Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function.
Progesterone acting via the progesterone receptor (PR) plays a critical role in maintaining uterine quiescence during pregnancy. In the present study, we tested the hypothesis that the transactivating capability of the PR is down-regulated in the myometrium at term by a change in uterine PR isoform ratio resulting from local activation of the nuclear factor (NF)-kappaB pathway. Overexpression of the truncated PR-C isoform in human myometrial cells inhibited PR-B transactivation. Expression of PR isoforms, PR-A, PR-B, and PR-C, was characterized by immunoblotting and quantitative PCR (Q-PCR) in fundal and lower uterine segment myometrium from pregnant women in labor and not in labor and in the pregnant mouse uterus during late gestation. We observed a marked increase in levels of PR-C and transcriptionally active PR-B specifically in fundal myometrium of women in labor. In pregnant mouse uterus, levels of PR-B and PR-C also increased between 15 days post coitum and term, whereas expression of PR-A was dramatically up-regulated at 19 days post coitum. In studies of uterine tissues of mice injected intraamniotically with surfactant protein A and of human myometrial and T47D breast cancer cells in culture, up-regulation of PR isoform expression was observed in response to activation of the NF-kappaB pathway. Chromatin immunoprecipitation analysis revealed IL-1beta induced binding of NF-kappaB to the PR promoter. Collectively, these findings suggest that up-regulation of inhibitory PR isoform expression by NF-kappaB activation in both laboring human fundus and pregnant mouse uterus near term may inhibit PR transactivation and thereby lead to a loss of uterine quiescence and the onset of labor.
Condon
Jennifer C
JC
Department of Biochemistry, North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038, USA.
Hardy
Daniel B
DB
Kovaric
Kelly
K
Mendelson
Carole R
CR
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007745:Labor Onset / Q000235:genetics / Q000378:metabolism; D007743:Labor, Obstetric / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009215:Myometrium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D016328:NF-kappa B; D020033:Protein Isoforms; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D004247:DNA