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J Clin Endocrinol Metab. 2014 Feb;99(2):E320-8. doi: 10.1210/jc.2013-2721. Epub 2013 Nov 25.

Negative effects of progesterone receptor isoform-A on human placental activity of the noncanonical NF-κB signaling.

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  • 1Department of Obstetrics, Gynecology, and Reproductive Sciences (B.W., N.P., M.R., T.R.), Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901; and Department of Obstetrics, Gynecology, and Women's Health (N.R.), Rutgers New Jersey Medical School, Newark, New Jersey 07101.

Abstract

CONTEXT:

Progesterone (P4)contributes to the maintenance of human pregnancy, in part by inhibiting activity of the human pro-labor genes CRH and cyclooxygenase-2 (COX-2). However, the molecular mechanisms underlying the action of P4 remain poorly defined. We have shown that in human placenta, the constitutively activated noncanonical nuclear factor (NF)-κB pathway positively regulates CRH and COX-2, which is further stimulated by glucocorticoid receptor signaling.

OBJECTIVE:

We investigated the role of P4 receptor (PR) in the regulation of nuclear activity of v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)/NF-κB2 and, in turn, expression of placental CRH and COX-2.

METHODS:

We used a variety of techniques including gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, quantitative RT-PCR, and immunohistochemical staining assays in human placental tissues and primary culture of human cytotrophoblast.

RESULTS:

We identified PR isoform-A (PR-A) as the only isoform of PR produced in human placenta. PR-A levels were lower in term placenta than in midterm placenta. Depletion of PR-A by short interfering RNA derepressed inhibition of CRH and COX-2 by P4 and the synthetic progestin 17α-hydroxyprogesterone caproate. Overexpression of PR-A inhibited transcription of CRH and COX-2, which was further downregulated by treatment with P4 or 17α-hydroxyprogesterone caproate. Such an inhibition was mediated by a negative functional interaction of PR-A with the activity of RelB/NF-κB2.

CONCLUSION:

P4 inhibits the pro-labor genes CRH and COX-2 via PR-A repression of the noncanonical NF-κB signaling in human placenta. Characterization of these pathways may identify potential drug targets for prevention of preterm birth.

[PubMed - indexed for MEDLINE]
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