Tumor necrosis factor (TNF)-α upregulates progesterone receptor-A by activating the NF-κB signaling pathway in human decidua after labor onset

doi:10.1016/j.placenta.2011.09.004

Placenta

Volume 33, Issue 1, January 2012, Pages 1-7

https://doi.org/10.1016/j.placenta.2011.09.004 Get rights and content

Abstract

To date, the relationship between inflammatory cytokines and progesterone receptors (PRs) has been little studied, although both mediate the mechanism of parturition in human deciduas. Thus, the aim of study was to investigate the role of an inflammatory cytokine, tumor necrosis factor (TNF)-α, in regulating progesterone withdrawal in decidua at human parturition. TNF-α levels and PR isoforms were compared in intrauterine deciduas from women who were in labor (IL, n = 10) or who were not in labor (NIL, n = 10). Nuclear factor-kappaB (NF-κB) signaling and PR status were analyzed in NIL deciduas after TNF-α stimulation. Immunohistochemistry, western blotting, ELISA and reverse transcription-polymerase chain reaction (RT-PCR) were used to localize and quantitate protein and mRNA expression. TNF-α immunostaining, protein levels, PR-A/PR-B ratio and COX-2 level were significantly higher in IL deciduas (all P < 0.05). NF-κB was activated by TNF-α after 24 h stimulation in a dose-dependent manner, and was significantly inactivated by the NF-κB inhibitor panepoxydone, which was associated with decreased PR-A and COX-2 expression (P < 0.05) in not in labor deciduas. In conclusion, TNF-α may have an important role in regulating progesterone withdrawal in human decidua following labor onset.

Introduction

The onset of labor in most mammals is preceded by a rapid fall in maternal progesterone levels, whereas maternal, fetal, and amniotic fluid concentrations of progesterone are sustained at high levels prior to onset of labor in humans [1]. The proposed mechanism responsible for parturition in humans thus involves ’functional’ progesterone withdrawal, and is mediated by decreased progesterone activity associated with alterations in the expression of progesterone receptors (PRs) [2], [3], [4]..

Several studies have investigated the source of the withdrawal signal responsible for the onset of labor, and have mainly focused on the myometrium, placenta, decidua, and fetal membranes [5], [6], [7], [8]. Much of the literature supports the idea that labor onset is associated with ‘decidual activation’, accompanied by increased proteolysis and extracellular matrix degradation, and there is evidence for local progesterone withdrawal in activated human deciduas [9], [10], [11]. PRs exist in the human decidua as at least two functional isoforms: a full-length PR-B and an N-terminal-truncated PR-A. PR-A is generally acknowledged to act as a transcriptional inhibitor of PR-B. After the initiation of contractions, a sharp decline in PR-B shifts the PR-A/PR-B ratio towards PR-A dominance. This shift in the decidua plays a pivotal role in decidual activation and the initiation of labor [9].

Activated decidua also produces high levels of pro-inflammatory cytokines [12].These cytokines affect the surrounding tissues, including the placenta, fetal membranes, and uterus in a paracrine secretory fashion [13], [14], to cause localized inflammatory responses [12]. They are also described as pro-labor factors, mediating labor onset mechanisms through the stimulation of COX-2 and prostaglandin (PG) synthesis [15]. PG serves as an important molecular mediator of matrix degradation, cervical ripening, and uterine contractions [16].

TNF-α has been shown to upregulate PR-C, another inhibitory truncated PR isoform, thus reducing PR-B transactivation or other steroid receptor expression and mediating progesterone withdrawal in the human myometrium [17], [18]. PR-C upregulation in laboring myometrium might have an effect on the activation of the nuclear factor-kappaB (NF-κB) pathway, which contributes to the onset of labor [17]. These results suggest that there might be a close association between the production of inflammatory cytokines and PR status in human deciduas at parturition. This study was therefore designed to explore the regulation of PR-A and its role in the decidua after labor onset.

Section snippets

Samples

Deciduas were obtained from consenting women undergoing cesarean deliveries in the Department of Gynecology and Obstetrics of the People’s Hospital of Jiangsu Province, China. The decidual tissues were taken by wiping-sterile gauze between the placenta and uterus immediately after placenta delivery. Samples were classified into two groups: not in labor (NIL, n = 10) and in labor (IL, n = 10). IL specimens were from patients with regular contractions and cervical dilation of >3 cm, who underwent

Results

The tissues sampled were confirmed to be decidua, not fetal membranes or placental villi (Fig. 1a–g). Vascular endothelial cells and interstitial cells are the two main cell components of the decidua. These cell types are positive for vimentin but not keratin (Fig. 1b and d), while placental trophoblasts are positive for keratin but not vimentin (Fig. 1c and a). Fetal membranes have a distinct histologic structure under the microscope, with continuous linear amnion epithelial cells, connective

Discussion

The results of this study demonstrated that deciduas collected from women in labor released higher levels of TNF-α than those from women who were not in labor. The high levels of inflammatory cytokines were not associated with systemic inflammatory response, because maternal plasma CRP levels, leukocytes, and body temperature were all normal prior to cesarean delivery. In addition, all clinical specimens were from pregnancies with no signs of infection. These data indicate that TNF-α was

Funding

The National Natural Science Foundation of China,Grant No. 81070511. The project of six peak talent of Jiangsu Province, Grant No. DG216D5019.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Tumor necrosis factor (TNF)-α upregulates progesterone receptor-A by activating the NF-κB signaling pathway in human decidua after labor onset

Abstract

Introduction

Section snippets

Samples

Results

Discussion

Funding

Conflict of interest

Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Reprod Immunol

Placenta

Phytomedicine

Eur J Pharmacol

J Reprod Immunol

Int Immunopharmacol

Placenta

Placenta

J Reprod Immunol

Am J Pathol

J Biol Chem

Best Pract Res Clin Obstet Gynaecol

Am J Obstet Gynecol

Maternal serum estrogen and progesterone concentrations preceding normal labor

Obstet Gynecol

Myometrial. Progesterone responsiveness

Semin Reprod Med

Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: evidence for prostaglandin-induced functional progesterone withdrawal

J Clin Endocrinol Metab

The progesterone receptor in human term amniochorion and placenta is isoform C

Endocrinology