Interleukin‐11 signaling is required for the differentiation of natural killer cells at the maternal–fetal interface

Ain, Rupasri; Trinh, My-Linh; Soares, Michael J.

doi:10.1002/dvdy.20183

Cited by 61 publications

(37 citation statements)

References 40 publications

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“…Binucleate uNK cells, representing senescent cells (39), were also significantly increased. This finding contradicts a previous report on IL11Rα −/− mice, in which IL15 production was compromised and uNK cell localization within the decidual compartment was virtually absent (40). Together, these findings suggest that IL11 signaling is required for normal uNK cell recruitment, but elevated levels also affect recruitment and/or differentiation and normal function.…”

Section: Discussioncontrasting

confidence: 95%

Interleukin-11 alters placentation and causes preeclampsia features in mice

Winship

Koga

Menkhorst

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women. We demonstrate that IL11 administered to mice causes development of PE features. Immunohistochemistry shows IL11 compromises trophoblast invasion, spiral artery remodeling, and placentation, leading to increased systolic blood pressure (SBP), proteinuria, and intrauterine growth restriction, although nonpregnant mice were unaffected. Real-time PCR array analysis identified pregnancy-associated plasma protein A2 (PAPPA2), associated with PE in women, as an IL11 regulated target. IL11 increased PAPPA2 serum and placental tissue levels in mice. In vitro, IL11 compromised primary human EVT invasion, whereas siRNA knockdown of PAPPA2 alleviated the effect. Genes regulating uterine natural killer (uNK) recruitment and differentiation were down-regulated and uNK cells were reduced after IL11 treatment in mice. IL11 withdrawal in mice at onset of PE features reduced SBP and proteinuria to control levels and alleviated placental labyrinth defects. In women, placental IL11 immunostaining levels increased in PE pregnancies and in serum collected from women before development of early-onset PE, shown by ELISA. These results indicate that elevated IL11 levels result in physiological changes at the maternal-fetal interface, contribute to abnormal placentation, and lead to the development of PE. Targeting placental IL11 may provide a new treatment option for PE.placenta | trophoblast | cytokines | pregnancy P reeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria, unique to humans, affecting ∼8% of pregnancies (1). The etiology is poorly understood (2); nevertheless, there is substantial evidence showing abnormal placentation is the key underlying cause. During pregnancy, highly invasive extravillous trophoblasts (EVT) acquire vascular-like properties to remodel uterine spiral arterioles. This creates low-resistance, large-diameter vessels that promote uteroplacental blood supply to sustain fetal growth (3, 4). It is widely accepted that inadequate trophoblast invasion and impaired uterine spiral artery remodeling is an initiating factor in the development of PE (5). This is thought to impair uteroplacental arterial flow and lead to placental oxidative stress (6). PE is associated with increased placental secretion of proinflammatory cytokines (7) and angiogenic regulators (8), thought to contribute to widespread maternal endothelial dysfunction. The clinical symptoms of PE are hypertension, proteinuria, and peripheral and/or cerebral edema. Symptoms can differentially manifest during the second (early-onset, EO), or third (late-onset, LO) trimester (9). In addition to the maternal symptoms, PE is also frequently associated with prematurit...

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Section: Discussioncontrasting

confidence: 95%

Interleukin-11 alters placentation and causes preeclampsia features in mice

Winship

Koga

Menkhorst

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…uNKC deficiencies were previously found in IL-15 Ϫ/Ϫ mice that have residual amounts of improperly developed NKC (71) and in IL-11 Ϫ/Ϫ or Hoxa-10 Ϫ/Ϫ mice bearing developmentally impaired deciduae (72,73). However, T-bet Ϫ/Ϫ mice that have an overall reduction in NKC number do contain normal numbers of uNKC (71).…”

Section: Discussionmentioning

confidence: 84%

Transcription Factor Runx3 Regulates Interleukin-15-Dependent Natural Killer Cell Activation

Levanon

Negreanu

Lotem

et al. 2014

Molecular and Cellular Biology

100

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“…Interestingly, recent evidence in mice shows that IL11 signaling is required for decidual-specific maturation of NK cells. It has also been suggested that defective decidual vasculature is present in the IL11Ra mutant uterus compared with wild-type mice (Ain et al 2004). As for human, increasing evidence indicates that IL11 has an important function in implantation.…”

Section: Interleukin 11mentioning

confidence: 99%

Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors

Singh

Chaudhry²,

Asselin

2011

Journal of Endocrinology

278

195

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The prerequisite of successful implantation depends on achieving the appropriate embryo development to the blastocyst stage and at the same time the development of an endometrium that is receptive to the embryo. Implantation is a very intricate process, which is controlled by a number of complex molecules like hormones, cytokines, and growth factors and their cross talk. A network of these molecules plays a crucial role in preparing receptive endometrium and blastocyst. Furthermore, timely regulation of the expression of embryonic and maternal endometrial growth factors and cytokines plays a major role in determining the fate of embryo. Most of the existing data comes from animal studies due to ethical issues. In this study, we comprehend the data from both animal models and humans for better understanding of implantation and positive outcomes of pregnancy. The purpose of this review is to describe the potential roles of embryonic and uterine factors in implantation process such as prostaglandins, cyclooxygenases, leukemia inhibitory factor, interleukin (IL) 6, IL11, transforming growth factor-b, IGF, activins, NODAL, epidermal growth factor (EGF), and heparin binding-EGF. Understanding the function of these players will help us to address the reasons of implantation failure and infertility.

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Interleukin‐11 signaling is required for the differentiation of natural killer cells at the maternal–fetal interface

Abstract: Interleukin-11 (IL-11

Cited by 61 publications

References 40 publications

Interleukin-11 alters placentation and causes preeclampsia features in mice

Interleukin-11 alters placentation and causes preeclampsia features in mice

Transcription Factor Runx3 Regulates Interleukin-15-Dependent Natural Killer Cell Activation

Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors

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