Ola Gutzeit, Rivka Hertz, Yuval Ginsberg, Ron Beloosesky, Zeev Weiner, Ofer Fainaru

Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel 

Objective: Immature myeloid cells (IMCs) are bone marrow-derived cells that normally differentiate into granulocytes, macrophages, and dendritic cells (DCs) but expand in pathological conditions. We have previously shown that IMCs accumulate in placentas, promote angiogenesis, peak during mid-pregnancy and correlate with neonatal birthweight. Progesterone has been shown to inhibit prmature labor and delivery. We thus hypothesized that progesterone may affect the placental IMC population.

Study Design: Mice bone marrow (BM) cells selected for CD11b+ expression by magnetic separation (MACS) were incubated for 5 days with/without progesterone. Myeloid cells were defined as Ly6G^med/Ly6C^high “monoctyic”- or Ly6G^high/Ly6C^med “granulocytic” IMCs by flow cytometry. Mosue preterm labor model: ICR pregnant mice (n=29) were pretreated with/without vaginal progesterone (1mg/day) or carrier (Replens) from 13E-16E. Lipopolysaccharide(LPS) (30µg)/vehicle was administered intrapertioneally at 15E-16E. Next, mice were sacrificed, BM and placental cells were immunostained and analyzed by flow cytometry.

Results: In culture, progesterone treated BM-IMCs demonstrated a significant monocytic-IMCs population decrease and a granulocytic-IMC population increase. The DC population decreased in the presence of progesterone.   In mice, LPS treatment led to an increase in IMCs populating the BM in both P-pretreated (41.5±9.5vs.1.3±0.3%,p=0.05) or non-pretreated mice (20.8±9.4vs.1.3±0.6%,p=0.05). In the placenta, LPS led to a decline in IMCs. Strikingly, progesterone pretreatment led to complete abrogation of this effect (control:28.2±6.1; P:29.6±4.7; LPS:23.0±2.6; P+LPS:35.4±2.5%; p=0.01).

Conclusion: Progesterone enhances the proliferation of bone marrow derived IMCs in vitro.  In mice, LPS leads to a decrease in placental IMCs. This effect was completely abrogated in progesterone pretreated mice. We thus speculate that the protective effect of progesterone in preventing preterm labor may be explained at least in part by this specific anti-inflammatory effect.