IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia

Harmon, Ashlyn C.; Cornelius, Denise C.; Amaral, Lorena M.; Paige, Adrienne; Herse, Florian; Ibrahim, Tarek; Wallukat, Gerd; Faulkner, Jessica; Moseley, Janae; Dechend, Ralf; LaMarca, Babbette

doi:10.3109/10641955.2015.1032054

Cited by 77 publications

(67 citation statements)

References 51 publications

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“…Plasma levels of IL-4 were 22.4 Ϯ 3.7 pg/ml in NP, 18.7 Ϯ 9.6 pg/ml in RUPP, and 42.3 Ϯ 8.2 pg/ml in RUPPϩ NPT Reg s (n ϭ 5/group). Additionally, as we have previously published (12), serum TGF-␤ trended toward a decrease in response to placental ischemia (NP 1,036 Ϯ 82 pg/ml vs. RUPP 567 Ϯ 88 pg/ml, n ϭ 4/group, P ϭ 0.06) and was normalized after adoptive transfer of NP T Reg s into RUPP rats (965 Ϯ 145 pg/ml, n ϭ 6) (Fig. 5B).…”

Section: Np T Reg Cell Supplementation Normalizes Tgf-␤ In Rupp Ratssupporting

confidence: 57%

“…Surprisingly, increases in the circulating levels of IL-10 were not detected after adoptive transfer of NP T Reg s into placental ischemic RUPP rats. We have recently shown that IL-10 supplementation significantly lowered blood pressure, TNF-␣, and AT 1 -AA, while increasing Tregs in RUPP rats (12). In that study, elevations in IL-10 were not detected; however, it could be that in each study, IL-10 is bound to its receptors and mediating anti-inflammatory function, such as repressing TNF-␣, AT 1 -AA, and stimulating T Reg s. In addition, IL-4, although not statistically significant, was elevated twofold with supplementation of RUPP rats with NP T Reg s. Not many studies have been performed with IL-4 during preeclampsia; however, we know that it is important in programming of T H 2 cells, which are known to be decreased in preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

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An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Cornelius

Amaral

Harmon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (T Regs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4 ϩ /CD25ϩ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 Ϯ 2 mmHg in NP (n ϭ 12) to 127 Ϯ 2 mmHg in RUPP (n ϭ 21) but decreased to 118 Ϯ 2 mmHg in RUPPϩNP TRegs (n ϭ 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-␣ and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 Ϯ 58.7 and 603 Ϯ 88.1 RLU·min Ϫ1 ·mgϪ1 in RUPP and significantly decreased to 178 Ϯ 27.8 and 171 Ϯ 55.6 RLU·min Ϫ1 ·mg Ϫ1 , respectively, in RUPPϩNP TRegs; AT1-AA was 17.81 Ϯ 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 Ϯ 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-␣, and AT 1-AA, which have been shown to increase blood pressure during pregnancy.hypertension; pregnancy; inflammation; oxidative stress; regulatory T cells PREECLAMPSIA IS A PREGNANCY-ASSOCIATED disorder that affects 5-8% of pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality (9,29,37). Hallmark characteristics of preeclampsia are new-onset hypertension after 20 wk gestation, proteinuria, chronic immune activation, fetal growth restriction, and maternal endothelial dysfunction. The pathophysiological mechanisms that lead to the development of preeclampsia are poorly understood. It is thought that poor invasion of trophoblasts leads to insufficient spiral artery remodeling, resulting in placental ischemia (4, 10, 31). The hypoxic environment that results from this placental ischemia is suggested to be an important factor in the development of oxidative stress and a shift in the balance of antiangiogenic and proangiogenic factors, which plays a role in endothelial dysfunction of the placenta and maternal vasculature (10). Previous studies from our laboratory in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia demonstrate that the total population of CD4-positive (CD4 ϩ ) T cells isolated from RUPP spleens and transferred to NP rats causes similar pathology to that seen in RUPP rats (46), demonstrating a role for this population in mediating pathophysiology in response to placental ischemia. Recent data from both clinical and animal model stud...

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Section: Np T Reg Cell Supplementation Normalizes Tgf-␤ In Rupp Ratssupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Cornelius

Amaral

Harmon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Total RNA was extracted using the RNeasy Protect mini kit supplied by Qiagen, as outlined in the instructions provided by the manufacturer. Real-time PCR was utilized, as previously described, to determine levels of tissue preproendothelin-1 (PPET-1) (11). Briefly, cDNA was synthesized from 1 g of RNA with Bio-Rad Iscript cDNA reverse transcriptase, and real-time PCR was performed using the Bio-Rad SYBR Green Supermix and iCycler.…”

Section: Methodsmentioning

confidence: 99%

Serelaxin improves the pathophysiology of placental ischemia in the reduced uterine perfusion pressure rat model of preeclampsia

Santiago-font

Amaral

Faulkner

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Preeclampsia is a hypertensive disorder of pregnancy that has limited therapeutic options. In healthy pregnancy, relaxin plays an important vasodilatory role to maintain vascular compliance; however, currently, there is no preclinical evidence to support the use of relaxin during preeclampsia. Therefore, the goal of this study was to test the hypothesis that recombinant human relaxin-2 (Serelaxin, Novartis; RLX) could reduce mean arterial pressure (MAP) and improve uterine artery resistance index (UARI) and nitric oxide bioavailability, and/or decrease prepro-endothelin-1 (PPET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and TNF-α) in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. On day 14 of gestation (GD14), pregnant rats were assigned to normal pregnant (NP), RUPP, RUPP+RLX, or NP+RLX groups. Treated rats received RLX at 0.4 μg/h or RLX2 4 μg/h RLX via minipump implanted on GD14. On GD18, carotid arterial catheters were inserted, and on GD19, MAP and tissues were collected. MAP was increased in RUPP rats compared with NP but was lowered with either dose of RLX. UARI and sFlt-1 were significantly improved in both treated RUPP groups. Total circulating nitrate-nitrite improved and placental PPET-1 and TNF-α were significantly decreased with the higher dose of RLX. Renal cortex PPET-1 was reduced with both doses of RLX. In conclusion, Serelaxin improved blood pressure, sFlt-1, TNF-α, UARI, and nitric oxide bioavailability and PPET-1 in a rat model of preeclampsia, thereby suggesting a potential therapeutic role for RLX in maintaining maternal health and prolonging pregnancy in the face of placental ischemia.

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“…In addition, IL-10 can suppress nitric oxide production, an important component of airway inflammation [99]. Upregulation of IL-10 was also demonstrated to normalize blood pressure and endothelial function [100,101]. Superoxide anion and hydrogen peroxide were found in higher concentrations in both asthma and hypertension patients compared with controls [102,103].…”

Section: Prioritization Of Candidate Genesmentioning

confidence: 99%

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

et al. 2018

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Background: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or~22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. Results: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension -713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system.

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IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia

Cited by 77 publications

References 51 publications

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Serelaxin improves the pathophysiology of placental ischemia in the reduced uterine perfusion pressure rat model of preeclampsia

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

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