Administration of Interleukin-17 Soluble Receptor C Suppresses T _H 17 Cells, Oxidative Stress, and Hypertension in Response to Placental Ischemia During Pregnancy

Abstract

Pre-eclampsia (PE), new onset hypertension with proteinuria during pregnancy, is associated with chronic inflammation and placental oxidative stress (ROS). Chronic IL-17 increases blood pressure (MAP), autoantibodies (AT1-AA) and ROS during pregnancy. The objective of this study was to determine if TH17 suppression via IL-17RC (recombinant receptor C) decreases pathophysiology associated with placental ischemia (RUPP). On gestation day 14, mini-osmotic pumps infusing 100 pg/day of IL-17RC were implanted into pregnant rats undergoing RUPP (Reduced Uterine Perfusion Pressure), gestation day18 carotid catheters were inserted, day 19 MAP was recorded, TH17 cells, oxidative stress and AT1-AA were measured and analyzed via one-way ANOVA. MAP increased from 101 ±2 mmHg in normal pregnant, NP (n=19), to 120 ±1 mmHg in RUPP (n=17),but decreased to 110±2 mmHg in RUPP+IL-17RC rats (n=22). Pup weight decreased from 2.28 ± 0.2 g in NP to 1.96 ± 0.3 g in RUPP rats, but was significantly increased to 2.01 ± 0.1 in RUPP+IL-17RC rats. TH17 cells were 1.77% in RUPP but decreased to 0.65% in RUPP+IL-17RC rats. Urinary isoprostanes normalized in RUPP +IL-17RC rats (52 pg/μg) compared to 89 pg/μg in RUPP controls. Placental ROS was 652 RLU in RUPP, but decreased to 337 RLU in RUPP+IL-17RC rats. AT1-AA was 17.27 ± 0.7 bpm in RUPP but decreased to 5.00 ± 0.5 bpm in RUPP+IL-17RC rats. With this study, we show that infusion of IL-17RC blunts TH17s, oxidative stress, AT1-AA, and hypertension in the RUPP model of PE indicating that TH17 cells may play an important role in disease pathophysiology.

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

“…35 We have previously reported that circulating CD4þIL-17Aþ lymphocytes are increased in the circulation and kidneys of HELLP rats, but not in the spleen, placenta, or liver indicating that the source of IL-17 does not come just from TH17 lymphocytes, which were not found to be significantly increased in rats with HELLP syndrome. 21 We have also previously reported that administration of IL-17 to pregnant rats increases MAP and CD4þ lymphocytes [36][37][38] Figure 3. The ET A blockade attenuates hypertension in HELLP rats.…”

A Role of sFlt-1 in Oxidative Stress and Apoptosis in Human and Mouse Pre-Eclamptic Trophoblasts1

“…PE is thought to be a multifactorial disease that involves oxidative stress, endothelial dysfunction, inflammation, and immunity [3][4][5]. Previous studies of PE have shown interactions between inflammation and endothelial dysfunction [6] and between inflammation and oxidative stress [7]. We also previously found a relationship between oxidative stress and immunity in placental trophoblasts in PE [8].…”

Autoimmunity: An Underlying Factor in the Pathogenesis of Hypertension

“…For example, T cells from angiotensin II-infused mice produce and release more IL-17, and IL-17 knockout mice are protected from angiotensin II-induced hypertension [18]. In addition, data from the LaMarca laboratory indicate that infusion of IL-17 into normal pregnant rats leads to chronic increases in blood pressure [19] and that blocking IL-17 activity with the soluble receptor to the cytokine prevents pregnancy-induced increases in blood pressure [20]. Although the mechanisms for IL-17-induced hypertension remain unclear, there is some evidence suggesting that IL-17 promotes hypertension by reducing endothelial nitric oxide synthase [21].…”