Progesterone and PIBF: new insights into treatment options for preeclampsia

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We have shown Preeclampsia (PE) to be a progesterone deficient state of pregnancy associated with increased TH1 lymphocytes, cytolytic natural killer (NK) cells, inflammatory cytokine, vasoactive pathways resulting in endothelial function and hypertension. Healthy normal pregnancy (NP) is associated with elevations in progesterone and TH2 lymphocytes, and uterine NK cells favoring immunotolerance toward the fetus. Importantly, NP lymphocytes express progesterone receptors, which stimulate Progesterone Induced Blocking Factor (PIBF) upon binding to progesterone, thus PIBF increases during NP. Therefore we hypothesize that PIBF blockade causes a proinflammatory hypertensive phenotype similar to PE. Rabbit anti-PIBF IgG (0.50 mg/mL) was administered i.p. on gestational day 15 (GD 15) to NP rats, on GD 18 carotid catheters were inserted and on GD 19 mean arterial blood pressure (MAP) and samples were collected. MAP in NP rats (n=7) was 99+ 3 mmHg, which increased to 113+4 mmHg in NP+ anti-PIBF (n=6), p<0.05. Plasma TNF-α was 35+8 pg/mL in NP rats and increased to 84+21 pg/mL in NP+ Anti-PIBF (n=4), p<0.05. Circulating total NK cells were 67+ 11 in NP rats (n=4), which decreased to 36+4 in NP+ Anti-PIBF, while cytolytic NK cells were 0.6 + 0.2 in NP and increased to 3.0+1 in NP+ Anti-PIBF, p<0.05. Circulating nitric oxide was 44+ 11 µM in NP rats (n=5), which decreased to 21+1 µM in NP+ Anti-PIBF (n=6), p<0.05, while, renal cortex preproendothelin-1 increased 15 fold in NP+ Anti-PIBF (n=6) compared to NP rats (n=5). In order to determine if PIBF supplementation improves a PE phenotype during pregnancy, PIBF (2.0 µg/mL) was administered i.p. on GD 15 to the reduced uterine perfusion pressure (RUPP) a rat model of PE and compared to control RUPP and NP rats. On GD19, MAP and samples were collected. MAP in NP rats (n=11) was 100+ 2 mmHg, 105 + 3 in NP+PIBF (n=8), 122+ 1 in RUPP rats (n=10), which improved to 110+2 mmHg in RUPP+PIBF rats (n=11), p<0.05. PIBF lowered circulating and placental cytolytic NK cells in RUPPs from 15+6, 2.4+1% gate to 3+2, 0.4+0.1% in RUPP+PIBF(p<0.05, n=4-8). Moreover PIBF supplementation increased circulating IL-4 and TH2 to 40±8 pg/mL, 2+0.6 % gate in RUPP+PIBF (n=4-8 p<0.05) compared to9 ±2 pg/mL, 0.5+ 0.1 % gate in RUPP. Importantly, vasoactive pathways preproendothelin-1 and nitric oxide were normalized in RUPP+PIBF rats compared to RUPP rats, p<0.05. Collectively, these data demonstrate an important role for PIBF to control the inflammatory milieu thereby normalizing vasoactive pathways and maintaining healthy blood pressures during pregnancy.