CXCL10, CCL2, and CXCL9. Our findings suggest that the preeclamptic state is linked with systemic inflammation and reduced numbers of T(regs).

Topics: Adult; CD4-Positive T-Lymphocytes; Chemokine CCL2; Chemokine CXCL10; Chemokine CXCL9; Female; Flow Cytometry; Forkhead Transcription Factors; Humans; Inflammation; Interleukin-2 Receptor alpha Subunit; Interleukin-8; Mexico; Pre-Eclampsia; Pregnancy; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

We studied the effects of soluble products of the placental tissue from women with normal pregnancy and gestosis on the cytokine secretion by endothelial EA.Hy926 cells. The secretory products of the placental tissue induced the production of angiogenin, bFGF, IL-8, MCP-1, and RANTES by endothelial cells. The secretion of bFGF by EA.Hy926 cells increased, while IL-8 secretion decreased under the effects of factors produced by the placental tissue in gestosis but not in normal pregnancy. This could be aimed at reduction of inflammation intensity in the placental tissue and maintenance of endothelial and trophoblast cells viability.

Topics: Cell Line; Chemokine CCL2; Chemokine CCL5; Cytokines; Endothelial Cells; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Ribonuclease, Pancreatic; Trophoblasts

The aim of the present study was to evaluate the hypothesis that preeclampsia is associated with increased systemic inflammatory responses of Th1-type as well as decreased Th2-type responses compared with normal pregnancy. We also sought to determine whether there was a correlation between these markers with severity of preeclampsia and fetal birth weight.. The study population consisted of maternal age, gestational age, and body mass index matched 138 pregnant women; 56 normotensive healthy pregnant women (group 1), 42 women with mild preeclampsia (group 2), 40 women with severe preeclampsia (group 3).. Plasma interleukin (IL)-8 and C-reactive protein (CRP) levels were significantly higher in group 3 than group 1 (p<0.05). Plasma IL-4, IL-12, and interferon (IFN)-γ levels were similar in all groups. Although plasma IL-8 and CRP levels of mild preeclamptic group were higher than control group and lower than severe preeclamptic group, the differences were not statistically significant. There was a positive correlation between IL-12 and fetal birth weight in severe preeclamptic group (p<0.05).. Elevated maternal serum pro-inflammatory cytokine IL-8 and CRP in severe preeclamptic women compared with normal pregnant women supports the hypothesis that preeclampsia is associated with increased inflammatory responses.

Topics: Adolescent; Adult; Birth Weight; C-Reactive Protein; Case-Control Studies; Female; Fetal Weight; Humans; Infant, Newborn; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-8; Middle Aged; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Severity of Illness Index; Young Adult

Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.

Topics: Abortion, Habitual; Adult; Cell Movement; Decidua; Down-Regulation; Embryo Implantation; Endometrium; Female; Fetal Growth Retardation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Inflammation; Interleukin-1; Interleukin-8; Matrix Metalloproteinases; Middle Aged; Oligonucleotide Array Sequence Analysis; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinase Inhibitory Proteins, Secretory; Up-Regulation

Activation of the receptor for advanced glycation end products (RAGE) mediates cellular injury. Soluble forms of RAGE [soluble RAGE (sRAGE), endogenous secretory (esRAGE)] bind RAGE ligands, thereby preventing downstream signaling and damage.. The objective of the study was to characterize the changes in maternal serum, amniotic fluid, and cord blood soluble receptor for advanced glycation end products (sRAGE) during physiological gestation and to provide insight into mechanisms responsible for RAGE activation in preeclampsia.. This was a cross-sectional study at a tertiary university hospital.. We studied 135 women in the following groups: nonpregnant controls (n = 16), healthy pregnant controls (n = 68), pregnant women with chronic hypertension (n = 13), or pregnant women with severe preeclampsia (sPE; n = 38).. sRAGE and esRAGE levels were evaluated in vivo by ELISA in maternal serum, amniotic fluid, and cord blood and in vitro after stimulation of the amniochorion and placental explants with lipopolysaccharide or xanthine/xanthine oxidase. Placenta and amniochorion were immunostained for RAGE. Real-time quantitative PCR measured RAGE mRNA.. Pregnant women had significantly decreased serum sRAGE compared with nonpregnant subjects (P < 0.001). sPE women had higher serum and amniotic fluid sRAGE and esRAGE relative to those expected for gestational age (P < 0.001). Cord blood sRAGE remained unaffected by sPE. RAGE immunoreactivity and mRNA expression appeared elevated in the amniochorion of sPE women. Xanthine/xanthine oxidase (but not lipopolysaccharide) significantly up-regulated the release of sRAGE (P < 0.001) in the amniochorion explant system.. Fetal membranes are a rich source of sRAGE. Elevated maternal serum and amniotic fluid sRAGE and esRAGE, paralleled by increased RAGE expression in the amniochorion, suggest activation of this system in sPE.

Topics: Adult; Amniotic Fluid; Case-Control Studies; Female; Fetal Blood; Glycation End Products, Advanced; Humans; Immunohistochemistry; Inflammation; Interleukin-8; Lipopolysaccharides; Organ Culture Techniques; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Reverse Transcriptase Polymerase Chain Reaction; Xanthine Oxidase; Young Adult

Information on leukocyte activation in newborn infants of preeclamptic mothers is scarce. IL-8 and GRO-α are the main pro-inflammatory cytokines involved in leukocyte activation. The objective was to evaluate IL-8 and GRO-α plasma levels in preterm newborns infants of preeclamptic mothers. Newborns with gestational age<36 weeks and birth weight<2000 g were included and divided: non-preeclamptic (n=64) and preeclamptic groups (n=55). Exclusion criteria were major congenital malformations, inborn errors of metabolism or chromosomal anomalies, congenital infections, death in delivery room, and maternal chronic hypertension without preeclampsia. IL-8 and GRO-α were measured by enzyme immunoassay in the first 48 h. Groups were similar in birth weight, gestational age, Apgar scores at 5 min, sepsis, RDS, mechanical ventilation, TPN, NEC, intraventricular hemorrhage and death. The preeclamptic group had more neutropenia, SGA, cesarean section, and less rupture of membranes>18 h. IL-8 was higher in the non-preeclamptic [157.1 pg/mL (86.4-261.3) and 26.54 pg/mL (3.6-87.2) p<0.001]. GRO-α levels were similar in both groups [229.5 pg/mL (116.6-321.3) and 185.5 pg/mL (63.9-306.7) p=0.236]. After multiple regression analysis only absence of preeclampsia was associated with high IL-8 levels. Our data suggest that leukocyte activation may be impaired in infants of preeclamptic mothers.

Topics: Adult; Apgar Score; Chemokine CXCL1; Female; Humans; Immunoenzyme Techniques; Infant, Newborn; Infant, Premature; Interleukin-8; Limit of Detection; Pre-Eclampsia; Pregnancy

Characterizing the protein factors released from placentae during pathogenesis remains a key objective toward understanding preeclampsia and related pregnancy disorders. Gel-free proteomics technologies applied to placental explant-conditioned media offers the potential of identifying these factors. Relative quantification mass spectrometry using isobaric tagging for relative and absolute quantification (iTRAQ) labeling was employed to compare the ''secretome'' between healthy term placental tissue cultured under both normoxic and hypoxic oxygen tensions. Of the 499 proteins identified, 45 were differentially expressed (P < .01 level), including interleukin 8 (IL-8) which was significantly upregulated under hypoxia. Global protein level changes are suggestive of decreased extracellular matrix remodeling under the same conditions. A significant enrichment of soluble liberated placental factors is achieved using this model system. Identifying these changes resulting from hypoxic conditioning is hypothesis generating and may provide new mechanistic insights into preeclampsia.

Topics: Culture Media, Conditioned; Extracellular Matrix; Female; Humans; Hypoxia; Interleukin-8; Oxygen; Placenta; Pre-Eclampsia; Pregnancy; Proteins; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Culture Techniques

The aim of this study was to investigate the relationship of maternal and umbilical cord interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) serum levels with the existence and severity of preeclampsia. A particular objective was the comparison of normal umbilical serum levels to preeclamptic values.. The study group consisted of 24 patients with third trimester singleton pregnancies complicated by preeclampsia (15 severe and 9 mild preeclampsia). The gestational age-matched 19 healthy pregnant women were compared by study group. Maternal and umbilical serum IL-6, IL-8, and TNF-alpha were calculated by using enzyme-linked immunosorbent assay.. Significantly increased maternal and umbilical serum levels of IL-6, IL-8, and TNF-alpha were found in preeclamptic patient group in comparison with the control group. Maternal serum IL-8 and TNF-alpha concentration were significantly higher in patients with severe preeclampsia than in mild preeclampsia. Increased umbilical serum levels of IL-6 and IL-8 were found in severe preeclampsia than in mild preeclampsia. There were significantly higher levels of maternal serum IL-8 and TNF-alpha in patients with preeclampsia with IUGR than in patients with preeclampsia with normal fetal growth.. Our findings suggest that increased concentrations of IL-6, IL-8, and TNF-alpha in the maternal and umbilical serum play a significant role in pathogenesis of preeclampsia. Alterations in maternal and umbilical serum levels of IL-6, IL-8, and TNF-alpha may also play role in preeclampsia complicated by intrauterine growth retardation. These associations may offer insight into the etiology and pathogenesis of preeclampsia.

Topics: Adult; Case-Control Studies; Female; Fetal Blood; Humans; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; Young Adult

Neutrophil interaction with activated endothelial cells (EC) is required for transmigration. We examined consequences of this interaction on NETosis. Co-culture of activated EC with neutrophils induced neutrophil extracellular trap (NET) formation, which was partially dependent on production of IL-8 by activated EC. Extended neutophil/EC co-culture resulted in EC damage, which could be abrogated by inclusion of either diphenyleneiodonium to inhibit the NAPDH oxidase pathway required for NETosis, or DNAse to disrupt NETs. These findings offer new insight into mechanisms whereby NETs trigger damage to the endothelium in sepsis, small vessel vasculitis and possibly the villous trophoblast in preeclampsia.

Topics: Cell Death; Coculture Techniques; Endothelial Cells; Endothelium; Extracellular Space; Female; Hereditary Autoinflammatory Diseases; Humans; Interleukin-8; Neutrophils; Pre-Eclampsia; Pregnancy

Neutrophils infiltrate systemic vasculature of women with preeclampsia, so we tested the hypothesis that factors in plasma of preeclamptic women activate endothelial cells to produce IL-8 resulting in transendothelial migration of neutrophils. Neutrophil migration was studied using the Transwell system. An endothelial cell line was grown to confluence on the inserts and treated with 10% plasma from normal nonpregnant (NNP), normal pregnant (NP) and preeclamptic (PE) women or with an oxidizing solution containing linoleic acid (OxLA). Compared to medium control, NNP plasma or NP plasma, PE plasma significantly stimulated IL-8 and neutrophil migration which was inhibited by vitamins E and C or IL-8 neutralizing antibody. Compared to medium control or LA, OxLA stimulated IL-8 and neutrophil migration which was inhibited by vitamins E and C or IL-8 antibody.. Factors present in plasma of preeclamptic women stimulate transendothelial migration of neutrophils which is due to induction of oxidative stress and production of IL-8.

Topics: Adult; Antioxidants; Ascorbic Acid; Cell Line; Cell Migration Assays, Leukocyte; Cell Movement; Coculture Techniques; Endothelial Cells; Female; Humans; Interleukin-8; Linoleic Acid; Neutrophils; Oxidation-Reduction; Oxidative Stress; Pre-Eclampsia; Pregnancy; Vitamin E

Several lines of evidence have shown that maternal cytokine levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, and IL-10 were altered in women with pre-eclampsia (PE) compared to those from normal pregnancies. In this study, we determined whether these cytokine levels are correlated before and after delivery in patients with PE.. Venous blood was obtained from 50 women diagnosed with severe PE at the time of admission and 24 hr after delivery. Plasma concentrations for TNF-alpha, IL-6, IL-8, and IL-10 were measured by ELISA.. There were no statistical differences for maternal levels of TNF-alpha, IL-6, IL-8, and IL-10 before and 24 hr postpartum. TNF-alpha and IL-10, but not IL-6 and IL-8, levels were significantly correlated before and 24 hr after delivery: TNF-alpha: y = 19.963 + 0.953*x; r(2) = 0.924; IL-10: y = 10.521 + 1.113*x; r(2) = 0.984, P < 0.001, respectively. Furthermore, TNF-alpha levels were correlated with IL-10 levels, but not with IL-6 and IL-8 levels.. The correlation patterns of TNF-alpha with IL-10 and TNF-alpha with IL-6 and IL-8 suggest disparity in functional regulations between these cytokines in maternal circulation in PE.

Topics: Adult; Biomarkers; Delivery, Obstetric; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Respiratory distress syndrome (RDS) incidence is increased in infants of preeclamptic mothers with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. RDS and HELLP syndrome have been associated with oxidative stress and inflammatory processes.. We hypothesize that end-tidal carbon monoxide corrected for inhaled CO (ETCOc), malondialdehyde (MDA) (markers of oxidative stress) and proinflammatory cytokine (IL-6, IL-8) production are higher in infants of preeclamptic mothers with HELLP syndrome than in those of preeclamptic mothers without HELLP syndrome.. Prospective study of 36 infants of preeclamptic mothers (GA <32 weeks) admitted to the Neonatal Intensive Care Unit. ETCOc was measured at 0-12, 48-72 and 168 h postnatally using the CO-Stattrade mark End-Tidal Breath Analyzer. Simultaneously, blood was sampled for MDA, IL-8 and IL-6.. At 0-12 h, ETCOc, MDA and IL-8 values (median[range]) were significantly higher in HELLP infants than in infants from preeclamptic mothers without HELLP (ETCOc 2.2 [1.5-3.9] vs. 1.8 [0.5-2.9] ppm; MDA 2.3 [1.3-4.1] vs. 1.5 [0.4-3.1] mumol/l; IL-8 145 [24-606] vs. 62 [26-397] pg/ml; all p <0.05). MDA remained significantly higher during the first 168 h of life (2.3 [0.8-5.8] vs. 1.1 [0.8-3.7] mumol/l, p = 0.02).. Oxidative stress and proinflammatory cytokine levels are increased in infants of preeclamptic mothers with HELLP syndrome. These processes may cause inactivation of surfactant explaining the increased RDS incidence in these infants.

Topics: Adult; Apgar Score; Breath Tests; Female; Fetal Blood; HELLP Syndrome; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Interleukins; Male; Oxidative Stress; Pre-Eclampsia; Pregnancy; Prospective Studies; Respiratory Distress Syndrome, Newborn

Parallel investigation, in a matched case-control study, of the association of different first-trimester markers with the risk of subsequent pre-eclampsia (PE).. The levels of different first trimester serum markers and fetal nuchal translucency thickness were compared between 52 cases of PE and 104 control women by non-parametric two-group comparisons and by calculating matched odds ratios.. In univariable analysis increased concentrations of inhibin A and activin A were associated with subsequent PE (p < 0.02). Multivariable conditional logistic regression models revealed an association between increased risk of PE and increased inhibin A and translucency thickness and respectively reduced pregnancy-associated plasma protein A (PAPP-A) and placental lactogen . However, these associations varied with the gestational age at sample collection. For blood samples taken in pregnancy weeks 12 and 13 only, increased levels of activin A, inhibin A and nuchal translucency thickness, and lower levels of placenta growth factor and PAPP-A were associated with an increased risk of PE.. Members of the inhibin family and to some extent PAPP-A and placental growth factor are superior to other serum markers, and the predictive value of these depends on the gestational age at blood sampling. The availability of a single, early pregnancy 'miracle' serum marker for PE risk assessment seems unlikely in the near future.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Female; Humans; Inhibins; Interleukin-8; Leptin; Logistic Models; Nuchal Translucency Measurement; Placenta; Placenta Growth Factor; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A; Retrospective Studies

Despite progress in immunobiology, pre-eclampsia (PE) remains one of the most common reasons for women to die during pregnancy. The widespread pathophysiological mechanisms are endothelial dysfunction, oxidative stress and inflammation. The aim of this study was to assess the alteration in the levels of leptin, interleukin (IL)-10 and inflammatory cytokines [tumour necrosis factor (TNF)-alpha, IL-6 & IL-8] in pre-eclamptic (severe and mild), healthy pregnant and non-pregnant women and correlate these parameters with disease severity.. The levels of leptin, IL-10 and inflammatory cytokines were measured by high sensitivity enzyme-linked immunoabsorbant assay. The study subjects were 54 pre-eclamptic women (ten severe and 45 milder), compared by age matched 50 healthy pregnant and 27 non-pregnant women. Kruskal-Wallis non-parametric analyses of variance followed by Mann-Whitney U-test were used for statistical analysis.. The levels of leptin, TNF-alpha, IL-6 & IL-8 in pre-eclamptic subjects were increased significantly when compared with the healthy control pregnant and non-pregnant (P < 0.000). The concentration of IL-10 has shown different pattern as its level decreased significantly (0.001) in pre-eclamptic women (overall) in comparison with control subjects (pregnant & non-pregnant). A combination of 80% or higher sensitivity and specificity was seen in the parameters analysed, except IL-8 and IL-10.. Our findings suggest a relationship among TNF-alpha, IL-6, IL-8, IL-10 and leptin and indicate that altered levels of above markers in PE might be used as markers of pro-inflammation/anti-inflammation and endothelial dysfunction in pre-eclamptic pregnancies. These results also advocate the abnormal leptin and cytokine responses in mother, which might be involved in the pathogenesis of PE.

Topics: Cytokines; Female; Humans; Immunoassay; Interleukin-10; Interleukin-6; Interleukin-8; Leptin; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

The aim of this study was to determine the maternal and umbilical cord serum levels of interleukin-8 (IL-8) in pregnancies complicated by preeclampsia with intrauterine normal growth and intrauterine growth retardation (IUGR), and in normotensive pregnancies.. The study was carried out on 15 patients with singleton pregnancies complicated by preeclampsia with appropriate for gestational age weight infants and 12 pregnant patients with preeclampsia complicated by IUGR. The control group consisted of 10 healthy normotensive delivering patients with singleton uncomplicated pregnancies. Maternal and umbilical serum IL-8 concentrations were estimated using the ELISA method.. There were no statistically significant differences in patient profiles between the groups. Systolic and diastolic blood pressure and mean arterial blood pressure were higher in the study groups in comparison with the control group. Lower birth weight and lower gestational age at birth were observed in the group of patients with preeclampsia complicated by IUGR. Increased maternal and umbilical serum levels of IL-8 were found in both preeclamptic patient groups in comparison with the control group. The umbilical cord blood concentrations of IL-8 in all groups of patients tended to be higher in comparison with the maternal blood.. It seems that these higher IL-8 concentrations may be associated with apoptosis, inflammation, neutrophil activation, endothelial cell damage and dysfunction, and increased endothelial permeability. They may also participate in an attempt to compensate for the imbalanced apoptosis and vascular resistance. Our findings suggest a possible significant role of IL-8 in the pathogenesis and sequelae of preeclampsia, especially in preeclamptic pregnancies complicated by IUGR.

Topics: Adult; Birth Weight; Case-Control Studies; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Interleukin-8; Pre-Eclampsia; Pregnancy

Preeclampsia is a pregnancy-specific syndrome. The immune system in preeclampsia is changed with an increased innate activity and there is a hypothesis of a shift towards Th1-type immunity. The aim of this study was to determine a spectrum of soluble immunological factors denoting different aspects of immune activation in third trimester sera from women with preeclampsia (N=15) and compare with levels in sera from normal pregnant women (N=15).. IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFN-alpha, IFN-gamma, TNF-alpha, GM-CSF, MIP-lalpha, MIP-1beta, MCP-1, eotaxin and RANTES were measured in serum using multiplex bead arrays. The levels of soluble CD14 and soluble IL-4 receptor were measured by enzyme-linked immunoassay (ELISA).. Preeclamptic women had significantly increased levels of circulating IL-6 (p=0.002), IL-8 (p=0.003) and soluble IL-4R (p=0.037), compared to women with normal pregnancies.. This study supports the hypothesis of increased inflammatory responses in preeclampsia, illustrated by the increased levels of IL-6 and IL-8. The finding of increased levels of soluble IL-4 receptor is an intriguing finding with several interpretations, which may partly support the hypothesis of a Th1 shift in preeclampsia.

Topics: Adult; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Receptors, Interleukin-4; Th1 Cells

Inflammation and endothelial dysfunction are prominent in preeclampsia. Microparticles (MPs) may link these processes, as MPs induce the production of pro-inflammatory cytokines by endothelial cells and cause endothelial dysfunction.. To study changes in expression of inflammation-related genes in human endothelial cells in response to MPs from preeclamptic patients.. Human umbilical vein endothelial cells (HUVECs) were incubated for various time intervals in the absence or presence of isolated MP fractions from preeclamptic patients (n = 3), normotensive pregnant women (n = 3), non-pregnant controls (n = 3), and interleukin (IL)-1alpha as a positive control. Total RNA was isolated and used for multiplex ligation-dependent probe amplification (MLPA) and real-time polymerase chain reaction (PCR).. IL-1alpha enhanced the expression of IL-1alpha, IL-2, IL-6, and IL-8; nuclear factor of kappa light chain enhancer in B-cells (NFkappaB)-1, NFkappaB-2, and NFkappaB-inhibitor; cyclin-dependent kinase inhibitor and monocyte chemotactic protein-1; and transiently increased tissue factor expression. RNA expression of inflammation-related genes and genes encoding adhesion receptors, however, were unaffected by any of the MP fractions tested.. MLPA is a suitable assay to test the inflammatory status of endothelial cells, because incubation with IL-1alpha triggered substantial changes in RNA expression in endothelial cells. Taken together, it seems unlikely that MPs from preeclamptic patients induce endothelial dysfunction by directly affecting the expression of inflammation-related genes in these cells.

Topics: Adult; Chemokine CCL2; Cytokines; Endothelial Cells; Female; Gene Expression Regulation; Humans; In Vitro Techniques; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; NF-kappa B; Particle Size; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Umbilical Veins

Systemic endothelial dysfunction is a central feature in the pathophysiology of preeclampsia. Its cell biologic and molecular basis is poorly understood. One leading hypothesis argues that endothelial dysfunction is caused by (at present largely unknown) circulating factors released from the ischemic placenta. This study investigated the effects of plasma factors of severe, early-onset preeclamptic women versus healthy pregnant women on endothelial gene expression in vitro.. Plasma samples were taken from eight severe early-onset preeclamptic women and eight matched pregnant control women. Primary human umbilical vein endothelial cell (HUVEC) and human glomerular microvascular endothelial cell (hGMEC) cultures were incubated with 20% (vol/vol) plasma for 4, 12, and 24 hours. Identical amounts of RNA isolated from HUVEC from three preeclamptic and three control samples were pooled for each time point, and subsequently hybridized on human 60-mer oligonucleotide microarrays containing 17,000 genes. Gene expression levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and interleukin-6 (IL-6) in HUVEC and hGMEC were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR).. Microarray analyses of individual genes identified no genes that were up- or down-regulated more than 2.7-fold, and analyses of gene ontologies showed no gene ontology significantly up- or down-regulated in HUVEC by preeclamptic plasma. IL-8 gene expression was modestly induced by preeclamptic plasma after 4, 12, and 24 hours of HUVEC and hGMEC incubation, as identified by real-time RT-PCR. The other genes analyzed did not show altered regulation by preeclamptic plasma factors.. In vitro, plasma from preeclamptic patients does not substantially alter endothelial gene expression profile. Only modest induction of IL-8 gene expression was observed. These results indicate that mechanisms other than soluble plasma constituents are likely involved in systemic endothelial cell activation in preeclampsia.

Topics: Adult; Antigens; C-Reactive Protein; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Humans; Infant, Newborn; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Oligonucleotide Array Sequence Analysis; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Umbilical Veins; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

Placental hypoxia and altered placental cytokine productions have been considered to play a significant role in the pathophysiology of preeclampsia. The objective of this study was to determine whether hypoxia could modify interleukin (IL)-6, IL-8, and IL-10 production by placental trophoblast cells (TCs) from normal and preeclamptic (PE) pregnancies.. Placentas were obtained from nine normal and nine PE pregnancies immediately after delivery. Placental TCs were isolated and cultured under normoxic (21% O(2)/air) and hypoxic (2% O(2)/5% CO(2)/92% N(2)) conditions for 48 hours. TC productions of IL-6, IL-8, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). Unpaired t tests or paired t test was used for the statistical analysis and data are expressed as means +/- SE (pg/mug cellular protein). A P value less than .05 was considered statistically significant.. PE-TCs produced significantly more IL-6, IL-8, and IL-10 than those of normal-TCs when they were cultured under normoxic condition, P < .05. Both normal-TCs and PE-TCs produced more IL-6 and IL-8 when they were cultured under hypoxic conditions. Hypoxia reduced IL-10 production by PE-TCs, but had no effect on IL-10 production by normal-TCs.. Hypoxia promotes both IL-6 and IL-8 but reduces IL-10 production by placental TCs from PE pregnancies.

Topics: Adult; Down-Regulation; Female; Fetal Hypoxia; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts; Up-Regulation

Recent evidence suggests a role of an excessive maternal inflammatory response in the pathogenesis of preeclampsia. Whether this imbalance can be transferred from mother to breast milk remains to be established.. 15 preeclamptic and 15 healthy pregnant women were recruited in this study. Colostrum and milk samples were collected postpartum in the first 48 h and at 30 days, respectively. Samples were analyzed for interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha and soluble IL-2R (sIL-2R) levels with chemiluminescence enzyme immunometric assays.. Colostrum cytokine levels corrected for gestational age and type of delivery were not significantly different in the two groups. Cytokine levels significantly decreased in mature milk versus colostrum in the control group (P < 0.05), but did not significantly decrease in the preeclampsia group (P > 0.05), except for TNF-alpha (P < 0.05). Mature milk IL-8 and TNF-alpha levels were higher in the preeclampsia group versus controls (P < 0.05).. Results of this study show that proinflammatory cytokines in breast milk exhibit biological variation at different periods of human lactation. In preeclampsia, high cytokine levels persist at least for 30 days. These results suggest that preeclampsia may affect milk cytokine balance and offer an immunological signal for the host defense in high-risk neonates.

Topics: Adult; Colostrum; Cytokines; Female; Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Milk, Human; Pre-Eclampsia; Pregnancy; Receptors, Interleukin-2; Solubility; Tumor Necrosis Factor-alpha

Preeclampsia is associated with oxidative stress, elevated plasma levels of linoleic acid (LA), and increased vascular smooth muscle expression of the inflammatory chemokine, interleukin-8 (IL-8). We hypothesized that increased levels of LA under conditions of oxidative stress would increased production of IL-8 by vascular smooth muscle cells because LA is the dietary precursor to arachidonic acid (AA) and its metabolites that mediate inflammation. We also hypothesized that oleic acid (OA), which is not metabolized to AA metabolites, would not increase IL-8 under conditions of oxidative stress.. To test this hypothesis, we cultured placental arterial smooth muscle (PASM) cells with an oxidizing solution enriched with LA (OxLA) or OA (OxOA). Media concentrations were analyzed for IL-8 and AA metabolites. Inhibitors were used to block the lipoxygenase and cyclooxygenase pathways.. Exposure of cells to OxLA, but not to OxOA, significantly increased production of IL-8. OxLA also significantly increased production of AA metabolites. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, blocked IL-8 and leukotriene B4 (LTB4) production induced by OxLA, whereas indomethacin, an inhibitor of the cyclooxygenase pathway, blocked IL-8, prostaglandin E2 (PGE2), and thromboxane B2 (TXB2) production. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated gene expression in PASM cells for representative lipoxygenase (LTB4) and cyclooxygenase (thromboxane) metabolite receptors.. PASM cells produced IL-8 in response to LA, but not OA, under conditions of oxidative stress. The IL-8 response was mediated by AA metabolites.

Topics: Arachidonic Acid; Cells, Cultured; Female; Gene Expression; Humans; Interleukin-8; Leukotriene B4; Linoleic Acid; Lipoxygenase; Muscle, Smooth, Vascular; Oleic Acid; Oxidative Stress; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane B2; Up-Regulation

Preeclampsia, a severe pregnancy-related disorder, involves an overt activation of the maternal innate immune system, proposed to result from the elevated release of inflammatory syncytiotrophoblast microparticles (STBM) and cytokines from underlying placental anomaly involving abnormal trophoblast differentiation. Activation of circulating neutrophils has recently been shown to lead to the generation of fibrous extracellular lattices containing DNA, termed NETs (neutrophil extracellular traps). Therefore, we examined whether placentally derived factors activated peripheral neutrophils to generate NETs, and whether NETs formation was increased in preeclamptic placenta. Activation of isolated circulatory neutrophils on treatment with placentally derived factors (interleukin-8 and STBM) was assessed by measuring CD11b expression using Flow cytometry. Furthermore, NETs generation by these activated neutrophils in vitro and in vivo in the placental tissue sections were examined using electron microscopy and fluorescence microscopy. We report that placentally-derived interleukin-8 and STBM efficiently activated neutrophils and triggered NETs formation. Large numbers of NETs were present directly in the intervillous space of preeclamptic placentae. NETs, therefore, appear to be an integral part of neutrophil activation, and their increased presence in preeclampsia suggests that NETs may play a role in the underlying pathology.

Topics: Cell-Derived Microparticles; Cells, Cultured; DNA; Extracellular Space; Female; Humans; Interleukin-8; Microscopy, Electron, Scanning; Neutrophil Activation; Neutrophils; Placenta; Pre-Eclampsia; Pregnancy; Tissue Culture Techniques; Trophoblasts

Preeclampsia is a common and major cause of maternal and perinatal morbidity and mortality. Human leucocyte antigen (HLA) susceptibility and impaired adaptation of the T lymphocyte sub-population and a bi-directional effect of T helper cytokines on the outcome of pregnancy have been reported in patients with preeclampsia. The association between maternal HLA class II and T helper cytokines in women with preeclampsia was investigated in seventy-six preeclamptic women and normotensive controls using Terasaki microlymphocytotoxicity test. T helper cytokines interleukin (IL)-8, IL-6, IL-4, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma were estimated in the maternal blood and placenta by enzyme-linked immunosorbent assay (ELISA). Histopathological evaluation of the placenta was also carried out. HLA class II DR2, DR4, DR5, DRw8, DRw10, DRw11, DRw18, and DQw2 had significant relative risk ratios for preeclampsia, while DQw3 was more common in the controls. DR4-DRw11-DQw2 haplotype was more common in preeclamptic women with intrauterine growth restriction, low birth weight and placental weight, increased expression of T helper cytokines IL-8, TNF-alpha and IFN-gamma and abnormal uteroplacental vasculature. These findings suggest that HLA class II DR4-DRw11 -DQw2 haplotypes may be associated with preeclampsia with intrauterine growth restriction through low placental weight from impaired placental development, as a result of increased expression of T helper 1 cytokines IL-8, TNF-alpha and IFN-gamma.

Topics: Adult; Birth Weight; Case-Control Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Histocompatibility Antigens Class II; HLA Antigens; Humans; Interferon-gamma; Interleukin-4; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Tumor Necrosis Factor-alpha

The purposes of this study were to examine endothelial nitric oxide synthase expression in endothelial cells and to determine whether the inhibition of endothelial nitric oxide synthase could impair endothelial barrier function in preeclampsia.. Messenger RNA and protein expression for endothelial nitric oxide synthase were examined in endothelial cells that were isolated from normal and preeclamptic pregnancies. Endothelial monolayer permeable response to interleukin-8 stimulation was determined. Normal endothelial cells that were treated with nitric oxide inhibitor were used to test the association of endothelial nitric oxide synthase and endothelial barrier function. Messenger RNA expression for endothelial nitric oxide synthase was determined by reverse transcription-polymerase chain reaction, and protein expression was determined by Western blot analysis. Endothelial permeability was measured by horseradish peroxidase leakage through endothelial cell filters. Interleukin-8 production was measured by enzyme-linked immunosorbent assay. Data were presented as mean+/-SE and analyzed by analysis of variance or nonparametric Mann-Whitney test.. Relative messenger RNA expression and protein expression for endothelial nitric oxide synthase were decreased significantly in endothelial cells from preeclampsia compared with cells from normal pregnancies (messenger RNA expression, 0.191+/-0.057 vs 0.508+/-0.061 [P <.01]; protein expression, 0.225+/-0.08 vs 0.786+/-0.098 [P<.01], respectively). Horseradish peroxidase leakage in normal endothelial cells was 0.30+/-0.26 micromol/L (interleukin-8, 1 pg/mL), 3.14+/-2.45 micromol/L (interleukin-8, 5 pg/ml), and 9.08+/-2.69 micromol/L (interleukin-8, 25 pg/mL; P<.01; compared with 0.77+/-0.47 micromol/L [control endothelial cells]). Horseradish peroxidase leakage in preeclamptic endothelial cells was 6.20+/-2.19 micromol/L, 8.44+/-85 micromol/L, and 15.79+/-2.06 micromol/L (P<.05) compared with 5.23+/-1.28 micromol/L, respectively. The ratio of horseradish peroxidase leakage was >7-fold increase in normal endothelial cells, but only a 4-fold increase in preeclamptic endothelial cells in response to interleukin-8 stimulation at 25 pg/mL. The inhibition of endothelial nitric oxide synthase with N(G)-Monomethyl-L-arginine resulted in an increase in interleukin-8-induced endothelial cell permeability. No difference for interleukin-8 production was observed between normal and preeclamptic endothelial cells (1.15+/-0.21 ng/mg protein vs 1.29+/-0.23 ng/mg protein, P>.5).. Increased endothelial permeability may be associated with decreased endothelial nitric oxide synthase expression and activity in endothelial cells from preeclampsia.

Topics: Case-Control Studies; Cell Membrane Permeability; Cells, Cultured; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Female; Horseradish Peroxidase; Humans; Interleukin-8; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Osmolar Concentration; Pre-Eclampsia; Pregnancy; RNA, Messenger; Umbilical Veins

We examined if there is systemic vascular inflammation and neutrophil infiltration in women with preeclampsia. Resistance-sized vessels (10 to 200 microm) of subcutaneous fat were evaluated from normal nonpregnant women, normal pregnant women, and preeclamptic women. Immunohistochemical staining was performed for: (1) interleukin-8 (IL-8), a potent neutrophil chemokine; (2) intercellular adhesion molecule-1 (ICAM-1; CD54), an endothelial cell adhesion molecule; and (3) CD66b, a neutrophil antigen. Vessels of preeclamptic patients had intense IL-8 staining in the endothelium and vascular smooth muscle, as compared with little or no staining for normal pregnant and normal nonpregnant patients. ICAM-1 was expressed on the endothelium of all patient groups. In preeclamptic patients, ICAM-1 was also expressed on vascular smooth muscle. Vessels of preeclamptic patients had significantly more CD66b staining of neutrophils than did normal pregnant or normal nonpregnant patients. There were significantly more vessels stained, more vessels with neutrophils flattened and adhered to endothelium, more vessels with neutrophils infiltrated into the intima, and more neutrophils per vessel. In conclusion, in women with preeclampsia, there was significant infiltration of neutrophils into maternal systemic vasculature associated with inflammation of the vascular smooth muscle indicated by increased expression of IL-8 and ICAM-1. Neutrophil infiltration provides a reasonable explanation for endothelial and vascular smooth muscle dysfunction in preeclampsia because neutrophils produce toxic substances, which may explain clinical symptoms.

Topics: Adipose Tissue; Antigens, CD; Antigens, Neoplasm; Cell Adhesion Molecules; Endothelium, Vascular; Female; GPI-Linked Proteins; Humans; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Muscle, Smooth, Vascular; Neutrophil Infiltration; Pre-Eclampsia; Pregnancy; Subcutaneous Tissue

The aim of this study was to investigate the changes in serum levels of leptin, cytokines and lipoproteins in women with pre-eclampsia and to evaluate their clinical significance in the pathogenesis of pre-eclampsia. We performed a prospective study involving 45 women with pre-eclampsia in the third trimester of pregnancy and 30 normotensive women in the third trimester of pregnancy. Serum level of leptin was measured by enzyme immunoassay using a Cayman chemical kit. Serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, soluble IL-2 receptor (slL-2R), IL-6 and IL-8 were measured by using a non-radioimmunoassay chemiluminescent method. Serum lipid concentrations were measured by an Abbott Aeroset (USA) autoanalyzer. Serum levels of apolipoprotein (Apo)A-I and ApoB were evaluated by nephelometrics assays. Differences between groups were evaluated with Student's unpaired t test and, when a variable was not normally distributed, the Mann-Whitney U test was used. The relationship between the variable was explored by the Pearson correlation test. Serum levels of leptin, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 in the pre-eclamptic women were significantly higher than in normotensive women (p < 0.001). In the pre-eclamptic women serum levels of triglycerides, total cholesterol and low-density lipoprotein (LDL)-cholesterol were significantly increased (p < 0.001), while high-density lipoprotein (HDL)-cholesterol and Apo-A were significantly decreased compared to levels in normotensive pregnant women (p < 0.001). No significant differences were noted between the groups in Apo-B (p > 0.05). Serum levels of TNF-alpha were significantly correlated with the serum levels of IL-6, IL-8, triglycerides, sIL-2R, Apo-A and hematocrit in pre-eclamptic women (r = 0.418, p < 0.05; r= 0.389, p < 0.01; r=0.312, p < 0.05; r= -0.318, p < 0.05; r= -0.340, p < 0.05 and r=0.41, p < 0.01, respectively). A negative correlation was seen between serum level of leptin and both IL-1beta and Apo-A in pre-eclamptic women (r=-0.44, p < 0.05; r=-0.39, p < 0.05, respectively). Serum levels of IL-6 were also significantly correlated with the serum levels of HDL-cholesterol, LDL-cholesterol and body mass index (BMI) in pre-eclamptic women (r=0.40, p < 0.01; r=-0.568, p < 0.01; r= -0.30, p < 0.05, respectively). In addition, serum level of IL-8 were significantly correlated with the serum levels of HDL-cholesterol, total cholesterol and BMI in pre-eclamptic women (r= 0.368,

Topics: Apolipoprotein A-I; Apolipoproteins B; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cytokines; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leptin; Lipoproteins; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Prospective Studies; Receptors, Interleukin-2; Receptors, Leptin; Triglycerides; Tumor Necrosis Factor-alpha

To determine if endothelial monolayer permeability could be altered by serum from preeclampsia (PE).. Confluent normal endothelial cells (ECs) were incubated with 20% serum from nonpregnant females, normal and PE pregnancies or combined with antioxidant superoxide dismutase (SOD) for 8 hr. Confluent PE ECs were incubated with 20% serum from normal pregnancies. EC barrier function of monolayer permeability was accessed by measuring EC electrical resistance (ER) and the leakage of horseradish peroxidase (HRP) passing through EC filters. Plasma concentrations of IL-8 and lipid peroxides by MDA were also measured. We determined 1) if serum from PE could affect EC permeable function; 2) if antioxidant and serum from normal pregnancies could preserve PE EC barrier function; 3) if lipid peroxides and cytokine IL-8 were increased in PE blood samples. Data are presented as mean+/-SE. ANOVA was used for statistical analysis. A p level less than 0.05 was considered statistically different.. 1) ER was significantly decreased and HRP passage was significantly increased in ECs incubated with serum from PE compared to serum from non-pregnant and normal pregnant females (ER: 36.30+/-2.60 vs. 51.30+/-4.00 and 53.90+/-5.80 Omega x cm2, p<0.01; HRP: 0.100+/-0.020 vs. 0.014+/-0.002 and 0.022+/-0.007 DeltaOD470 nm, p<0.01, respectively). 2) ER was improved in PE ECs incubated with serum from normal pregnancies compared to controls, 52.28+/-3.13 vs. 34.50+/-3.80 Omega x cm2, p<0.01. 3) SOD attenuated decreased EC ER induced by PE serum, 55.58+/-3.61 Omega x cm2 (SOD+PE serum) vs. 42.34+/-3.24 (control) and 35.46+/-2.44 (PE serum), p<0.01, respectively. 4) Both MDA and IL-8 concentrations were higher in plasma or serum samples from PE than those in samples from nonpregnancies and normal pregnancies, MDA: 28.65+/-1.45 vs. 22.40+/-1.47 and 25.53+/-0.89 micromol/mL, p<0.01; IL-8: 5.35+/-1.08 vs. 1.69+/-0.47 and 2.28+/-0.73 pg/mL, p<0.05, respectively. Conclusions. 1) Sera from PE but not from nonpregnant women or normal pregnancies increase EC monolayer permeability. 2) Increased lipid peroxides and IL-8 are candidates altering EC barrier function. 3) Antioxidant SOD preserves increased EC monolayer permeability induced by PE serum, suggesting that EC oxidative stress may be associated with altered EC barrier function in preeclampsia.

Topics: Adult; Case-Control Studies; Cells, Cultured; Electric Impedance; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-8; Intracellular Membranes; Lipid Peroxides; Permeability; Plasma; Pre-Eclampsia; Pregnancy; Umbilical Veins

To determine the plasma concentrations of placental growth factor (PLGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), soluble tumor necrosis factor alpha receptor (sTNFp55), interleukin-2 receptor (IL-2R), and interleukins 6 and 10 (IL-6, IL-10) in normotensive and preeclamptic women, and to evaluate the correlations between these cytokines and the diastolic blood pressure and fibronectin levels.. A prospective case-control study. Thirty-five women with preeclampsia were compared with 34 healthy women with uncomplicated pregnancies. Peripheral venous blood samples were obtained and plasma levels of PLGF, VEGF, TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 were measured by an enzyme-linked immunoassay and fibronectin by a radial immundiffusion technic.. In preeclampsia PLGF and VEGF levels were significantly lower, and TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 levels were significantly higher than in normotensive pregnancy (p < 0.001). The plasma levels of PLGF and VEGF significantly decreased, whereas TGF-beta1, sTNFp55, IL-2R, IL-6 and IL-10 levels significantly increased with the increments in diastolic blood pressure and fibronectin levels (p < 0.001).. Altered concentrations of various cytokines might explain the shallow placentation and endothelial cell dysfunction described in preeclampsia. The clinical severity of preeclampsia seems to correlate with the severity of the cytokine abnormalities.

Topics: Adult; Blood Pressure; Case-Control Studies; Cytokines; Diastole; Endothelial Growth Factors; Female; Fibronectins; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Lymphokines; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Receptors, Interleukin-2; Receptors, Tumor Necrosis Factor; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To test the hypothesis that preeclampsia is associated with increased endothelial cell chemokine production of monocyte chemoattractant protein-1 and interleukin-8 necessary for monocyte recruitment to the vascular endothelium.. Plasma was collected from women with severe preeclampsia and normal pregnant women at term and measured for monocyte chemoattractant protein-1, interleukin-8, and lipid peroxide levels by enzyme-linked immunosorbent assays and malondialdehyde assays. Human umbilical vein endothelial cells were cultured with 5% plasma from normal or preeclamptic patients and the media assayed for monocyte chemoattractant protein-1 and interleukin-8 production.. In women with severe preeclampsia, plasma levels of monocyte chemoattractant protein-1, interleukin-8, and lipid peroxides were elevated (1.5-fold, 2.5-fold, and 4.5-fold higher, respectively) compared with normal pregnant women. Human umbilical vein endothelial cells cultured with plasma from preeclamptic women significantly increased the production of both monocyte chemoattractant protein-1 (2.3-fold) and interleukin-8 (1.5-fold) compared with plasma from normal pregnant women. Monocyte chemoattractant protein-1 and interleukin-8 production was decreased by the antioxidant vitamin E in human umbilical vein endothelial cells treated with preeclamptic plasma, suggesting that the production of these cytokines may be regulated by signaling mechanisms sensitive to oxidative stress.. These findings support the hypothesis that circulating factors in the plasma of women with preeclampsia activate endothelial cell monocyte chemoattractant protein-1 and interleukin-8 production, and although not directly examined in this study, may increase monocyte adherence to the vascular endothelium.

Topics: Adult; Antioxidants; Cells, Cultured; Chemokine CCL2; Endothelium, Vascular; Female; Humans; Interleukin-8; Lipid Peroxides; Pre-Eclampsia; Pregnancy; Umbilical Veins; Vitamin E

Pre-eclampsia is characterized by neutrophil activation. Interleukin-8 (IL-8) is a strong neutrophil chemo-attractant and activator.. We measured serum IL-8 in 13 pre-eclamptic Afro-Caribbean women and 13 gestational age-, race- and parity-matched normotensive and non-proteinuric controls. We also determined serum tumor necrosis factor-alpha (TNF-alpha), the phenotypes of the IL-8 binding Duffy blood group antigen receptor and the von Willebrand factor (vWF) plasma levels.. Serum IL-8, TNF-alpha, Duffy negative phenotype frequency and plasma vWF were higher in pre-eclamptic women compared with controls. IL-8 correlated positively with both TNF-alpha and vWF in the entire study group.. Higher IL-8 levels in pre-eclampsia may result from increased production (secondary to increased TNF-alpha levels) and/or reduced clearance (related to a high frequency of Duffy negative phenotype).

Topics: Adult; Black People; Duffy Blood-Group System; Erythrocytes; Female; Gene Frequency; Humans; Interleukin-8; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; von Willebrand Factor

Preeclampsia is a potentially life-threatening disease for both mother and fetus. Endothelial dysfunction is pivotal in the pathogenesis of this disorder, possibly reflecting a state of persistent inflammation. In the present study, we examined whether signs of inflammation with production of chemokines and leukocyte activation were present in the fetal circulation during preeclampsia. Venous cord blood was sampled during cesarean sections from 36 neonates born after uncomplicated pregnancies and from 35 born after severe preeclamptic pregnancies with premature newborns. The expression of adhesion molecules on neutrophils and monocytes was analyzed by flow cytometry, and plasma levels of chemokines and soluble adhesion molecules were analyzed by enzyme immunoassay. Newborns of preeclamptic mothers had increased expression of CD15s (P=0.003), CD49d/CD29 (P=0.01/0.005), and CD31 (P=0.007) on neutrophils and CD15s (P<0.001), CD11c (P=0.009), and CD54 (P=0.001) on monocytes. This activation of neutrophils and monocytes was accompanied by raised plasma levels of the CXC chemokines interleukin-8 (P=0.007) and growth-related oncogene-alpha (P=0.01) and decreased plasma levels of soluble E-selectin (P=0.001) and L-selectin (P=0.002). Although raised levels of adhesion molecules on leukocytes or decreased levels of soluble adhesion molecules in plasma were not related to prematurity or the degree of preeclampsia, raised interleukin-8 levels were found only in neonates of preeclamptic mothers with the highest blood pressures. Our findings suggest the activation of neutrophils and monocytes in the fetus during preeclampsia involving enhanced chemokine activation, possibly contributing to the fetal morbidity of this disorder.

Topics: Adult; Birth Weight; Blood Pressure; Cell Adhesion Molecules; Chemokine CXCL1; Chemokines; Chemokines, CXC; Chemotactic Factors; E-Selectin; Female; Fetal Blood; Flow Cytometry; Gestational Age; Growth Substances; Humans; Infant, Newborn; Infant, Premature; Intercellular Signaling Peptides and Proteins; Interleukin-8; Leukocytes; Maternal Age; Monocytes; Neutrophils; Pre-Eclampsia; Pregnancy

Our purpose was to determine placental interleukin (IL)-8 production and its correlation with the prostacyclin production in normal and preeclamptic pregnancies and to evaluate the beneficial effect of IL-8 on prostacyclin production.. We determined 1) the in vitro production of IL-8 and prostacyclin by placental villous tissues from normal and preeclamptic pregnancies and 2) the production of prostacyclin by villous tissues from preeclampsia treated with recombinant human IL-8 (rhIL-8). IL-8 levels were measured by enzyme-linked immunosorbent assay and prostacyclin by radioimmunoassay of 6-keto PGF1alpha, the stable metabolite of prostacyclin.. 1) Placental production of IL-8 and 6-keto PGF1alpha were significantly less in preeclampsia than in normal pregnancies, P<0.05. 2) Placental production of 6-keto PGF1alpha and IL-8 was significantly correlated in preeclampsia, P<0.01. 3) Placental tissues treated with IL-8 exhibited a concentration-dependent increase in 6-keto PGF1alpha production.. Placental tissues from preeclampsia produce significantly less IL-8 than tissues from normal pregnancies, which correlates with decreased prostacyclin production. IL-8 improves placental prostacyclin production in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy

A large array of cytokines show high activity in amniotic fluid. Attempts have been made to quantify the concentrations or to track rising levels for diagnostic purposes when examining disturbances of the feto-maternal unit. However, the kinetics of cytokine production in the amniotic fluid are not well understood, and there is lack of knowledge about concomitant levels in fetal and maternal blood.. The presence of cytokines in fetal and placental cells was demonstrated by immunohistochemistry using mAb. Cytokines were quantified by enzymimmunoassay in amniotic fluid and fetal and maternal blood. This was done with regard to two disease states that quite frequently complicate the course of pregnancy, namely chorioamnionitis and intrauterine growth retardation. The cytokines examined were G-CSF, GM-CSF, TNF-alpha, IL-1, IL-6, and IL-8.. In chorioamnionitis, all cytokines, except GM-CSF, were elevated about 100 times in the amniotic fluid. An accompanying increase in maternal and fetal blood was only found for IL-6 and G-CSF; IL-8 was elevated in fetal blood only. Intrauterine growth retardation was characterized by elevated levels of TNF-alpha in the amniotic fluid, whereas G-CSF, GM-CSF, and IL-1 beta were significantly reduced. Immunohistochemistry showed that under normal conditions the cytokines are to be found in a characteristic distribution in certain cell types in the fetus, the placenta, and the placental bed. With rising concentrations, more cells seemed to be recruited for cytokine production, especially macrophages and decidual cells. In chorioamnionitis, fetal extramedullary granulopoiesis was augmented, and in intrauterine growth retardation, erythropoiesis as well as granulopoiesis were depressed.. Not only inflammatory disease but also intrauterine growth retardation is characterized by a changing cytokine pattern. Alterations in fetal hematopoiesis observed at postmortem examination of perinatal deaths can be correlated to changes in cytokine production within the feto-maternal unit.

Topics: Amniotic Fluid; Chorioamnionitis; Cytokines; Embryonic and Fetal Development; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Concentrations of five cytokines, GM-CSF, G-CSF, IL-1, IL-6 and IL-8, were determined within five compartments under four different conditions: at the time of a Caesarean section performed between 25 and 38 weeks' gestational age in normal pregnancy without uterine contraction (n = 12), in normal pregnancy with labour already established (n = 8), in pregnancy complicated by amniotic infection (n = 11), or under the conditions of preeclampsia with fetal intrauterine dystrophy (n = 13), cytokine concentrations were determined in fetal arterial and venous blood, in amniotic fluid, and in retroplacentally obtained maternal blood and peripheral maternal blood. With dystrophy, the concentrations of GM-CSF, G-CSF and IL-1 were about 20-50% lower (P < 0.01) in the amniotic fluid, and IL-6 and IL-8 were elevated in maternal peripheral blood (P < 0.01) but not within maternal retroplacental blood. Thus, preeclampsia/intrauterine dystrophy is characterized by reduction of some cytokines within the amniotic fluid compartment and concomitant reactive augmentations of other cytokines within the maternal and fetal organism. With amniotic fluid infection, concentrations of G-CSF, IL-6 and IL-8 were elevated in all compartments (P < 0.001) but GM-CSF and IL-1 showed a significant rise only within amniotic fluid and retroplacental maternal blood (P < 0.001), a rise that was apparently not transmitted to peripheral maternal or fetal blood. Care was taken to exclude the presence of uterine contractions in the group of controls, because this condition by itself causes severe elevation of cytokine concentrations, which are pronounced within amniotic fluid.

Topics: Amniotic Fluid; Chorioamnionitis; Cytokines; Female; Fetal Blood; Fetal Growth Retardation; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Labor, Obstetric; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications

To determine if plasma concentrations of defined cytokines are increased in women with preeclampsia, and to correlate any increases with the elevated concentrations of the vascular cell adhesion molecule (VCAM)-1.. Twenty primigravidas with preeclampsia were compared to 20 healthy primigravidas. Plasma levels of cytokines, tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-6, IL-8, IL-1 beta, IL-1 receptor antagonist (IL-1ra), granulocyte macrophage-colony-stimulating factor (GM-CSF), and VCAM-1, were measured by enzyme-linked immunosorbent assay.. Concentrations of IL-6 and IL-1ra were significantly higher (P < .01) in preeclamptic women (2.56 and 251.85 pg/mL, respectively) compared to normal pregnant patients (2.06 and 142.00 pg/mL, respectively). There were no significant changes in concentrations of TNF alpha, IL-8, GM-CSF, and IL-1 beta in preeclamptic patients (14.09, 50.52, 125.8, and 2.08 pg/mL, respectively) compared to normal patients (11.96 44.46, 121.3, and 2.01 pg/mL, respectively). Serum concentrations of VCAM-1 were increased in women with preeclampsia (preeclamptic group 841.9 +/- 49.7 ng/mL, control group 560.2 +/- 47.9 ng/mL; t = 3.673, P < .001). Interleukin-6 and IL-1ra concentrations correlated with VCAM-1 concentrations (IL-6: r = 0.539, z = 2.9, P < .005; IL-1ra: r = 0.451, z = 2.428, P < .02).. Increased cytokine concentrations may contribute to the endothelial damage that occurs with preeclampsia and may explain the mechanism underlying leukocyte activation in this disorder. The increased cytokine concentration may also be responsible for the endothelial adhesion that accompanies preeclampsia.

Topics: Adult; Cell Adhesion Molecules; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Pre-Eclampsia; Pregnancy; Receptors, Interleukin-1; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1