Levels of dimethylarginines and cytokines in mild and severe preeclampsia.

BACKGROUND: The objectives were 1. to evaluate if the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine was altered in mild and severe forms of preeclampsia, and 2. to assess the relationship between dimethylarginines and the cytokine response in preeclampsia. METHODS: Asymmetric and symmetric dimethylarginine were measured with high performance liquid chromatography in women with mild (n=13) and severe (n=32) preeclampsia and in normotensive pregnant controls (n=20). Interleukin-4, -6, -8, -10 and tumor necrosis factor-alpha were analyzed by immunoassays in women with mild (n=8) and severe (n=17) preeclampsia and in normotensive pregnant controls (n=14). The Mann Whitney U-test and Spearman Rank test were used for statistical analysis. RESULTS: The plasma levels of dimethylarginine were increased in preeclamptic subjects. The elevation of symmetric dimethylarginine was more pronounced than that of asymmetric dimethylarginine. The control levels of interleukin-6, -8 and -10 were significantly higher at term than at gestational week 32-36. Interleukin-6 and -8 were significantly elevated in subjects with severe, but not mild, preeclampsia, whereas TNF-alpha and IL-10 were not significantly altered. Symmetric dimethylarginine levels correlated significantly with arterial blood pressure and serum levels of creatinine and uric acid. Dimethylarginine levels in plasma were, however, not related to the cytokine response. CONCLUSIONS: Plasma concentrations of both asymmetric and symmetric dimethylarginine were significantly elevated both in mild and severe preeclampsia. Symmetric, but not asymmetric, dimethylarginine correlated to the severity of the condition. Plasma levels of interleukin-6 and -8 were also elevated in severe preeclampsia but no direct correlations were found between these cytokines and dimethylarginines.     

Role of cytokines in endometriosis-associated infertility

Endometriosis, which is common in women of reproductive age, may affect fertility. It is also clear that mechanical disruption of the pelvic anatomy may cause infertility. However, our understanding of the association between the early stage of endometriosis and infertility remains incomplete. Bloody peritoneal fluid (PF) is frequently observed in the cul-de-sac of endometriosis patients and contains various biologically active factors. We found that the concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in PF from patients with endometriosis were significantly higher than that of patients with endometriosis. There were significantly positive correlations between the levels of TNF-alpha and IL-6. We compared the levels of these cytokines with regard to the R-AFS stages and scores, but no differences were observed. In contrast, these cytokines correlate with the number and extent of red color peritoneal endometriosis. TNF-alpha increased the expression of IL-6 messenger RNA and protein in endometriotic stromal cells derived from chocolate cyst in a dose-dependent manner. The addition of IL-6 inhibited the development of mouse preimplantation embryo and impaired sperm function. We concluded that increased levels of IL-6 in peritoneal fluid of patients with active red endometriosis might be related to endometriosis-associated fertility.     

Role of vitamin D in influencing angiogenesis in preeclampsia

ABSTRACT

Objective: Vitamin D plays a key role during pregnancy and is involved in implantation and maintenance of pregnancy. Its deficiency is associated with pregnancy complications like preeclampsia, characterized by abnormal angiogenesis.Method: The current article summarises studies examining the role of vitamin D in pregnancy, with special emphasis on preeclampsia.Results and conclusion: An imbalance in pro- and anti-angiogenic factors is reported in women with preeclampsia. Cell culture studies have demonstrated that vitamin D can influence the process of angiogenesis. However, the role of maternal vitamin D in influencing placental angiogenesis in preeclampsia is unclear and needs to be explored.     

Role of cytokines in progression of endometriosis

Peritoneal fluid in women with endometriosis contains an increased number of activated macrophages that secrete a variety of cytokines, including interleukin (IL)-6, IL-8, vascular endothelial growth factor, and tumor necrosis factor-alpha (TNF-alpha). Cytokines may be involved in the control of implantation and the growth of endometrial cells outside the uterus. In addition, several cytokines have been implicated in or directly associated with angiogenic activity in endometriosis. There could be a relationship between the levels of cytokines in the peritoneal fluid of patients with endometriosis and the status of the lesions in such patients. Peritoneal endometriosis can be classified as having red, black, or white lesions. Red lesions are known to be an active form of early endometriosis, because vascularization and mitotic activity are shown to be most prominent in these lesions. We found that the peritoneal fluid levels of TNF-alpha and IL-8 were significantly higher in patients with endometriosis, and correlated with the size and number of active lesions. In addition, TNF-alpha and IL-8 stimulated the growth of ectopic endometrial stromal cells. These cytokines with angiogenic activity may therefore have significant roles in the pathogenesis of endometriosis.     

Role of oxidative stress in the pathogenesis of preeclampsia

Hypertensive disorders of pregnancy are associated with an increased risk of maternal and fetal morbidity and mortality. The cause and the pathogenesis of the pregnancy-induced syndrome, preeclampsia, is still poorly understood. Published evidence of altered biomarkers for the endothelial dysfunction suggests that the initiating event in preeclampsia is the reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium. This review focuses on the role of free radicals in generating the oxidative stress taking antioxidants into consideration which tend to overcome it as well as the role of placenta in preeclamptic pregnancy.     

Role of inflammatory cytokines in male infertility

Male infertility is a serious diagnostic problem and in many cases the exact cause of failure to reproduce remains unknown. New diagnostic methods are being evaluated in search of more precise diagnosis and possibility of casual treatment. Measuring the level of cytokines, both in seminal plasma and serum, does not only expand the diagnostic options, but also, through the growing knowledge of immune processes, can give rise to new therapeutic methods of improving the quality of semen and increasing the chance to reproduce. The article reviews the role of proinflammatory cytokines in its pathogenesis.     

Placental imbalance of Th1- and Th2-type cytokines in preeclampsia

OBJECTIVES: To characterize the changes in the level of T helper 1 (Th1)- [interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha] and Th2-type cytokine (IL-10) and the ratios of Th1/Th2 (IL-2/IL-10 and TNF-alpha/IL-10) in placentae from women with preeclampsia and women with gestational hypertension. METHODS: Placental levels of IL-2, TNF-alpha, and IL-10 were determined with radioimmunoassay and Th1/Th2 ratios (IL-2/IL-10 and TNF-alpha/IL-10) calculated in the placentae from 22 women with preeclampsia, 15 women with gestational hypertension, and 32 normal term pregnant women. RESULTS: Although preeclampsia had the trend of the increase in the placental levels of IL-2 and TNF-alpha and the trend of the decrease in placental IL-10, there were not significant difference in placental levels of IL-2, IL-10, and TNF-alpha among preeclampsia, gestational hypertension, and normal pregnancy (P > 0.05 for all). Placental ratios of IL-2/IL-10 and TNF-alpha/IL-10 were significantly higher in preeclampsia than in normal pregnancy (P = 0.035 and P = 0.005, respectively). No differences of Th1/Th2 ratios were found between preeclampsia and gestational hypertension and between gestational hypertension and normal pregnancy (P > 0.05 for all). CONCLUSIONS: Alterations of placental balances of cytokines with Th1 predominance were demonstrated in preeclampsia. These associations may offer insights into the pathogenesis of preeclampsia.     

Role of some cytokines on reproduction

Background

The etiology of female reproductive failure may be very complex owing to a neuro-endocrine-immune association. Dysregulated immunity has been implicated in reproductive failure. Lower TH1 cytokines is supportive for physiological pregnancy.

Aim of the study

To measure serum levels of pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ) and anti-inflammatory cytokines (IL-10 and IL-6) in reproductive failure women.

Patients and methods

A cross- sectional study was carried out in Kammal El-Sammrari Hospital from 2008 to 2010. Forty-five women with reproductive failure participated in the study. Serum levels of cytokines (IL-6, IL-10, TNF-alpha and IFN-gamma) were done by Enzyme Linked Immuno Sorbent Assay (ELISA) and compared with age, body mass index and ethnicity matched thirty fertile women.

Results

There is a significant increase in IL-10 (18.09) (p = 0.002) and IFN-γ (49.62) (p = 0.0001) in women with reproductive failure. TNF-α and IL-6 showed no significance different with fertile group.

Conclusions

There is increase in IL-10 and IFN-γ in women with reproductive failure.     

Connection between human leucocyte antigens D region and T helper cytokines in preeclampsia

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)-α and interferon (IFN)-γ 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-α and IFN-γ 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-α and IFN-γ.     

Role of cytokines in human intestinal villous development

Villous development of the intestine is beginning to be understood in terms of the underlying molecular mechanisms. There is increasing information on the role of cytokines as extrinsic regulators in this process. This article summarizes information available on various cytokines that have been studied in this context.     

Role of cytokines in preterm labor and birth

Preterm birth (defined as delivery prior to 37 weeks' gestation) complicates 5-10% of all births. It is a major cause of perinatal mortality and morbidity. Approximately 20% of all preterm births are iatrogenic resulting from obstetric intervention for maternal and/or fetal indications. Of the remainder, 2/3 are spontaneous preterm labor with or without preterm premature rupture of the membranes (pPROM). Preterm labor is a syndrome rather than a diagnosis since the etiologies are varied. Risk factors include, among others, pPROM, cervical insufficiency, pathologic uterine distention (polyhydramnios, multiple gestation), uterine anomalies, intrauterine infection/inflammation, and social factors (stress, smoking, heavy work). The final common pathway appears to be activation of the inflammatory cascade. Bacterial colonization and/or inflammation of the choriodecidual interface induces production of pro-inflammatory cytokines that, in turn, lead to neutrophil activation and the synthesis and release of uterotonins such as prostaglandins (which cause uterine contractions) and metalloproteinases (that weaken fetal membranes and remodel cervical collagen). This monograph reviews the role of cytokines in the pathophysiology of preterm labor and delivery.     

Expression of inflammatory cytokines in placentas from pregnancies complicated with preeclampsia and HELLP syndrome

Abstract

Objective: To investigate the expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in villous trophoblast, syncytial knots and decidua placentas from pregnancies complicated with preeclampsia (PE), Hemolysis, Elevated Liver enzymes and Low Platelet count (HELLP) syndrome and gestational age-matched controls.

Methods: Study group included 35 placentas from pregnancies complicated with PE and 35 placentas from pregnancies with HELLP syndrome. Control group included 35 placentas from idiopathic preterm labor. Placentas were matched according to the gestational age. Expression of TNF-α, IL-6 and IL-10 was determined by immunohistochemistry and semi-quantitative HSCORE method in villous trophoblast, syncytial knots and decidua. Non-parametric statistics were used for analyses.

Results: There was no difference in the expression of TNF-α, IL-6 and IL-10 in all the studied placental segments between PE, HELLP and gestational age-matched control group. TNF-α (F?=?32, 41, p?<?0.001), IL-6 (F?=?58, 53, p?<?0.001) and IL-10 (F?=?17, 62, p?<?0.001) expression was significantly different in different placental cell types, the highest expression of cytokines was in decidua.

Conclusion: There was no difference in cytokine expression in villous trophoblast, syncytial knots and decidua among the studied placental groups. The expression of cytokines was highest in decidua in all the studied placental groups.     

Role of cytokines and other inflammatory mediators

In spite of impressive advances in biochemistry and molecular biology, it has not yet been possible to fit the individual biochemical components of cervical ripening and dilatation to a uniform clinical moiety or to uncover any regulatory mechanisms. The production of interleukin-8 by activated fibroblasts and macrophages plays a key role in cervical ripening, since this cytokine induces chemotaxis, activation, and degranulation of neutrophilic granulocytes with the consequent release of various proteases, including collagenase. In addition, the extravasation of neutrophilic granulocytes is mediated—as in the early stage of an acute inflammatory reaction—by a brief increase in adhesiveness of vascular endothelium. This is known to be modulated by the cytokine-induced increase in the expression of endothelial adhesion molecules. Furthermore, an increase in pro-inflammatory cytokine and proteinase concentrations in preterm delivery seems to occur at earlier stages of cervical dilatation than in term delivery. It is also well known that in patients with chorioamnionitis, the levels of pro-inflammatory cytokines are elevated in amniotic fluid, maternal serum, cervical secretion, placenta, and other compartments of the placento-maternal unit, and are associated with preterm uterine contractions. We have demonstrated for the first time that cytokine concentrations in the lower uterine segment in patients with chorioamnionitis are strongly elevated. We conclude from our data that increased concentrations of pro-inflammatory cytokines may also play a pivotal role in cervical softening and dilatation during chorioamniotic infection. Our data agree with the hypothesis of Liggins who stated nearly 20 years ago that cervical ripening may be an inflammatory reaction, which leads to increased prostaglandin synthesis, preterm labour and finally to preterm delivery.     

Differential levels of T helper cytokines in preeclampsia: pregnancy, labor and puerperium.

BACKGROUND: There are suggestions that T helper 1 cytokines may be detrimental to early pregnancy and T helper 2 cytokines protective of the pregnancy. Their role in preeclamptic pregnancy, labor and puerperium, is not clear. MATERIALS AND METHODS: Twenty-eight preeclamptic women and their matched controls were evaluated, at the Departments of Obstetrics and Gynecology, Faculty of Medicine, Kuwait University and Maternity Hospital, Kuwait. Outcome measures evaluated were serum levels of TNF alpha and interleukin-4 at 12, 24, 36 weeks of gestation, advanced labor and at 1 hour and daily postpartum until they were undetectable, using ELISA technique. RESULTS: T helper cytokines showed higher serum levels in preeclampsia than normotensive pregnancy (p < 0.01, 0.01), in established labor (p < 0.05) and at 1 hour postpartum (p < 0.01 for IL-4) and p < 0.02 for TNF alpha. There was significant increase of IL-4 between 12 to 24 weeks in normal pregnancy compared to preeclampsia (p < 0.001) but not for TNF alpha. By 24 hours postpartum, IL-4 was still detectable in eight parturients compared to one patient with detectable TNF alpha (p < 0.04). Detectable IL-4 levels after 24 hours postpartum were associated with intrauterine growth retardation (p < 0.03). CONCLUSION: IL-4 has a dichotomous role in pregnancy. Normotensive pregnancy is associated with high increase in IL-4 in the first half of the pregnancy, but in the second half of pregnancy and puerperium, high levels of IL-4 are associated with preeclampsia.     

Role of cytokines in preterm labour and brain injury

Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.     

脐血内皮祖细胞中整合素连接激酶在子痫前期发病机制中的作用

目的 探讨整合素连接激酶(integrin linked kinase,ILK)在子痫前期患者脐血内皮祖细胞中的表达及其在新生血管形成中的作用. 方法 采用逆转录聚合酶链反应和Western印迹实验分别检测35例正常孕妇(正常妊娠组)和30例子痫前期孕妇(子痫前期组,其中轻度18例,重度12例)的脐血内皮祖细胞中ILK mRNA和蛋白的表达,采用小管形成实验检测内皮祖细胞血管形成能力;分析ILK mRNA和蛋白表达的差异及其与血管管状结构形成的相关性.统计学分析采用方差分析和相关分析. 结果 (1)正常妊娠组内皮祖细胞中ILK mRNA相对吸光度(A)值较子痫前期组显著升高(0.64±0.05与0.45±0.06),轻度子痫前期组较重度者显著升高(0.47±0.07与0.39±0.08)(q=18.76和5.13,P＜0.05);正常妊娠组内皮祖细胞中ILK蛋白A值较子痫前期组明显升高(32±2与26±1),轻度子痫前期组较重度者显著升高(25±2与20±2)(q=18.47和4.72,P均＜0.05).(2)正常妊娠组小管结构形成的数量较子痫前期组显著增多(330±8与135±7),重度子痫前期组的小管形成的数量明显少于轻度者(116±8与148±6)(q=152.70和5.42,P均＜0.05).(3)内皮祖细胞中ILK mRNA及其蛋白表达与其小管形成均呈正相关关系,正常妊娠组相关系数(r)分别为0.69和0.73,子痫前期组分别为0.67和0.72;轻度子痫前期组分别为0.65和0.68,重度组分别为0.63和0.74(P均＜0.05). 结论 子痫前期患者内皮祖细胞中ILK mRNA及其蛋白表达下降可能与子痫前期的发生密切相关.