Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

Previous studies by our lab have established that placental‐ischemia stimulated T‐helper 17 cells (T(H)17s) cause increased cytolytic natural killer (cNK) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 (IL‐17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL‐17 into a subset of normal pregnant (NP) Sprague Dawley rats from gestation day (GD) 12–19 (NP+IL‐17). On GD 19, mean arterial pressure (MAP), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP+IL‐17 (P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP+IL‐17 as did placental weight (NP: 0.65 ± 0.03 g; NP+IL‐17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF‐α increased to 281.4 ± 55.07 pg/mL in NP+IL‐17 from 145.3 ± 16.03 pg/mL in NP (P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP+IL‐17. Total NK cells were increased in the placenta (NP: 14.3 ± 3.49%; NP+IL‐17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells (NP: 3.31 ± 1.25%; NP+IL‐17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/mL in NP to 20.9 ± 7.76 pg/mL in NP+IL‐17 (P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/mL in NP to 14.9 ± 0.98 pg/mL in NP+IL‐17(P < 0.05). In the placenta, both granzyme A (NP: 246.1 ± 16.7 pg/mg; NP+IL‐17: 324.3 ± 15.07 pg/mg, P < 0.05) and granzyme B (NP: 15.18 ± 3.79 pg/mg; NP+IL‐17: 27.25 ± 2.34 pg/mg, P < 0.05) increased in response to IL‐17 infusion. Finally, vascular reactivity of uterine arteries was significantly impaired in response to IL‐17 infusion. The results of this study suggest that IL‐17 plays a significant role in the activation of cNK cells during pregnancy.