With More than 2000 Times Increased Plasma Concentration, Interleukin‐17A Does Not Increase Arterial Blood Pressure in Mice

Abstract

Background T-lymphocytes are important for angiotensin II (ANGII)-hypertension in mice. T-helper 17 cells produce the pro-inflammatory cytokine interleukin-17 (IL-17). Plasma IL-17A is increased in both hypertensive animals and humans. IL-17A KO mice are protected against ANGII-induced hypertension. Anti-IL-17 treatment of hypertensive mice decreases blood pressure. There is a lack of data directly documenting a hypertensive effect of IL-17A. The objective of this study was to investigate the direct effect of IL-17A on blood pressure in mice. It was hypothesised that continuous i.v. infusion of IL-17A in mice will increase blood pressure and amplify ANGII-induced hypertension. Methods A model of continuous IL-17A i.v. infusion and blood pressure measurement was used by implantation of indwelling catheters in the femoral vein and artery. Femoral artery catheter was used for continuous blood pressure recording every 5 min and to collect undisturbed arterial blood in live non-stressed mice. After a 5-day recovery time upon operation, baseline blood pressure was measured for 3 days. Then, mice received IL-17A at 0.1, 1.0 and 10 ug/day for 2, 2 and 4 days respectively. In another experiment, mice were given ANGII (60ng/kg/min) and IL-17A (1 ug/day) or saline for 9 days. In an acute bolus experiment, mice received 10, 20, 40 and 80 ug IL-17A in one bolus i.v. infusion with 10 min. interval. Continuous blood pressure measurements were obtained and EDTA blood was collected before and after infusion from all mice. Plasma IL-17A levels was assessed before and after infusion using ELISA. Results IL-17A dosis-step-up experiments with concentrations 0.1, 1.0 and 10 ug/day did not cause any blood pressure increase, instead blood pressure decreased significantly from 106 (102-112) mmHg at baseline to 104 (99-110) mmHg, 102 (98-108) mmHg and 99 (95-103) mmHg during IL-17A infusion of dose 1, 2 and 3 respectively. Plasma IL-17A levels of these mice after experiment increased significantly up to 2500 times compared to baseline levels from 0.6 (0.5-1.1) pg/ml to 2523 (0.5-8252) pg/ml. Also, IL-17A did not accentuate ANGII-induced hypertension. Instead, blood pressure was reduced in mice receiving ANGII with IL-17A compared to ANGII and saline treated mice from 136 (130-139) mmHg to 124 (121-126) mmHg. Plasma IL-17A was significantly higher in IL-17A and ANGII treated mice compared to saline and ANGII treated mice. ANGII did not elevate plasma IL-17A levels compared to baseline levels. In the dose-step-up experiment heart rate was significantly reduced from 661 (637-585) BPM at baseline to 631 (604-652) BPM at the highest dose given. Conclusion In summary, despite up to 2500 times increase in circulating IL-17A from 2 different vendors and prolonged infusion for up to 9 days, no increase in blood pressure was observed during IL-17 infusion alone, and IL-17A did not accentuate ANGII effects neither. Instead a blood pressure reducing effect was observed. These data suggest that in complex models with inflammation, IL-17A is likely to act redundantly in concert with other mediators to increase blood pressure, but IL-17A dose not seem to have any direct blood pressure increasing effects in mice despite prolonged exposure.