Changes in Placental CRH, Urocortins, and CRH-Receptor mRNA Expression Associated with Preterm Delivery and Chorioamnionitis

abstract Context: The pathogenesis of preterm delivery (PTD) is not clear, although inflammation/infection play a major role. Corticotropin releasing-hormone (CRH) and Urocortins (Ucns) are involved in the pathophysiology of PTD. Objective: This study evaluates trophoblast mRNA expression of CRH, Ucn, Ucn2, Ucn3, and their receptors [CRH-type 1 receptor (CRH-R1), CRH-R2] in infective conditions. To determine whether infection or glucocorticoids contribute to change their placental mRNA expression, the effects of lipopolysaccharide or dexamethasone was evaluated. Design: Placentas were obtained from spontaneous PTD; premature rupture of membranes (pPROM) and pPROM with chorioamnionitis. Setting: Placental specimens were collected from women receiving perinatal care at our Division of Obstetrics and Gynecology. Patients or Other Participants: Pregnant women delivered preterm were enrolled. Interventions: mRNA expression was evaluated by RT-PCR. Main Outcome Measure: Because CRH and Ucns are involved in immunological functions we evaluated their involvement in PTD with or without infection. Results: CRH, Ucn2, and CRH-R1 mRNA expression were higher, while Ucn and CRHR-2 were lower in pPROM with chorioamnionitis than in PTD and pPROM. Ucn3 mRNA expression was lower in pPROM with and without chorioamnionitis than in PTD. The addition of lipopolysaccharide in trophoblast explants decreased Ucn, Ucn3, and CRH-R2 and increased CRH, Ucn2, and CRH-R1 mRNA expression in a dose-dependent manner. Dexamethasone increased CRH and decreased Ucn2 mRNA expression in a dose dependent manner. Conclusions: Our findings showed a significant impact of pPROM with chorioamnionitis on placental CRH peptides and receptors, suggesting that placental expression of stress-related pathways is activated in infective process

Effects of urocortin 2 and urocortin 3 on IL-10 and TNF-a expression and secretion from human trophoblast explants

7reservedObjectives The aim of the present study was to evaluate the effect of Ucn2 and Ucn3 on cytokine expression and secretion from placental explants. Study design Placentas were collected from healthy pregnancies at term elective caesarean delivery and trophoblast explants were prepared and treated with Ucn2 or Ucn3 in presence/absence of the selective CRH-R2 antagonist, astressin 2b. The mRNA expression and secretion of IL-10 and TNF-α were evaluated by Real Time RT-PCR and ELISA, respectively. Main outcome measures To evaluate the possible role of Ucn2 and Ucn3 in inflammatory pathways. Results Ucn2 increased the mRNA expression and secretion of IL-10 and TNF-α, and Ucn3 increased the mRNA expression and secretion of IL-10, but did not modify the secretion of TNF-α. Ucn3 treatment reversed the LPS-induce increase of TNF-α expression and release, an effect blocked by astressin 2b. Ucn2 potentiated the LPS-induced increase of TNF-α expression and release, an effect reversed by astressin 2b. Conclusions The present study showed that Ucn2 and Ucn3 differentially regulate the LPS-induced TNF-α and IL-10 expression and secretion in trophoblast explants acting through CRH-R2. A pro inflammatory effect of Ucn2 and an anti-inflammatory effect of Ucn3 in placental immunomodulatory mechanisms is suggestedmixedNovembri, R.; Torricelli, M.; Bloise, E.; Conti, N.; Galeazzi, L.R.; Severi, F.M.; Petraglia, F.Novembri, R.; Torricelli, M.; Bloise, E.; Conti, N.; Galeazzi, L. R.; Severi, F. M.; Petraglia, F

Activin A and its Regulatory Molecules in Placenta and Fetal Membranes of Women with Preterm Premature Rupture of the Membranes Associated with Acute Chorioamnionitis.

LABELED PROBLEM: To investigate regulation of activin A and related molecules in placenta/fetal membranes from preterm premature rupture of membranes (pPROM) associated with acute chorioamnionitis (ACA). METHOD OF STUDY: Tissues were obtained from women with spontaneous preterm deliveries (PTD), pPROM without ACA, pPROM with ACA. Activin A, follistatin, and nodal and cripto mRNA were measured by RT-PCR. RESULTS: Activin A mRNA was up-regulated in tissues from pPROM, in presence or absence of HCA, respect to PTD and in pPROM with ACA respect to pPROM without ACA. Follistatin mRNA expression did not differ between the groups. In placenta, nodal mRNA showed the same trend of activin A, while cripto was down-regulated in pPROM with ACA than other groups. Nodal and cripto were not expressed by fetal membranes. CONCLUSION: The study shows the involvement of activin A pathway in pPROM with ACA. Further studies will focus on its role in placental immune functions

Postdate pregnancy: Changes of placental/membranes 11β-hydroxysteroid dehydrogenase mRNA and activity

11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and 11β-HSD2) are involved in the complex mechanism of human parturition. The present study examined mRNA expression and activity of membrane 11β-HSD1 and placental 11β-HSD2 in postdate pregnancies according to response of labor induction. In comparison to postdate women who had spontaneous delivery or after induction the non-responders showed significantly low c and high 11β-HSD2 expression and activity These data suggest that disrupted expression and activity of 11β-HSDs may occur in some postdate pregnancies

Heat-killed Lactobacillus rhamnosus GG modulates urocortin and citokine release in primary trophoblast cells

A number of studies are showing that probiotic treatment induces an anti-inflammatory state. Intrauterine infection can lead to preterm delivery by modulating immune function and efforts to prevent this condition are ongoing nowadays. Lactobacillus rhamnosus GG (LGG) is a probiotic known to ameliorate inflammation by increasing local anti-inflammatory mediators in urinary and gastrointestinal tracts. The present study then analyzed the effect of heat-killed LGG over β-hCG, progesterone, interleukins (IL) 4 and 10, tumor necrosis factor-α (TNF-α), corticotropin releasing hormone (CRH) and urocortin (Ucn) release by primary trophoblast cells. Normal human term placentas (n = 6) were collected and purified trophoblast cells were incubated in the presence of LGG, lipopolysaccharide (LPS) or either LGG + LPS during 3 h, after which the target substances were quantified by ELISA and real-time PCR. LGG did not affect β-hCG, progesterone, or CRH secretion. Conversely, LGG increased IL-4 protein and mRNA expression (P < 0.05) while IL-10 and Ucn secretion were increased in a dose dependent manner and the highest dose of LGG increased significantly IL-10 mRNA (P < 0.05). LGG did not alter TNF-α, while LPS exposure increased TNF-α protein (P < 0.001) and mRNA expression (P < 0.01). Conversely, LGG treatment reversed LPS-induced TNF-α release at both protein (P < 0.01) and mRNA levels (P < 0.05) in a dose dependent fashion. In conclusion, LGG stimulates IL-4, IL-10 and Ucn expression and reverses LPS-induced TNF-α release from trophoblast cells, with no change in β-hCG or progesterone release, suggesting that this probiotic may play a role as an immunomodulatory agent in human placenta without altering basic trophoblast functions. © 2010 Elsevier Ltd. All rights reserved

Urocortin 2 and urocortin 3 in endometriosis: evidence for a possible role in inflammatory response

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