Cytokine levels in amniotic fluid and inflammatory changes in the placenta from normal deliveries at term (original) (raw)
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American Journal of Reproductive Immunology, 2004
Increased expression of pro-inflammatory cytokines in placentas of women undergoing spontaneous preterm delivery or premature rupture of membranes. AJRI 2004; 52:45-52 Ó Blackwell Munksgaard, 2004 PROBLEM: The objective of this study was to determine the levels of cytokines in the placentas of women undergoing preterm delivery (PTD) or premature rupture of membranes (PROM) as compared with women undergoing normal delivery at term. METHOD OF STUDY: Placentas were obtained from 30 subjects with spontaneous PTD, 30 women with PROM and 30 women with a history of normal delivery at term. Levels of interleukin (IL)-2, interferon (IFN)-c, tumor necrosis factor (TNF)-a, TNF-b, IL-4, IL-5, IL-6 and IL-10 and IL-12 were estimated by ELISA in detergent lysates of placentas from the subjects. RESULTS: We found significantly increased levels of the Th1 cytokines IL-2 and IFNc and of the Th1-inducing cytokine IL-12 in placentas from the PTD and PROM groups as compared with those delivering at term. In contrast, the levels of the Th2 cytokines IL-4, IL-6 and IL-10 were significantly higher in placentas from term pregnancy. CONCLUSIONS: These data support our observation of a pro-inflammatory cytokine bias in women with PTD and PROM.
Biology of Reproduction, 2002
Each of the proinflammatory cytokines interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF) ␣ has been identified in reproductive tissues during labor. The cellular origin of these cytokines is unclear. The aim of this study was to localize these proinflammatory cytokines in myometrium (upper and lower segment), cervix, and fetal membranes at term. Biopsies were taken from women undergoing cesarean section either before or after the onset of labor. Immunohistochemistry was used to localize each of the cytokines IL-1, IL-6, IL-8, and TNF␣. Leukocytes were localized using an antibody to CD45. In myometrium and cervix, immunostaining for IL-1 was predominantly in leukocytes. In fetal membranes, IL-1 localized to leukocytes and to the stromal cells of the decidua. In myometrium, IL-6, IL-8, and TNF␣ were restricted to leukocytes, which were present in greater numbers in tissue obtained during labor. In cervix, IL-6, IL-8, and TNF␣ localized to leukocytes and glandular and surface epithelium. IL-8 also localized to cervical stromal cells. In fetal membranes, IL-6 and TNF␣ were expressed by decidual stromal cells, infiltrating leukocytes, and extravillous trophoblasts. In membranes, IL-8 localized to leukocytes in the chorion but was not detected in the amnion. In fetal membranes collected at labor, IL-8 was expressed in decidual stromal cells. Infiltrating leukocytes are a major source of cytokines in uterine tissues during labor.
Placenta, 2002
Virtually all known cytokines have been demonstrated to be expressed in the placenta and associated fetal and maternal membranes during normal gestation. In addition to playing their traditional roles as modulators of immunological function, cytokines derived from the placenta and extraplacental membranes, together with other locally-derived growth factors, appear to be implicated in various aspects of implantation and placental development. Imbalances in the intrauterine cytokine milieu around the time of implantation and invasion may play a causative role in disorders associated with early pregnancy failure, and are also associated with the abnormal trophoblast development seen in gestational trophoblastic disease. Cytokines thus appear to be an important component of a paracrine/autocrine communication network operating within the feto-maternal interface to ensure the successful establishment of pregnancy.
Cytokine secretion by human fetal membranes, decidua and placenta at term
Human Reproduction, 1998
and interleukin-10 (IL-10) are thought to play pivotal roles in immune recognition, acceptance of the fetal allograft, maintenance of pregnancy and parturition. Their secretion and regulation within the third trimester uterus is, however, less well defined. We therefore investigated the release of these cytokines by third trimester amnion, chorion, placenta and decidua, and studied the influence of prostaglandin E 2 (PGE 2 ) infusion on their release in a dynamic placental cotyledon perfusion system. MCP-1 was released predominately by the chorion (78.2 ⍨ 7.3 pg/mg wet tissue weight; mean ⍨ SEM), decidua (112.4 ⍨ 5.2 pg/mg) and placenta (101.8 ⍨ 5.0 pg/mg) with low amounts from the amnion (1.3 ⍨ 0.4 pg/mg). High concentrations of IL-8 were released by the amnion (39.9 ⍨ 5.3 pg/mg), chorion (52.8 ⍨ 1.9 pg/mg), decidua (42.2 ⍨ 1.5 pg/mg) and placenta (45 ⍨ 1.3 pg/mg). Release of RANTES was not detectable from the amnion but was detected in moderate amounts from the chorion (6.0 ⍨ 1.2 pg/mg), decidua (15.2 ⍨ 1.4 pg/mg) and placenta (26.9 ⍨ 1.6 pg/mg). Low concentrations of IL-10 were secreted by the chorion (6.8 ⍨ 0.8 pg/mg), decidua (9.0 ⍨ 0.9 pg/mg) and placenta (3.3 ⍨ 0.3 pg/mg) with none detectable from the amnion. MCP-1, IL-8, RANTES and IL-10 were all released by perfused placental cotyledons. PGE 2 stimulated release of MCP-1, IL-8 and IL-10 into the maternal and of MCP-1 and IL-8 into the fetal circulation of the placenta but had no effect on RANTES release. It is suggested that MCP-1 and IL-8 may be involved in the inflammatory process of parturition and IL-10 in the protection of the fetal allograft. In addition, PGE 2 may have an important immunomodulatory role within the uterus at term.
American Journal of Obstetrics and Gynecology, 2003
OBJECTIVE: Vascular disease in the umbilical placental circulation is associated with fetal growth restriction and adverse outcome. It may be identified antenatally by the study of umbilical artery Doppler flow velocity waveforms. The cause of this vascular disease is unknown. We have previously provided indirect evidence for endothelial cell activation and a proinflammatory cytokine response. Recently, a family of inhibitors of cytokine signaling has been identified, referred to as the suppressors of cytokine signaling (SOCS). Activation of SOCS occurs when cytokines are produced in stimulated cells. We tested the hypothesis that endothelial cell activation was present in umbilical placental vascular disease and was associated with production of proinflammatory cytokines and members of the family of SOCS. STUDY DESIGN: Placentas were collected at delivery and microvascular endothelial cells were isolated. We studied 13 normal pregnancies and 10 with umbilical placental vascular disease identified by an abnormal umbilical artery Doppler study. Placental pieces were digested with collagenase and purified by adherence to Dynabeads coated with monoclonal antibody against CD31. The RNA was extracted from isolated endothelial cells. The messenger RNA expression of cytokine production (interleukin-6 and interleukin-8) and the members of SOCS family (CIS, SOCS1, SOCS2, and SOCS3) were assessed by use of semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: In the microcirculation of the placenta, endothelial cell expression of interleukin-6 messenger RNA (2.50 ± 0.60 vs 1.25 ± 0.26) and interleukin-8 messenger RNA (2.83 ± 0.55 vs 1.58 ± 0.27) was upregulated in umbilical placental vascular disease in comparison to normal pregnancy. The endothelial cell mRNA expression of SOCS2 (3.36 ± 0.77 vs 1.76 ± 0.29) and SOCS3 (2.77 ± 0.60 vs 1.48 ± 0.26) was enhanced in placental vascular disease. There was no significant difference in expression of CIS and SOCS1 in microvessel endothelial cells. CONCLUSION: We have demonstrated that microvessel endothelium of the fetal placental vasculature produces both the proinflammatory cytokines (interleukin-6 and interleukin-8) and members of SOCS family (SOCS2 and SOCS3) in umbilical placental vascular disease. This cytokine production may play a key role in the interaction of endothelial cells of the placenta villi with neighboring cells. The up-regulation of SOCS2 and SOCS3 indicates these are the major negative regulators in umbilical placental microvessel endothelial cell activation pathways. By its occurrence, this also confirms the presence of a proinflammatory cytokine response. (Am J Obstet Gynecol 2003;189:1445-51.)
A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition
American Journal of Obstetrics and Gynecology, 1998
OBJECTIVE: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor.STUDY DESIGN: After informed consent was obtained, amniocentesis and cordocentesis were performed in 41 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for both aerobic and anaerobic bacteria, as well as for mycoplasmas. Fetal plasma interleukin-6 was assayed by a sensitive and specific immunoassay. Statistical analyses included contingency tables and survival analysis with time-dependent Cox regression hazard modeling.RESULTS: Microbial invasion of the amniotic cavity was present in 58.5% (24/41) of patients. Fetuses with fetal plasma interleukin-6 concentrations >11 pg/mL had a higher rate of spontaneous preterm delivery within 48 and 72 hours of the procedure than those with fetal plasma interleukin-6 levels ≤11 pg/mL (88% vs 29% and 88% vs 35%, respectively; P < .05 for all comparisons). Moreover, patients with initiation of labor and delivery within 48 hours of the procedure had a higher proportion of fetuses with plasma interleukin-6 values >11 pg/mL than patients delivered >48 hours (58% [7/12] vs 8% [1/13], respectively; P < .05). Survival analysis indicated that fetuses with elevated fetal plasma interleukin-6 levels had a shorter cordocentesis-to-delivery interval than those without elevated fetal plasma interleukin-6 concentrations (median 0.8 days [range 0.1 to 5] vs median 6 days [range 0.2 to 33.6], respectively; P < .05). Time-dependent Cox regression hazard modeling indicated that fetal plasma interleukin-6 level was the only covariate significantly associated with the duration of pregnancy after we adjusted for gestational age, amniotic fluid interleukin-6 level, and the microbiologic state of the amniotic cavity (P < .01).CONCLUSION: A systemic fetal proinflammatory cytokine response is followed by the onset of spontaneous preterm parturition in patients with preterm premature rupture of membranes. (Am J Obstet Gynecol 1998;179:186-93.)