Progesterone Receptor Antagonists Activate Macrophages and Induce Preterm Remodeling of the Cervix and Preterm Birth
- Michael Kirby, Ph.D, Loma Linda University School of Medicine
- Steven Yellon, Ph.D, Loma Linda University School of Medicine
Progesterone is essential to establish and maintain pregnancy. Loss of progesterone, through reduced concentrations in circulation, or receptor blockage (PR antagonist), promotes an inflammatory process that terminates pregnancy. The present study tested the hypothesis that PR antagonist treatment differentiates classic inflammatory macrophages (MΦ) as part of the mechanism that drives preterm remodeling of the cervix. CD-1 mice were injected on day 16 post-breeding with Vehicle as controls or pure PR antagonist, onapristone (Ona; 30 mg/kg BW), or mixed progesterone and glucocorticoid receptor antagonist, mifepristone (RU486; 6mg/kg BW). In accordance with NIH approved guidelines, the cervix was excised postmortem from treated groups of mice at intervals before and on the day of birth. Cervix section (10 μm) from each mice were stained by immunohistochemistry for CCR7 (phenotypic activation marker of classic inflammatory MΦ) and counterstained with methyl green to visualize cell nuclei which were counted to normalize the census of CCR7-stained cells to account for local tissue hypertrophy. Data was analyzed with an ANOVA (p<0.05). Results show that Ona and RU486 treatment groups delivered preterm (D17; ~24 hrs after injection) vs. Vehicle controls at term (D18-19). The number of CCR7-stained cells in the cervix increased significantly prior to birth in preterm RU486 treated mice; to the same extent as in controls before term birth. Along with similar preliminary data for Ona treated mice, these findings support the hypothesis that PR antagonist treatments advance an inflammatory process that may activate resident MΦ’s and promote preterm remodeling of the cervix. Whether inhibition of pathways involved in classic inflammatory processes is a therapeutic approach to treat women with preterm remodeling of the cervix and at risk for preterm birth remains to be determined.