Abstract
Preeclampsia (PE), new onset hypertension in response to placental ischemia during pregnancy, is associated with chronic inflammation characterized by elevated tumor necrosis factor (TNF-α), interleukin-6 (IL-6), agonistic autoantibody to the Ang II type 1 receptor (AT1-AA). In addition, evidence for a shift towards proinflammatory CD4+TH1 vs CD4+TH2 profile exist in PE. Therefore we tested the hypothesis that IL-4, a cytokine essential for TH2 differentiation and proliferation, would improve pregnancy outcomes in response to placental ischemia (RUPP) by shifting the immune profile toward CD4+TH2. Interleukin-4, 600 ng/day, was administered via a mini-osmotic pump on day 14 of gestation into normal pregnant (NP) rats and into RUPP rats immediately following the reduced uterine perfusion pressure (RUPP) procedure and carotid catheters were inserted on gestation day 18. Blood pressure (MAP), TNF-α, IL-6, AT1-AA and circulating TH2 cells were measured on GD 19. MAP in NP rats (n=10) was 96 + 2, 101 + 2 in NP+IL-4 rats (n=14), 130 + 4 in RUPP rats (n=6), which improved to 108 + 2 mmHg in RUPP+IL-4 rats (n=15), p< 0.05. Plasma levels of TNF-α and IL-6 were 25 + 6, 29 + 3 in NP rats (n=7-8/group), 116 + 30, 224 + 62 in RUPP rats (n=9-10/group), which decreased to 23 + 5 and 135 + 48 pg/mL in RUPP+IL-4 rats (n=5-7/group), p<0.05. Importantly, plasma levels of AT1-AA were 0.3 + 0.4 in NP rats (n=8), 0.3 + 0.2 in NP+IL-4 rats (n=5), 18 + 0.3 in RUPP rats (n=9), which were blunted to 4 + 1 bpm in RUPP+IL-4 rats (n=14), p<0.05. Circulating TH2 cells were 17.3 ± 2.7 in NP rats (n=3), 9.0 ± 2.0 in RUPP rats (n=5), which improved to 13.4 ± 3.2 % gated in RUPP+IL-4 rats (n=9). This study illustrates that administration of IL-4 decreases TNF-α, IL-6, AT1-AA, possibly by increasing TH2/IL-4 in RUPP rats, which ultimately led to a reduction in hypertension in response to placental ischemia of pregnancy.
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