Abstract
Two important clinical features of preeclampsia (PE) are hypertension and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE exhibits both of these features. Moreover, RUPP and PE women have elevated vasoconstrictor peptide endothelin-1 (ET-1) and inflammation. Interleukin-2 (IL-2) is a cytokine that regulates NK cell activity and is elevated in miscarriage, PE, and RUPP rats. The objective of this study was to examine a role for IL-2 in NK cell activation, fetal growth restriction, and hypertension during pregnancy by either infusion of IL-2 or blockade of IL-2 (basiliximab) in normal pregnant (NP) and RUPP rats. On gestational day 14, NP and RUPP rats received low (LD), middle (MD), or high dose (HD) IL-2 (0.05, 0.10, or 0.20 ng/ml) IP or basiliximab (0.07 mg per rat) by IV infusion. On day 19, blood pressure (MAP), pup weights, and blood were collected. Basiliximab had no effect on blood pressure, however, significantly lowered NK cells and may have worsened overall fetal survival in RUPP rats. However, IL-2 LD (102 ± 4 mmHg) and IL-2 HD (105 ± 6 mmHg) significantly lowered blood pressure, ET-1, and activated NK cells compared to control RUPPs (124 ± 3 mmHg, p < 0.05). Importantly, IL-2 in RUPP rats significantly reduced fetal weight and survival. These data indicate that although maternal benefits may have occurred with low dose IL-2 infusion, negative effects were seen in the fetus. Moreover, inhibition of IL-2 signaling did not have favorable outcome for the mother or fetus.
Highlights
Preeclampsia (PE) is a multi-system disorder characterized by new onset hypertension during pregnancy [1,2,3,4,5,6]
The effect of IL-2 infusion on blood pressure and fetal weights in reduced uterine perfusion pressure (RUPP) and normal pregnant (NP) rats mean arterial pressure (MAP) was significantly elevated in RUPP vs. NP rats (124 ± 3 vs. 101 ± 2 mmHg, p < 0.05) (Fig. 1), and significantly decreased in RUPP rats treated with the Low dose (LD) IL-2 (102 ± 4 mmHg, p < 0.05 vs. RUPP) and high dose (HD) IL-2 (105 ± 6 mmHg, p < 0.05 vs. RUPP, Fig. 1)
We have previously shown that RUPP rats have elevated effector T cells, natural killer (NK) cells, and IL-2 compared to normal pregnant rats [21]
Summary
Preeclampsia (PE) is a multi-system disorder characterized by new onset hypertension during pregnancy [1,2,3,4,5,6]. PE is associated with increased cytokines, natural killer (NK) cells, T-helper 1 (TH1) cells, TH17 cells, and a decrease in T regulatory (T regs) and TH2 cells [2, 3, 6]. Natural killer cells can be influenced by memory CD4+ TH1 cells through their secretion of interleukin-2 (IL-2) which is elevated in preeclamptic women and associated with other pathological conditions of pregnancies [10,11,12,13,14]. Healthy pregnancy is associated with higher uterine NK cells within their placentas than PE patients. We believe that pathophysiology and adverse outcomes seen in PE may be in part due to the increase in cytolytic NK cells and decrease in uterine NK cells. Uterine NK cells, which are noncytolytic in nature, are characterized by their release of the anti-inflammatory cytokines IL-5 and IL-13 [15, 16], and they communicate with T reg cells to create a feto-tolerant uterine environment [15,16,17,18]
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