Dataset Information

Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-?B-mediated inflammation.

ABSTRACT: Increased inflammation and abnormal placentation are common features of a wide spectrum of pregnancy-related disorders such as intra uterine growth restriction, preeclampsia and preterm birth. The inflammatory response of the human placenta has been mostly investigated in relation to cytokine release, but the direct molecular consequences on trophoblast differentiation have not been investigated. This study measured the general effects of LPS on both extravillous and villous trophoblast physiology, and the involvement of the transcription factors PPAR? and NF-?B, specifically using 1^st trimester explants and HTR-8/ SVneo cell line models. While both proteins are known for their roles in inflammatory pathways, PPAR? has been identified as an important molecule in trophoblast differentiation, suggesting its potential role in mediating a crosstalk between inflammation and trophoblast differentiation. Here, LPS (1?µg/ml) exposure of first trimester placental villous explants resulted in secretion of inflammatory cytokines, induction of apoptosis and reduction in trophoblast cell proliferation. Additionally, LPS significantly reduced expression of the trophoblast differentiation proteins GCM1 and ?-hCG, and increased invasion of the extravillous trophoblast. Activation of PPAR? by Rosiglitazone (10?µM) reversed the LPS-mediated effects on inflammatory cytokine release, trophoblast apoptosis and proliferation compared to controls. Lastly, markers of trophoblast differentiation and invasion reverted to control levels upon activation of PPAR? and concomitant inhibition of NF-?B (either by Rosiglitazone or NF-?B specific inhibitor), revealing a new role for NF-?B in trophoblast invasion. This study reveals a novel PPAR? - NF-?B axis that coordinates inflammatory and differentiation pathways in the human placenta. The ability to reverse trophoblast-associated inflammation with Rosiglitazone offers promise that the PPAR? - NF-?B pathway could one day provide a therapeutic target for placental dysfunction associated with both inflammation and abnormal trophoblast differentiation.

SUBMITTER: Kadam L

PROVIDER: S-EPMC6376060 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-κB-mediated inflammation.

Kadam Leena L Kilburn Brian B Baczyk Dora D Kohan-Ghadr Hamid Reza HR Kingdom John J Drewlo Sascha S

Scientific reports 20190214 1

Increased inflammation and abnormal placentation are common features of a wide spectrum of pregnancy-related disorders such as intra uterine growth restriction, preeclampsia and preterm birth. The inflammatory response of the human placenta has been mostly investigated in relation to cytokine release, but the direct molecular consequences on trophoblast differentiation have not been investigated. This study measured the general effects of LPS on both extravillous and villous trophoblast physiolo ...[more]

PMID: 30765769

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Project description:BACKGROUND:The placenta is a highly specialized temporary organ that is related to fetal development and pregnancy outcomes, and epidemiological data demonstrate an increased risk of placental abnormality after in vitro fertilization and embryo transfer (IVF-ET). METHODS:This study examines alterations in the transcriptome profile of first-trimester placentas from IVF-ET pregnancies and analyzes the potential mechanisms that play a role in the adverse perinatal outcomes associated with IVF-ET procedures. Four human placental villi from first-trimester samples were obtained through fetal bud aspiration from patients subjected to IVF-ET due to oviductal factors. An additional four control human placental villi were derived from a group of subjects who spontaneously conceived a twin pregnancy. We analyzed their transcriptomes by microarray. Then, RT-qPCR and immunohistochemistry were utilized to analyze several dysregulated genes to validate the microarray results. Biological functions and pathways were analyzed with bioinformatics tools. RESULTS:A total of 3405 differentially regulated genes were identified as significantly dysregulated (>?2-fold change; P <?0.05) in the IVF-ET placenta in the first trimester: 1910 upregulated and 1495 downregulated genes. Functional enrichment analysis of the differentially regulated genes demonstrated that the genes were involved in more than 50 biological processes and pathways that have been shown to play important roles in the first trimester in vivo. These pathways can be clustered into coagulation cascades, immune response, transmembrane signaling, metabolism, cell cycle, stress control, invasion and vascularization. Nearly the same number of up- and downregulated genes participate in the same biological processes related to placental development and maintenance. Procedures utilized in IVF-ET altered the expression of first-trimester placental genes that are critical to these biological processes and triggered a compensatory mechanism during early implantation in vivo. CONCLUSION:These data provide a potential basis for further analysis of the higher frequency of adverse perinatal outcomes following IVF-ET, with the ultimate goal of developing safer IVF-ET protocols.

Project description:The brush-border glycoproteins of first-trimester human placentas were investigated by using two external labelling techniques: (1) sequential digestion with neuraminidase and galactose oxidase, followed by reduction with NaB3H4, which 3H-labels terminal galactose and galactosamine residues; and (2) sequential treatment with periodate and NaB3H4, which 3H-labels terminal sialic acid residues. The labelling procedures were performed on intact tissue so that the results would more closely approximate the topography of the brush border in vivo. The microvilli were isolated, subjected to sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, and the [3H]glycoproteins detected by fluorography. Densitometer scans of the fluorograms of the [3H]galactoproteins showed that, under reducing conditions, 90% of the protein-associated radioactivity was incorporated into two glycoproteins. The major [3H]galactoprotein of early placental microvilli had an estimated molecular mass of 92 kDa (desialylated) and migrated as a diffuse band. A minor 180 kDa glycoprotein was less consistently labelled. No change in the apparent molecular mass of either component was detected in the absence of beta-mercaptoethanol, suggesting that the 180 kDa component was not a dimer of the 92 kDa glycoprotein. The remaining 10% the radioactivity was equally distributed among several minor membrane components. Densitometer scans of the fluorograms of the [3H]sialoproteins showed that, under either reducing or non-reducing conditions, 90% of the 3H was preferentially incorporated into the 92-110 kDa region of the gel. Although no distinct bands were visible, the higher-molecular-mass region of this area was always most heavily labelled. A minor 180 kDa glycoprotein was also 3H-labelled. The pattern of brushborder [3H]glycoproteins from first-trimester placentas differed markedly from that of term placental microvilli and from placental fibroblast plasma membranes that were 3H-labelled by identical external labelling techniques. These results indicate that: (1) the glycoprotein determinants of brush-border topography change during pregnancy; (2) within the placenta, the major 92 kDa (desialylated) determinant, which has not been previously described, is unique to the trophoblastic cells.

Dataset Information

Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-?B-mediated inflammation.

Publications

Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-κB-mediated inflammation.

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