17-Hydroxyprogesterone caproate improves T cells and NK cells in response to placental ischemia; new mechanisms of action for an old drug

Elfarra, Jamil; Cottrell, Jesse; Cornelius, Denise C.; Cunningham, Mark; Faulkner, Jessica; Ibrahim, Tarek; LaMarca, Babbette; Amaral, Lorena M.

doi:10.1016/j.preghy.2019.11.005

Cited by 16 publications

(17 citation statements)

References 59 publications

(71 reference statements)

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“…in the RUPP rat model of PreE (Elfarra et al, 2020) and found that the synthetic hormone, which is commonly used to prevent preterm delivery in healthy pregnancies, has antiinflammatory and vasodilatory effects (Dodd et al, 2013). Because the naturally occurring hormone progesterone reduces cytotoxic NK cell activity in the uterus (Dosiou and Giudice, 2005;Elfarra et al, 2020), 17-OHPC may act similarly (Elfarra et al, 2020).…”

Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

“…Within circulation and in the placenta in PreE, non-cytolytic, type 2 NK cells are decreased while cytolytic, type 1 NK cells are increased ( Fukui et al, 2012 ), increasing apoptosis and therefore the production of debris. Elfarra et al tested 17-hydroxyprogesterone caproate (17-OHPC) in the RUPP rat model of PreE ( Elfarra et al, 2020 ) and found that the synthetic hormone, which is commonly used to prevent preterm delivery in healthy pregnancies, has anti-inflammatory and vasodilatory effects ( Dodd et al, 2013 ). Because the naturally occurring hormone progesterone reduces cytotoxic NK cell activity in the uterus ( Dosiou and Giudice, 2005 ; Elfarra et al, 2020 ), 17-OHPC may act similarly ( Elfarra et al, 2020 ).…”

Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

“…In the RUPP model, 17-OHPC normalized HTN and pup weight, decreased fetal demise rates, reduced uterine artery resistance, and increased circulating and placental Th2 cells while suppressing pro-inflammatory CD4+ T cells and cytokines to restore immune balance ( Elfarra et al, 2020 ). Circulating Th2 cells were significantly increased in RUPP rats with 17-OHPC treatment ( Elfarra et al, 2020 ).…”

Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

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Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Murray

Gumusoglu

Santillan

et al. 2022

Front. Bioeng. Biotechnol.

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Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE’s clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis.

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Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

Section: -Hydroxyprogesterone Caproatementioning

confidence: 99%

See 1 more Smart Citation

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Murray

Gumusoglu

Santillan

et al. 2022

Front. Bioeng. Biotechnol.

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“…In search of potential treatments for preeclampsia, several studies investigating the beneficial effects of anti‐inflammatory compounds have also reported alterations in local or systemic NK‐cell populations as secondary outcomes. The administration of the anti‐inflammatory cytokine IL‐4 in a RUPP rat model reduced the proportions of total and cytolytic NK cells in the placenta, 217 as did treatment with 17α‐hydroxyprogesterone caproate (17‐OHPC) 218 . Targeting reactive oxygen species by treatment with a superoxide dismutase mimetic, tempol, also lowered the proportions of circulating total and cytotoxic NK cells 219 .…”

Section: Introductionmentioning

confidence: 99%

Cellular immune responses in the pathophysiology of preeclampsia

Miller

Motomura

Galaz

et al. 2021

Journal of Leukocyte Biology

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Preeclampsia, defined as new‐onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi‐systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti‐angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal‐fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

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“…For flow cytometry, 1 X 10 6 cells were incubated for 10 minutes at 4 °C with antibodies against rat natural killer cell markers ANK61 and ANK44 as previously described. (26) Cells that stained for ANK61+ and ANK44+ were designated as activated NK cells respectively. The percent of (ANK44+/ANK61+) positive stained cells above the negative control was determined for individual rats and the mean values for each experimental group were calculated.…”

Section: The Effect Of Tnf-α Blockade On Nk Cells In Rupp Ratsmentioning

confidence: 99%

Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia

Cunningham

Jayaram

Deer

et al. 2020

Hypertension in Pregnancy

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Preeclampsia (PE) is associated with placental ischemia, hypertension (MAP), increased cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS). The reduced uterine perfusion pressure (RUPP) rat model of PE, exhibits many characteristics of PE. We have shown that blockade of TNF-α, via etanercept (ETAN), decreases MAP, however, the effect of ETAN on cNK cells and mt ROS is unknown. We hypothesized that ETAN would decrease cNK cell and mt ROS in RUPP rats. Rats were divided into 3 groups: normal pregnant (NP) (n=20), RUPP (n=20), RUPP + ETAN (0.4 mg/kg) (n=20). On gestational day 14, RUPP surgery was performed, and ETAN was administered on day 18, MAP, blood and tissue mitochondria were collected on day 19. MAP was elevated in RUPP vs. NP (118 ± 2 vs. 102± 1 mmHg, p<0.05) which was reduced to 110 ± 2 in RUPP + ETAN (p<0.05). cNK cells were increased in circulation (5.9 ± 1.8 vs. 4.0 ± 1.4 % gated cells), placenta (4.8 ± 1.3 vs. 1.9 ± 0.7 %;), and kidney (3.1 ± 0.5 vs. 0.8 ± 0.5% gated cells; of RUPP vs. NP (p<0.05) and were lowered to 1.5 ± 0.5%, 1.7 ± 0.7%, 0.8 ± 0.5% gated cells in RUPP + ETAN ( p<0.05). Placental and renal mt ROS was reduced with ETAN treatment. TNF-α blockade lowered cNK cells, and mt ROS in placental ischemic rats, which could have contributed to lowered blood pressure observed in response to placental ischemia.

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17-Hydroxyprogesterone caproate improves T cells and NK cells in response to placental ischemia; new mechanisms of action for an old drug

Cited by 16 publications

References 59 publications

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Cellular immune responses in the pathophysiology of preeclampsia

Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia

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