Abstract P161: Inhibition of Progesterone Induced Blocking Factor Causes Clinical Characteristics of Preeclampsia in Sprague Dawley Rats

Abstract

Preeclampsia (PE) affects 5-7% of all pregnancies in the U.S and it is characterized by new onset hypertension in association with progesterone deficiency, elevated natural killer (NK) cells and inflammatory cytokines. Despite being a leading cause of maternal death and perinatal morbidity, the mechanisms responsible for the pathogenesis of PE are unclear. Progesterone is crucial for establishing and maintaining pregnancy and it exerts immune modulatory effects by the lymphocyte-derived protein progesterone induced blocking factor (PIBF). Its immunological effects include inhibition of natural killer (NK) cell activity and can regulate the proinflammatory balance. PIBF has been shown to act through IL-4/TH2, which are reduced during PE and increased during normal pregnancy, however the role of PIBF deficiency in PE pathology is not well examined. Thus, this study was designed to test the hypothesis that PIBF blockade stimulates cytolytic NK cells to cause the symptoms of PE during pregnancy. Rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneal on gestation day 15 to normal pregnant Sprague Dawley (NP) rats and on day 18 carotid catheters were inserted and on GD 19 blood pressure and samples were collected. MAP in NP rats (n=7) was 99± 3 mmHg, which increased to 116± 2 in NP+ anti-PIBF LD (n =10) and 113±4 in NP+ anti-PIBF HD (n=4), p<0.05. Neither placental weight nor pup weight was affected by PIBF blockade. Circulating total and cytolytic NK cells were 67± 11 and 0.6 ± 0.2 in NP rats (n=4), which total NK cells decreased to 28±7 in NP+ Anti-PIBF LD and 36±4 in NP+ Anti-PIBF HD while cytolytic NK cells were increased to 2.0±1 in NP+ Anti-PIBF LD and 3.0±1 in NP+ Anti-PIBF HD, p<0.05. Plasma IL-4 and IL-10 levels were 22±5, 25±6 in NP (n=5), which decreased to 6±1, 8±1 in NP+ Anti-PIBF LD (n=6, p<0.05) and 16 ±4, 15±5 in NP+ Anti-PIBF HD (n=4). Plasma TNF-alpha levels were 35±8 in NP, 32±6 in NP+ Anti-PIBF LD and 84±21 in NP+ Anti-PIBF HD. Collectively, our findings demonstrate that PIBF blockade increases inflammation and blood pressure to levels similar to what is observed in PE, thus indicating the importance of progesterone signaling pathways for the maintenance of healthy pregnancy.