Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor

Holdsworth-Carson, Sarah J.; Permezel, Michael; Rice, Gregory E.; Lappas, Martha

doi:10.1530/rep-08-0496

Cited by 30 publications

(15 citation statements)

References 56 publications

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“…Placental PPARg is particularly notable because it has strong antiinflammatory properties, including inhibition of pro-inflammatory cytokine gene transcription (Lappas et al 2002). Previous studies assessing the expression of placental PPARs (collected following vaginal delivery) have indicated that preterm (w34 weeks of gestation) and term placentas have equivalent PPARA (PPARa) mRNA and protein levels; however, protein expression of PPARD (PPARd) and PPARG (PPARg) is significantly higher in preterm placentas compared with term placentas (Holdsworth-Carson et al 2009). However, DNA binding of all the PPAR isoforms did not differ between the preterm and term tissues (HoldsworthCarson et al 2009), suggesting an equal functional capacity of PPARs across late gestation.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of docosahexaenoic acid on preterm and term placental pro-oxidant/antioxidant balance

2013

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Docosahexaenoic acid (DHA) supplementation in pregnancy may confer some clinical benefits; however, this compound can exert pro-oxidant effects. In this study, we investigated the effects of DHA on pro-oxidant/antioxidant balance in term and preterm placental explants, assessing oxidative stress marker concentrations, antioxidant capacity and pro-inflammatory cytokine production. Term (nZ8) and preterm (nZ9) placental explants were exposed to lipopolysaccharide (LPS, 1 ng/ml), DHA (1, 10 and 100 mM), and DHA and LPS simultaneously or pre-treated with DHA for 24 h prior to LPS treatment. The production of malondialdehyde (MDA, lipid peroxidation), 8-hydroxy-2-deoxy guanosine (8-OHdG, oxidative DNA damage) and pro-inflammatory cytokines (tumour necrosis factor a (TNFa), interleukin 6 and interferon-g) and total antioxidant capacity were measured. DHA at a concentration of 100 mM induced oxidative stress in term placentas, while at all the three concentrations, it induced oxidative stress in preterm placentas. DHA and LPS resulted in reduced MDA levels in term (P!0.005) and preterm (PZ0.004) placentas and reduced 8-OHdG levels in preterm placentas (PZ0.035). DHA pre-treatment, but not co-treatment with LPS, reduced 8-OHdG levels (P!0.001) in term placentas. DHA increased antioxidant capacity only in term placentas (P!0.001), with lower antioxidant capacity being observed overall in preterm placentas compared with term placentas (P%0.001). In term placentas, but not in preterm ones, DHA co-treatment and pre-treatment reduced LPS-induced TNFa levels. The ability of DHA to alter placental pro-oxidant/antioxidant balance is dependent on the DHA concentration used and the gestational age of the placental tissue. DHA has a greater capacity to increase oxidative stress in preterm placentas, but it offers greater protection against inflammation-induced oxidative stress in term placentas. This appears to be a result of DHA altering placental antioxidant capacity. These data have implications for the timing and concentration of DHA supplementation in pregnancy.

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Section: Discussionmentioning

confidence: 99%

Differential effects of docosahexaenoic acid on preterm and term placental pro-oxidant/antioxidant balance

2013

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“…1H and I) expression was significantly lower after spontaneous preterm labour. Western blotting could not be performed on foetal membranes from the chorioamnionitis group due to protein degradation (Holdsworth-Carson et al 2009). …”

Section: Resultsmentioning

confidence: 99%

A novel role for GSK3 in the regulation of the processes of human labour

Lim

Lappas

2015

Reproduction

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Preterm birth remains the largest single cause of neonatal death and morbidity. Infection and/or inflammation are strongly associated with preterm delivery. Glycogen synthase kinase 3 (GSK3) is known to be a crucial mediator of inflammation homeostasis. The aims of this study were to determine the effect of spontaneous human labour in foetal membranes and myometrium on GSK3a/b expression, and the effect of inhibition of GSK3a/b on pro-labour mediators in foetal membranes and myometrium stimulated with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. Term and preterm labour in foetal membranes was associated with significantly decreased serine phosphorylated GSK3a and b expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3b expression in myometrium. The specific GSK3a/b inhibitor CHIR99021 significantly decreased lipopolysaccharide (ligand to TLR4)-stimulated pro-inflammatory cytokine gene expression and release; COX2 gene expression and prostaglandin release; and MMP9 gene expression and pro MMP9 release in foetal membranes and/or myometrium. CHIR99021 also decreased FSL1 (TLR2 ligand) and flagellin (TLR5 ligand)-induced pro-inflammatory cytokine gene expression and release and COX2 mRNA expression and prostaglandin release. GSK3b siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1b and TNFa-induced pro-inflammatory cytokine and prostaglandin release. In conclusion, GSK3a/b activity is increased in foetal membranes after term and preterm labour. Pharmacological blockade of the kinase GSK3 markedly reduced pro-inflammatory and pro-labour mediators in human foetal membranes and myometrium, providing a possible therapeutics for the management of preterm labour.

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“…Studies about the expression of PPARs in gestational tissues in PTL are few. Holdsworth-Carson et al 27 have shown that PPARb protein expression in choriodecidua is higher in the PTL group than in the TL group, whereas the amount of PPARa and PPARg is not different between the PTL and TL groups. Consistently, we showed that the PPARb amount was higher in the PTL with CAM group than in the TL group, whereas its amount in the PTL without CAM group was not different with that in the TL group.…”

Section: Regulation Of Pgdh In Chorion By Pparsmentioning

confidence: 96%

“…A study by the same group found that the expression of PPARb and PPARg in the placenta and PPARb in fetal membranes increases in labor at preterm. 27 In contrast, Berry et al 21 reported that PPARa mRNA in choriodecidua declines with labor, whereas PPARg and PPARb mRNA remain unchanged with labor.…”

mentioning

confidence: 98%

Expression of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion Is Associated with Peroxisome Proliferator-Activated Receptor Isoform Expression in Term Labor

Ding

et al. 2015

The American Journal of Pathology

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Chorionic NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus. Peroxisome proliferator-activated receptors (PPARs) are implicated to be involved in parturition. In this study, we investigated whether PPARs are involved in control of PGDH expression in chorion. The chorionic tissues were collected from the following groups of the women with singleton pregnancy: term no labor (TNL), term labor (TL) and preterm labor (PTL). Chorionic trophoblasts were isolated and cultured in vitro. Immunocytochemistry analysis showed that PPARα, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PGDH, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PPARα, PPARβ, and PPARγ were reduced in TL tissues compared to that of TNL group. PPARα, PPARβ, and PPARγ expression correlated to PGDH in TNL tissues, whereas only PPARγ expression correlated to PGDH in TL chorion tissues. PGDH expression was decreased in PTL tissues compared with TL group, whereas the expression of PPARs was not significantly different between TL and PTL groups. The agonists of three PPARs dose-dependently stimulated PGDH activity, mRNA, and protein expression in cultured chorionic cells. PPARs did not affect the stability of PGDH mRNA but stimulated the transcriptional activity of HPGD gene. Our results suggest that PPARs play pivotal roles in maintenance of PGDH expression in chorion during human pregnancy.

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Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor

Cited by 30 publications

References 56 publications

Differential effects of docosahexaenoic acid on preterm and term placental pro-oxidant/antioxidant balance

Differential effects of docosahexaenoic acid on preterm and term placental pro-oxidant/antioxidant balance

A novel role for GSK3 in the regulation of the processes of human labour

Expression of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion Is Associated with Peroxisome Proliferator-Activated Receptor Isoform Expression in Term Labor

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