Cytokines In Amniotic Fluid Research Articles

Systemic administration of betamethasone delays endotoxin-induced preterm labor in the murine model

Objective: The purpose of this study was to determine whether the administration of betamethasone decreases the endotoxin-induced preterm parturition rate and inhibits the risk of cytokines in the murine model. Study design: Endotoxin was administered intraperitoneally at gestational day 15 (75% of gestation). In phase I, the duration of gestation was measured in 36 gravid C3H/HeOu mice that were equally divided into four treatment groups: control, endotoxin only, and two different dose regimens of betamethasone followed by endotoxin. In phase II, maternal serum and amniotic fluid concentrations of cytokines (interleukin-1α, tumor necrosis factor-α, and interleukin-6) were measured at 4 hours after endotoxin injection in 44 gravid mice divided equally in the four treatment groups. Results: The group that was exposed only to endotoxin was delivered at a significantly earlier gestational age compared with the control group (16.2 ± 0.4 days vs 19.6 ± 0.2 days; P < .01). The two groups that were pretreated with betamethasone before the endotoxin were delivered at gestational ages similar to the control group. There was a marked increase of tumor necrosis factor-α and interleukin-6 levels in amniotic fluid of mice that were treated with endotoxin only compared with the control group (P < .001). No difference in cytokine levels was found in those mice that were premedicated with betamethasone compared with the control group. Conclusion: Antenatal administration of betamethasone to mice delayed preterm parturition that was induced by endotoxin. Elevations of amniotic fluid cytokine concentrations that were observed with endotoxin were not observed with pretreatment with betamethasone. (Am J Obstet Gynecol 2003;188:439-43.)

Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection

Objectives: To evaluate the role of interleukins (IL-1, IL-6), tumor necrosis factor α (TNFα) and for the first time interferon gamma (IFNγ) and epidermal growth factor (EGF) in the pathogenesis of premature rupture of membranes (PROM) with and without confirmed intrauterine infection. Methods: Amniotic fluid was retrieved by transabdominal amniocentesis from 30 patients with PROM and 20 normal pregnant women with intact membranes of matched gestational age. Microbial state of amniotic cavity included culture for aerobic and anaerobic bacteria, mycoplasmas and ureaplasma whether or not clinical signs of chorioamnionitis were present. Maternal serum and amniotic fluid IL-1, IL-6, TNFα and IFNγ concentrations were determined by the corresponding immunoradiometric assay, whereas EGF concentration was determined by a specific radioimmunoassay. Results: Nearly all cases of PROM with infection revealed elevated amniotic fluid cytokines (IL-1β, IL-6, TNFα, IFNγ, EGF) whereas half of them revealed elevated serum cytokines. In cases of PROM without confirmed infection, there were no significant changes of maternal serum cytokines, whereas two-thirds of them revealed elevated amniotic fluid cytokines. Conclusions: The rise of cytokines in amniotic fluid of cases of PROM with infection may represent: (a) enhanced macrophage activity for immunosurveillance of the fetus; (b) a preparatory step for the initiation of labor; and (c) a valuable tests for diagnosing chorioamnioitis. The mechanism responsible for PROM in the presence or absence of infection is likely to be of different nature.

Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks’ gestation or less

OBJECTIVE: We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity. METHODS: The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks’ gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor-α and interleukin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor-α concentration and adverse neonatal outcomes, adjusted for birth weight. RESULTS: Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor-α concentration, or both. Amniotic fluid cytokine concentrations were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31–34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-α. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor-α was associated with respiratory distress syndrome (adjusted odds ratio [OR] 1.7), grade 3–4 intraventricular hemorrhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0). CONCLUSION: Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.

Amniotic Fluid Infection, Cytokines, and Adverse Outcome Among Infants at 34 Weeksʼ Gestation or Less

Amniotic Fluid Infection, Cytokines, and Adverse Outcome Among Infants at 34 Weeksʼ Gestation or Less

The correlation between histologic placentitis and amnionitis and the amnioniotic fluid's inflammatory cytokines in case of spontaneous pre-term labor with intact membrane

Pre-term labor is presumed to result from spreading of lower genital infection to upper part, subsequently to decidual and choioamniotic tissues. Host response to this injury include the expression of protein which is responsible to the inflammatory reactions. The expression of the inflammatory cytokines such as IL-β, IL-6, IL-8 and TNF-α increase in case of infection. These cytokines may play an essential role in the pathophysiology of spontaneous pretem labor with intact membrane. An observational analytic cohort study was caried out on cases of spontaneous pre-term labor with intact membrane. The objectives of this study are to examine the relationship between 1) the histologic amnionitis and placentitis and the incidence of preterm delivery,2) the expression of amniotic fluid's IL-β, IL-6, IL-8 and TNF-α and the incidence of preterm delivery, 3) the level of amniotic fluid's IL-β, IL-6, IL-8 and TNF-α and the grade of histologic amnionitis and placentitis in case of pre-term labor with intact membrane. Cases of spontaneous pre-term labor with intact membrane which underwent transabdominal amniocentesis at admission and managed as standard procedure for pre-term labor with intact membrane. All of the cases were observed until the delivery of the baby, eithir preterm or term. The membrane and the placenta were cut postnatally and then the histologic acute inflammation eyaluated based on the criteria of Salafia.The level of amniotic fluid IL-β, IL-6, IL-8 and TNF-α were analyzed quantitatively by Elisa method. This study showed that the degree of histologic amnionitis and placentitis, and the level of amniotic fluid's IL-β, IL-6, IL-8 and TNF-α were significantly higher in pre-term compared to terrn deliveries (p&lt;0.05) and there were a positive correlation between the grade of histologic inflammation and the level of amniotic fluid's cytokines (Spearmann Rank Correlation test; p&lt;0,05) in cases of preterm labor with intact membrane. The higher the grade of histologic amnionitis and placentitis, the higher the level of arnniotic fluid's IL-β, IL-6, IL-8 and TNF-α resulting in a higher risk of pre-term delivery in case of prererm labor with intact membrane. These correlation moy indicate a progression of inflammation from placenta and membrane into the amniotic cavity. (Med J Indones 2001; 10: 203-9) Keywords: Inflammation, Preterm Labour

Cytokines and other important inflammatory mediators in gestation and bacterial intraamniotic infections.

Intraamniotic infections caused by viruses, bacteria or mycoplasmas are frequently followed by damage of fetus or increased perinatal morbidity and mortality. Cytokines are key substances regulating a number of biological processes including reproductive and inflammatory processes. An association between intraamniotic infections, rising concentrations of inflammatory cytokines in amniotic fluid and preterm labor is suggested. A great effort is made to find reliable markers typical for intraamniotic infections with high predictive value that make possible prompt identification of patients with intraamniotic infection. This review concerns inflammatory mediators, especially IL-1, IL-6, IL-8, TNF-alpha, and other important biologically active substances as prostaglandins and NO metabolites and their roles in intraamniotic infections. Finally, we discuss their relevance for diagnosis of intraamniotic infections.

Costimulatory molecules in the developing human gastrointestinal tract: A pathway for fetal allergen priming

Background: Antigen-specific responses can be detected in umbilical cord blood mononuclear cells. The fetal immune system must therefore attain a level of maturity compatible with the initiation of such responses as well as be exposed to antigen. Objective: We sought to assess the expression of costimulatory molecules in fetal gut and the presence of cytokines in amniotic fluid at this time as a preliminary analysis of the suitability of the fetal gut as a site of antigen priming during intrauterine life. Methods: Human fetal gut was analyzed for cells expressing costimulatory molecules through use of immunohistochemistry. Amniotic fluid was studied by ELISA, for cytokines regulating the nature of the response, and as a source of the common dietary antigen ovalbumin. Results: MHC class II–positive cells were abundant over the period examined (11-24 weeks of gestation), other surface antigens showing spatial and temporal variation in expression. From 11 to 14 weeks of gestation, CD68-positive and CD40-positive cells, like MHC class II–positive cells, were present throughout the lamina propria; few CD3-positive cells (T cells) were observed. With the emergence of lymphoid aggregates (14-16 weeks), CD83-positive cells (dendritic cells) and CD20-positive cells (B cells) could be detected in fetal gut; however, expression was restricted to the lymphoid aggregates. In contrast, MHC class II, CD40, and CD68 continued to be expressed in the lamina propria. CD28-positive cells were also evident from 14 weeks of gestation, occurring throughout the lamina propria and lymphoid aggregates; this corresponded to the increasing numbers of CD3-positive cells. The occasional CD86-positive, CD40L-positive, or CTLA4-positive cell could be seen in or around lymphoid aggregates after 14 weeks of gestation. Lymphoid follicles forming after 16 weeks of gestation contained MHC class II–positive, CD83-positive, CD20-positive, CD40-positive, CD86-positive, CD3-positive, CD28-positive, CD40L-positive, and CTLA4-positive cells. MHC class II–positive, CD40-positive, CD68-positive, CD3-positive, and CD28-positive cells continued to be present in the lamina propria at this time. At all times studied, CD14 was not expressed in the lamina propria or lymphoid follicles. Prostaglandin E2, TGFβ1, and IL-10 dominated the amniotic fluid cytokine milieu, and ovalbumin was also detectable in amniotic fluid from 3 of 26 women who had detectable circulating levels. Conclusion: Of the costimulatory molecules studied, CD40 was the most abundant. However, both of the ligand families studied (CD40-CD40L and CD86-CD28/CD152) could provide the costimulatory signals required for the initiation of antigenspecific reactivity in the gastrointestinal tract of the human fetus as early as 16 weeks of gestation. The cytokine milieu would favor the development of TH2-type reactivity to antigens, such as ovalbumin, that are present at this time.(J Allergy Clin Immunol 2001;108:235-41.)

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Allergen-specific reactivity at birth is now a commonly described phenomenon, and interest in this observation is heightened by the association between altered immunologic reactivity at this time and subsequent development of atopy. The lymphoid tissue or tissues in which antigen priming occurs during fetal development are not known, but in this issue of the Journal, Jones et al (p 235 ) provide evidence that the fetal gut is a plausible site at which antigen priming can occur. MHC class II+ cells, CD3+ T cells, and cells expressing the costimulatory molecules required to initiate an antigen-specific immune response are all present from 16 to 19 weeks of gestation, as are dietary antigen and cytokines (in amniotic fluid) that favor a TH2-biased response.

Amniotic fluid lipopolysaccharide-binding protein and soluble CD14 as mediators of the inflammatory response in preterm labor

Objective: Our purpose was to determine the association of lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14) with the proinflammatory response among women in preterm labor. The binding of lipopolysaccharide (LPS) with LBP and sCD14 activates macrophages at LPS concentrations up to 1000 times lower than required with LPS alone. LBP and sCD14 in amniotic fluid could explain the high concentrations of cytokines present in the amniotic fluid of culture-positive women and the presence of cytokines in the amniotic fluid of culture-negative women. Study Design: A cohort of 169 afebrile women in preterm labor with intact membranes had amniotic fluid collected by transabdominal amniocentesis for culture and for LBP, sCD14, and interleukin 6 (IL-6) determinations by enzyme-linked immunosorbent assay. IL-6 levels of >2 ng/mL were considered elevated. Statistical analyses included analysis of variance, multiple comparisons with Bonferroni correction, and linear regression. Results: All 169 amniotic fluid samples had measurable LBP and sCD14. Subjects were categorized by amniotic fluid culture results and IL-6 concentration into 3 groups: (1) positive amniotic fluid culture, (2) negative amniotic fluid culture, elevated IL-6 concentration, and (3) negative amniotic fluid culture, low IL-6 level. Geometric mean LBP and sCD14 levels differed significantly among groups such that levels were approximately twice as high among pregnancies with positive amniotic fluid culture or elevated IL-6 compared with those without evidence of inflammation (both P <.001). sCD14 was inversely associated with enrollment gestational age independent of amniotic fluid culture results and IL-6 concentrations. Among culture negative, low IL-6 pregnancies, sCD14 decreased 3.5% for each additional week of gestation (95% confidence interval [CI], 0.01%-6.4%; P =.02). LBP levels showed a similar trend in this group (P =.09). One hundred eleven subjects had detectable IL-6 levels. Among these subjects, IL-6 increased by 2.1-fold for every 10-fold increase in LBP (95% CI, 1.1-4.0; P =.02) and by 28.4-fold for every 10-fold increase in sCD14 (95% CI, 10.4-77.4; P <.001) with adjustment for gestational age by linear regression. Conclusions: LBP and sCD14 are present in amniotic fluid of preterm pregnancies and are linearly associated with amniotic fluid IL-6 concentrations. These molecules may amplify the cytokine response and thereby help explain the presence of cytokines in amniotic fluid when culturable quantities of microbes are absent. (Am J Obstet Gynecol 2001;184:1241-8.)

Cytokine Levels in Midtrimester Amniotic Fluid in Normal Pregnancy and in the Prediction of Pre‐eclampsia

Midtrimester amniotic fluid cytokines may reflect the function of the maternal immune system in the maternal-fetal interface and thus be predictive of pre-eclampsia. We determined the concentrations of interleukin (IL)-6, IL-8, IL-10, IL-11, IL-12, IL-15, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta in amniotic fluid at 14-16 weeks of gestation from women with normal pregnancies and from those who subsequently developed severe pre-eclampsia. The concentrations of the cytokines in amniotic fluid did not significantly differ between patients and normal controls. The median concentration of IL-6 was 950 pg/ml in normal pregnant women and 578 pg/ml in the patient group. The median concentration of IL-8 was 606 pg/ml in normal controls and 294 pg/ml in the patient group. The levels of IL-6, IL-8 and TGF-beta correlated positively with each other. TNF-alpha concentrations were low and similar in both groups. IL-10 and IL-12 were detected at very low levels in 37 and 7% of the samples, respectively. No difference was found in IL-15 concentrations between the groups. IL-11 was found only at low levels in both groups. Although none of the cytokines measured was predictive of pre-eclampsia, this study provides information of cytokines in amniotic fluid during the period when the spiral arteries are remodelled.

Vaginal indicators of amniotic fluid infection in preterm labor

Objective: To determine whether vaginal interleukin-6, interleukin-8, neutrophils, bacterial vaginosis, and selected vaginal bacteria are predictors of amniotic fluid (AF) infection among women in preterm labor. Methods: One hundred ninety-seven afebrile women in preterm labor with intact membranes had vaginal and AF samples collected for Gram stain, culture, and interleukin-8 and interleukin-6 determinations. Vaginal interleukin-6, interleukin-8, neutrophils, and vaginal flora were compared in women with positive and negative AF cultures. The negative AF culture group was subdivided according to AF interleukin-6 concentration. Logistic regression was used to examine the associations between vaginal cytokines and flora and AF infection or elevated AF interleukin-6. Results: The vaginal interleukin-8 concentration and neutrophil count were significantly higher with both AF infection and elevated concentrations of AF interleukin-6 and interleukin-8. The vaginal interleukin-6 concentration was not associated with AF infection or high concentration of AF cytokines. Amniotic fluid infection was associated with bacterial vaginosis or intermediate vaginal flora by Gram stain, absence of hydrogen peroxide–producing Lactobacillus, and presence of vaginal Bacteroides ureolyticus and Fusobacterium. Vaginal interleukin-8 levels greater than 30 ng/mL had 80% sensitivity and a positive predictive value of 35%, and an abnormal vaginal Gram stain (more than five neutrophils per 400× field, bacterial vaginosis species, or intermediate flora) had 90% sensitivity and a positive predictive value of 27% to detect AF infection or elevated AF interleukin-6. Conclusion: A high vaginal interleukin-8 concentration, abnormal vaginal Gram stain, absent hydrogen peroxide–producing Lactobacillus, and anaerobic vaginal flora were strongly associated with AF infection among women in preterm labor.

Sonographic diagnosis of cervical incompetence for prevention and management

ABSTRACTCervical shortening, as seen by transvaginal sonography increased concentrations of maternal salivary estriol, inflammatory cytokines in amniotic fluid, and fetal fibronectin expression in cervicovaginal mucus are all detected weeks to months before a preterm birth, providing evidence that spontaneous preterm birth is the result of a long-term process, with varying clinical manifestations and dynamics and a dilated cervix as the common terminal pathway.Routine pelvic examination has not been shown to be predictive of preterm labor. The examination of the cervix by transvaginal sonography is more objective and has been shown to be superior to the digital examination in estimating the risk of premature birth. Thereby, the sonographic structure of the cervix (length, funneling) determines, more than any other clinical findings, the interval to the delivery.During normal pregnancy, the pregnant woman spends part of her time in an upright position. Therefore, we have established longitudinal sonographi...

Abnormal TGFbeta levels in the amniotic fluid of Down syndrome pregnancies.

The status of cytokines in amniotic fluid (AF) from chromosomally abnormal pregnancy is largely undefined. TGFbeta plays a key role in fetal growth and differentiation and is responsible for the immunoregulatory activity of AF in normal pregnancy, but its status in Down syndrome (DS) pregnancies is unknown. In addition we investigated the IL-2 status of AF from DS pregnancies. Midtrimester AF from chromosomally normal (n = 25) and abnormal pregnancies with DS (n = 15) were assayed for bioactive and latent TGFbeta levels using the mink lung epithelial cell growth inhibition bioassay and for IL-2 activity by the CTLL-2 cell proliferation bioassay and by ELISA. Levels of bioactive TGFbeta (mean 4.6+/-0.6 U/mL) were significantly increased in DS AF compared with the normal samples (mean 2.8+/-0.3 U/mL, P<0.003) but latent TGFbeta levels did not differ between DS and normal groups. In addition DS AFs showed reduced IL-2 like bioactivity compared with normal samples (P = 0.0006) but IL-2 immunoactivity was undetectable in DS and normal AFs by ELISA. DS AFs display increased TGFbeta activity and lacked IL-2 immunoactivity. The reduced ability of DS AFs to stimulate CTLL-2 cell proliferation is unrelated to the IL-2 status of AF. Altered TGFbeta levels may prove useful as an additional biochemical index for the detection of DS pregnancies.

Indomethacin blocks interleukin 1β–induced myometrial contractions in pregnant rhesus monkeys*1

Objective: We sought to determine whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1β–induced increases in uterine contractions in a nonhuman primate model. Study Design: Maternal and fetal vascular catheters, intra-amniotic fluid pressure catheters, and fetal electrocardiographic and myometrial electromyographic electrodes were implanted in 11 rhesus monkeys at 124 ± 2 days’ gestation (term, 167 days). After postsurgical stabilization (136 ± 2 days) indomethacin 50 mg was administered orally twice daily for 5 days (n = 6). On day 3 human recombinant interleukin 1β 10 μg was infused into the amniotic cavity over 2 hours. Five days after the last indomethacin dose the study was repeated without indomethacin treatment. Uterine activity was continuously monitored and quantified as the hourly contraction area (millimeters of mercury · seconds per hour) in the experimental group and a control group (n = 5) that received interleukin 1β alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostaglandin E2 and F2α, the inflammatory cytokines interleukin 1β, interleukin 6, interleukin 8, tumor necrosis factor α, and interleukin 1 receptor antagonist by specific assays. Results: Uterine activity was increased severalfold from baseline after interleukin 1β infusion alone and in the absence of indomethacin treatment (P <.05). There was no increase in uterine contractility when interleukin 1β was infused concurrently with indomethacin treatment. Concentrations of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1β infusion in both the presence and absence of indomethacin. Amniotic fluid prostaglandins E2 and F2α were suppressed during indomethacin treatment but rose significantly after interleukin 1β infusion in the absence of indomethacin. Except for higher interleukin 6, cytokine levels were unaltered by indomethacin. Conclusions: After interleukin 1β infusion, indomethacin blocked the development of uterine activity. Amniotic fluid prostaglandins were suppressed by indomethacin treatment, but cytokines and leukocytes were not. These results suggest that prostaglandins or possibly other indomethacin-suppressible compounds stimulate uterine activity after interleukin 1β infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects. (Am J Obstet Gynecol 2000;183:173-80.)

Indomethacin blocks interleukin 1β–induced myometrial contractions in pregnant rhesus monkeys

Objective: We sought to determine whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1β–induced increases in uterine contractions in a nonhuman primate model. Study Design: Maternal and fetal vascular catheters, intra-amniotic fluid pressure catheters, and fetal electrocardiographic and myometrial electromyographic electrodes were implanted in 11 rhesus monkeys at 124 ± 2 days’ gestation (term, 167 days). After postsurgical stabilization (136 ± 2 days) indomethacin 50 mg was administered orally twice daily for 5 days (n = 6). On day 3 human recombinant interleukin 1β 10 μg was infused into the amniotic cavity over 2 hours. Five days after the last indomethacin dose the study was repeated without indomethacin treatment. Uterine activity was continuously monitored and quantified as the hourly contraction area (millimeters of mercury · seconds per hour) in the experimental group and a control group (n = 5) that received interleukin 1β alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostaglandin E2 and F2α, the inflammatory cytokines interleukin 1β, interleukin 6, interleukin 8, tumor necrosis factor α, and interleukin 1 receptor antagonist by specific assays. Results: Uterine activity was increased severalfold from baseline after interleukin 1β infusion alone and in the absence of indomethacin treatment (P <.05). There was no increase in uterine contractility when interleukin 1β was infused concurrently with indomethacin treatment. Concentrations of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1β infusion in both the presence and absence of indomethacin. Amniotic fluid prostaglandins E2 and F2α were suppressed during indomethacin treatment but rose significantly after interleukin 1β infusion in the absence of indomethacin. Except for higher interleukin 6, cytokine levels were unaltered by indomethacin. Conclusions: After interleukin 1β infusion, indomethacin blocked the development of uterine activity. Amniotic fluid prostaglandins were suppressed by indomethacin treatment, but cytokines and leukocytes were not. These results suggest that prostaglandins or possibly other indomethacin-suppressible compounds stimulate uterine activity after interleukin 1β infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects. (Am J Obstet Gynecol 2000;183:173-80.)

Early life events in allergic sensitisation.

The timing of events leading to allergic sensitisation has become a very important area in the attempt to halt the dramatic increase in the prevalence of diseases such as asthma, eczema and hay fever. Recent research has demonstrated that events taking place during the gestational period may well play a role in determining whether or not a genetic susceptibility becomes translated into disease processes. Maternal atopy seems to have an important effect on the developing immune response of the infant and increases the chances of the child developing allergy in later life. Maternal IgE, IgG and amniotic fluid cytokines, combined with the presence of allergen in the feto-maternal environment are all possible factors involved in the ultimate outcome in terms of infant Th-1/Th-2 responses to common environmental antigens. Immune modulation at this stage of development may, in the future, be a way forward in the prevention of allergy.

Interleukin-10 modifies the effects of interleukin-1beta and tumor necrosis factor-alpha on the activity and expression of prostaglandin H synthase-2 and the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase in cultured term human villous trophoblast and chorion trophoblast cells.

The concentrations of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta), two inflammatory cytokines in amniotic fluid, have been shown to rise during chorioamnionitis. This is probably related to activation of the immune system in order to intensify the inflammatory process and to protect the maternal and fetal organism from infectious agents. These cytokines activate the PG biosynthetic pathway in several tissues, but few studies have examined effects on PG-metabolizing enzymes. When PGs are produced by increased synthesis and/or decreased metabolism at the chorio-decidual interface, labor can be induced. Interleukin-10 (IL-10) is known to act as an antiinflammatory cytokine. The goals of this study were to evaluate the interaction of IL-10 with IL-1beta and TNFalpha on PG synthesis and to determine the effects of IL-10, IL-1beta, and TNFalpha on PG metabolism using purified cultures of villous trophoblast and chorion trophoblast cells prepared from placentas of patients at term. Cells were treated with IL-1beta and TNFalpha with or without IL-10 for various times up to 24 h. Levels of messenger ribonucleic acid (mRNA) encoding PGH synthase-2 (PGHS-2) and NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) were quantified by Northern blotting, and PGE2 and 13,14-dihydro-15-keto-PGF2alpha (PGFM) output in the medium was measured by RIA. IL-1beta increased PGHS-2 mRNA and PGE2 output from villous and chorion trophoblasts and decreased PGDH mRNA in villous trophoblasts (all P < 0.05). These effects were reversed by IL-10. We found no change in PGHS-2 mRNA or PGE2 output in either trophoblast type treated with TNFalpha, but TNFalpha reduced PGDH mRNA in villous trophoblast, and this effect was reversed by IL-10 (both P < 0.05). We conclude that proinflammatory cytokines can influence PG output through effects on PG synthesis and metabolism and that these effects may be opposed by an antiinflammatory cytokine. These interactions may be important in the progression of preterm labor with underlying infection and in term labor in regions of the uterus where cytokine production is increased.

Elevated Cytokines and Cerebral Palsy

Neurology| September 01 1999 Elevated Cytokines and Cerebral Palsy AAP Grand Rounds (1999) 2 (3): 30–31. https://doi.org/10.1542/gr.2-3-30 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Elevated Cytokines and Cerebral Palsy. AAP Grand Rounds September 1999; 2 (3): 30–31. https://doi.org/10.1542/gr.2-3-30 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: cerebral palsy, cytokine, interferons Source: Grether JK, Nelson KB, Dambrosia JM, Phillips TM. Interferons and cerebral palsy. J Pediatr. 1999;134:324–332. In a retrospective study, Grether et al investigated the association between spastic cerebral palsy (CP) and serum levels of neonatal interferons (IFNs), other inflammatory cytokines, thyroid hormones, complement and coagulation factors. The subjects were selected from a population based case-control study of CP risk factors conducted in the San Francisco area between 1983 and 1985. One hundred and ninety-two children were identified with CP at 3 years of age. From this group, a subset of children with moderate to severe spastic CP was selected based upon the availability of archived blood from newborn metabolic screening and neonatal exposure to intrauterine infection, asphyxia or maternal problems in the second half of pregnancy. Also included was a small group of children with no apparent cause for their CP. The final study cohort included 31 mostly term children with spastic CP for whom neonatal blood spots were available, and 65 children of unknown gestational age and weight randomly selected from the control group. Blood was eluted from blood spots that had been stored over time at −15°F and analyzed for various constituents. Fourteen of the 31 children with spastic CP were found to have levels of all 3 IFNs higher than any child in the control group and were at or above the maximum adult normal values. IL-1, 6, 8, TNF alpha and other inflammatory mediators were also high in this group. In contrast, thyroid hormones, total T4, T3 and complement proteins C3, 4 and 9 were lower than in the controls. Seven of the 9 children with increased IFNs had spastic diplegia, a subtype of CP. In the remaining 17 of the cases, IFNs were low and in the range observed in the control group. The concentration of other cytokines, thyroid hormones and complement were also within the normal range. Although these children with CP had no evidence of inflammation, 70% of them had one or more coagulation factors that were abnormal. The most frequent form of CP in this group was spastic hemiplegia. The etiology of CP remains elusive in the majority of children. Recently, strong epidemiological evidence has been presented linking maternal intrauterine infection with neonatal white matter disease or periventricular leukomalacia (PVL) in the preterm infant. Yoon reported a correlation between elevated cytokines in amniotic fluid, histologic chorioamnionitis, PVL on neurosonography and CP.1 In children who died with PVL, immunohistochemical studies have shown an overproduction of cytokines in hypertrophic astrocytes and microglial cells of the CNS.2,3 Sixty to 100% of neonates with PVL develop CP, most commonly spastic diplegia. Cytokine mediated inflammatory reactions appear to be involved in the evolution of brain damage. In this small (N=31) retrospective exploratory study, Grether et al found that nearly half of the 31 children with CP had evidence of inflammation during the neonatal period with markedly elevated serum IFNs and other inflammatory mediators. This is the first report... You do not currently have access to this content.

Amniotic fluid glucose and cytokines values in the early diagnosis of amniotic infection in patients with preterm labor and intact membranes.

Our goal was to compare sensitivity, specificity, and predictive values of glucose and cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF)] in amniotic fluid (AF) to detect an AF-positive culture. Amniocentesis was performed on 113 patients with preterm labour (PTL) and intact membranes. Fluid was cultured for aerobic and anaerobic bacteria, and for mycoplasmas. AF analysis included cytokines and glucose determinations. The prevalence of positive AF cultures was 11.5% (13/113). Anaerobic bacteria were isolated in 9 patients (69.2%). The glucose <16 mg/dl and cytokines values; IL-1 >640 pg/ml, IL-6 >55,000 pg/ml, IL-8 >1,000 pg/ml, TNF >672 pg/ml, were significantly correlated (P < 0.01) with AF culture result. Glucose had a sensitivity of 69.2% and a specificity of 96% for the prediction of positive AF culture. The sensitivity and specificity of the cytokines ranged from 61.5-53.4% and 79.8-8.99%, respectively. In the diagnosis of the AF-positive culture, glucose <16 mg/dl is more sensitive than cytokines.

Amniotic Fluid Lactoferrin in Intrauterine Infection

Lactoferrin (LF) has been found in most biological fluids including amniotic fluid and cervical mucus in pregnant women and is released from neutrophils in response to inflammation. It is an important component of the host defence against microbial infections due to its antimicrobial properties. Premature labour is caused by amniotic infection and high concentrations of inflammatory cytokines in amniotic fluid with infection are well established. In the present study, LF levels of intrauterine infection in amniotic fluid were measured and the biological significance of LF was investigated. The effects of LF on IL-6 production in cultured amnion cells were also investigated. The concentrations of LF and IL-6 in amniotic fluid with chorioamnionitis (CAM) were 8.76±0.65μg/ml and 6.92±4.88ng/ml (n=28), respectively, and both were significantly higher (P<0.01) than those without CAM (0.86±0.81μg/ml and 0.34±0.25ng/ml; n=31). LF and IL-6 levels were significantly higher (P<0.01) with CAM. A significant positive correlation between LF and IL-6 levels in amniotic fluid was found (r=0.91, P<0.01). To our knowledge, this was the first study of its kind, which shows that IL-6 production induced by lipopolysaccharide in cultured cells was significantly inhibited below physiological concentration of LF in the amnion. In addition, the immunohistochemical localization of LF in fetal membranes was investigated. In the fetal membranes with CAM, strong positive staining was observed in amniotic and chorionic membranes, with leucocyte migration, while weak staining was observed in membranes without CAM. These results show conclusively that LF suppresses amniotic IL-6 production under the conditions of intrauterine infection.