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Progesterone Receptor Plays a Major Antiinflammatory Role in Human Myometrial Cells by Antagonism of Nuclear Factor-B Activation of Cyclooxygenase 2 Expression

Departments of Biochemistry (D.B.H., D.R.C., C.R.M.), Obstetrics and Gynecology (C.R.M.), and Pharmacology (B.A.J., D.R.C.), North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9038

Address all correspondence to: Carole R. Mendelson, Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, E-mail: carole.mendelson{at}utsouthwestern.edu.

Spontaneous labor in women and in other mammals is likely mediated by a concerted series of biochemical events that negatively impact the ability of the progesterone receptor (PR) to regulate target genes that maintain myometrial quiescence. In the present study, we tested the hypothesis that progesterone/PR inhibits uterine contractility by blocking nuclear factor B (NF-B) activation and induction of cyclooxygenase-2 (COX-2), a contractile gene that is up-regulated in labor. To uncover mechanisms for regulation of uterine COX-2, immortalized human fundal myometrial cells were treated with IL-1ß ± progesterone. IL-1ß alone caused a marked up-regulation of COX-2 mRNA, whereas treatment with progesterone suppressed this induction. This was also observed in human breast cancer (T47D) cells. In both cell lines, this inhibitory effect of progesterone was blocked by RU486. Using chromatin immunoprecipitation, we observed that IL-1ß stimulated recruitment of NF-B p65 to both proximal and distal NF-B elements of the COX-2 promoter; these effects were diminished by coincubation with progesterone. The ability of progesterone to inhibit COX-2 expression in myometrial cells was associated with rapid induction of mRNA and protein levels of inhibitor of B, a protein that blocks NF-B transactivation. Furthermore, small interfering RNA-mediated ablation of both PR-A and PR-B isoforms in T47D cells greatly enhanced NF-B activation and COX-2 expression. These effects were observed in the absence of exogenous progesterone, suggesting a ligand-independent action of PR. Based on these findings, we propose that PR may inhibit NF-B activation of COX-2 gene expression and uterine contractility via ligand-dependent and ligand-independent mechanisms.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

Ligands:   Progesterone  |  RU486

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