Abstract
The R educed U terine P erfusion P ressure (RUPP) rat model of placental ischemia mimics many characteristics of preeclampsia (PE) including hypertension, fetal growth restriction, and increased T H 17s, IL-17, and cytolytic natural killer cells (cNKs). IL-17 stimulates NK cytotoxicity in vitro . This study tested the hypothesis that blockade of IL-17 signaling would inhibit activation of cNKs to improve blood pressure and fetal growth in RUPP rats. On gestation day (GD) 14, osmotic pumps infusing IL-17 RC (100 pg/d), a soluble receptor for IL-17, were implanted into pregnant rats undergoing RUPP (RUPP+IL17 RC). On GD 19, circulating and placental T H 17s and cNKs were quantified via flow cytometry in normal pregnant (NP), RUPP, and RUPP+IL17 RC rats. cNK activation, placental ROS, fetal and placental weights, and MAP were also assessed. As we have previously shown, placental T H 17 populations (% gated) were significantly increased in RUPP (23.1±3.9%, n=9) compared to NP (8.5±3.9%, n=9) rats and were suppressed in RUPP+IL17 RC (8.3±3.1%, n=9). Circulating T H 17s followed the same trend. Placental cNKs, significantly increased from 7.2±2.8% in NP to 16.6±3.3% in RUPP, and were normalized to 7.2±2.8% after IL-17 blockade (p<0.05 vs RUPP). Placental cNK proteins and circulating cNKs showed a similar trend. Placental levels of the cNK cytokine, TNFα, increased from 28.5±.01 pg/mg in NP to 46.2±6.0 pg/mg in RUPP and was normalized to 28.5±4.6 pg/mg in RUPP+IL-17 RC (p<0.05 vs RUPP). Placental MIP3a, a cNK chemokine, had a similar trend. Assessment of in vitro cytotoxic activity of placental NK cells from rats in each group demonstrated a 5-fold increase in cytotoxicity by RUPP NK cells compared to NP NK cells. This was blunted in NK cells from RUPP+IL17 RC rats. Placental ROS was increased in RUPP compared to NP and significantly decreased with IL-17 blockade. Fetal weight decreased from 2.4±0.04 g in NP to 2.1±0.04 g in RUPP and increased to 2.3±0.05 g in RUPP+IL17 RC (p<0.05 vs RUPP). Placental weights followed a similar trend. MAP increased from 93 mmHg in NP to 120 mmHg in RUPP, and was decreased to 105 mmHg in RUPP+IL17 RC (p<0.05 vs RUPP). These data demonstrate a direct role for IL-17 signaling to mediate NK cytotoxic activation in response to placental ischemia during pregnancy.
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