The Involvement of Interleukin (IL)-15 in Regulating the Differentiation of Granulated Metrial Gland Cells in Mouse Pregnant Uterus

Ye, Weiguo; Zheng, Li‐Mou; Young, John Ding‐E; Liu, Chau‐Ching

doi:10.1084/jem.184.6.2405

Cited by 92 publications

(62 citation statements)

References 24 publications

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“…Uterine natural killer cells are the most abundant immune cell type at the maternal−fetal interface (27). IL11 significantly reduced placental IL15, required for uNK cell maturation and differentiation (37), and IL18, secreted by uNKs to mediate normal tissue remodeling (38). In accordance, decidual uNK cell numbers were reduced in IL11-treated pregnant mice at mid-gestation.…”

Section: Discussionsupporting

confidence: 63%

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: Discussionsupporting

confidence: 63%

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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“…Whether a4b7 + leukocytes are involved in uNK cell differentiation is unclear, although cells of the monocyte/ macrophage lineage have been reported to play a key role as immunoregulatory cells at the maternal/fetal interface. Published data obtained from in situ hybridization studies suggest that macrophages present in the pregnant mouse uterus may be responsible for the production of IL-15 [22], and it has also been shown that macrophages are the major source of IL-12 and IL-18 in most tissues [23,24]. These cytokines were recently shown to be capable of activating NK cells [25,26], and King and co-workers described IL-15 receptor expression on human decidual NK cells [27].…”

Section: Discussionmentioning

confidence: 98%

Functional involvement of P‐selectin and MAdCAM‐1 in the recruitment of α4β7‐integrin‐expressing monocyte‐like cells to the pregnant mouse uterus

et al. 2004

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Leukocyte recruitment to the pregnant mouse uterus has been suggested to be associated with highly regulated expression of distinct patterns of vascular adhesion receptors. One of the most striking observations is the combined expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and P-selectin by maternal vessels of the vascular zone during the critical period of initial placenta development. The predominant cell population within these vessels is of the monocyte/macrophage lineage and expresses the mucosal integrin a4b7, which represents the ligand for MAdCAM-1; neutrophils and lymphocytes are rare. To directly assess the importance of identified adhesion receptors, we undertook longterm in vivo inhibition studies using monoclonal antibodies to inhibit the contribution of MAdCAM-1 in leukocyte trafficking to the decidua or to deplete a4b7 + leukocytes. In addition, implantation sites of mouse strains genetically deficient in specific adhesion receptors were investigated. Our results underline the importance of predicted adhesion pathways in the recruitment of monocyte-like cells, especially those expressing a4b7. Interestingly, maternal/ fetal units with inhibited recruitment of a4b7 + leukocytes or the absence of these cells are characterized by reduced size and frequency of uterine NK cells.

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“…Several cytokines have been implicated in the induction of perforin in cytotoxic cells, including IL-2 (34), IL-6 (35), and IL-15 (36). Of these, IL-15 has been identified as a modulator of perforin expression in mouse uNK cells (37), and it is not inconceivable that NOS-2 acts through IL-15 to regulate perforin expression. NOS-2 has been shown to be a required component of IL-12 signaling in NK cells during early Leishmania major infection (38).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Synthase-2 and Expression of Perforin in Uterine NK Cells

Burnett

Hunt

2000

The Journal of Immunology

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In human, mouse, and rat pregnancy, maternal NK cells accumulate and differentiate at implantation sites. These cells, termed uterine NK (uNK) cells, express NO synthase (NOS)-2 and develop cytolytic molecules such as perforin and granzymes during differentiation in situ. In this study, relationships between expression of the NOS-2 gene, uNK cell population density and tissue distribution, and synthesis of perforin were investigated. Uteri from wild-type (WT) and NOS-2−/− mice were collected at gestation days (g.d.) 8, 10, 12, 14, and 16 (n, >2/g.d.). Histochemical staining failed to reveal any differences between the population densities or tissue distributions of uNK cells in WT and NOS-2−/− uteri at any stage of gestation. By contrast, immunohistochemical staining with anti-perforin Abs demonstrated significantly fewer perforin-positive uNK cells in two uterine compartments of NOS-2−/− mice in comparison to the same compartments in WT mouse uteri. Perforin-positive uNK cells were reduced in NOS-2−/− metrial glands at g.d. 8, 10, and 12 and in decidua basalis at g.d. 12 (p < 0.05). Analysis of perforin protein by immunoblotting confirmed this observation. Northern blot hybridization studies showed that loss of perforin protein in NOS-2−/− mice was accompanied by decreased steady-state levels of perforin mRNA. These results demonstrate that migration of uNK cells into the uterus, selection of residency sites, and proliferation in situ are independent of NOS-2. By contrast, their differentiation, including transcription and translation of the cytotoxic molecule perforin, was shown to rely on normal expression of the NOS-2 gene.

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The Involvement of Interleukin (IL)-15 in Regulating the Differentiation of Granulated Metrial Gland Cells in Mouse Pregnant Uterus

Cited by 92 publications

References 24 publications

Interleukin-11 alters placentation and causes preeclampsia features in mice

Interleukin-11 alters placentation and causes preeclampsia features in mice

Functional involvement of P‐selectin and MAdCAM‐1 in the recruitment of α4β7‐integrin‐expressing monocyte‐like cells to the pregnant mouse uterus

Nitric Oxide Synthase-2 and Expression of Perforin in Uterine NK Cells

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