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Gab3 is selectively required for MAPK activation but not AKT or STAT5 signaling downstream of IL-2 or IL-15 activation. a-g) WT, Gab3 R27C and Gab3 KO NK cells stimulated directly ex vivo with IL-2 or IL-15 at various time points. a) Phosphorylation of STAT5. b,c) Phosphorylation of downstream targets of PI3K including b) p70 kinase and c) AKT, and d) RpS6. e-g) Phosphorylation of MAPK signaling including e) ERK, f) p38, and g) JNK. h) Proposed working model of where Gab3 functions downstream of the IL-2/IL-15 receptor signaling complex. Statistical analysis was done using a two-way ANOVA with Tukey post-test (experiments were performed in duplicate with at least n≥2 mice). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001
Source publication
The scaffolding protein Grb2-associated binding protein 3 (Gab3) is a member of the Gab family, whose functions have remained elusive. Here, we identify Gab3 as a key determinant of peripheral NK cell expansion. Loss of Gab3 resulted in impaired IL-2 and IL-15–induced NK cell priming and expansion due to a selective impairment in MAPK signaling but...
Contexts in source publication
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... we assessed development of NK cells in the bone marrow by flow cytometry as previously described (20). Consistent with the normal peripheral NK cell numbers, no changes were observed in the frequency of NK-committed progenitors or NK1.1 + NK cells in the bone marrow (Fig.S3a,b). ...
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... NK cells from both Gab3 R27C and Gab3 KO mice showed markedly reduced proliferation as assessed by Cell Trace Violet dilution and Ki67 expression (Fig.2d) while no apparent loss of NK cell viability was observed. Consistent with the survival, we observed a normal induction of Mcl-1, a critical survival factor induced by IL-2 or IL-15 (27), in Gab R27C and Gab3 KO NK cells compared to WT (Fig.S3c). Finally, we investigated cell cycle progression using EDU incorporation in conjunction with 7-AAD staining during IL-2 and IL-15 expansion. ...
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... investigated downstream signaling in WT, Gab3 R27C and Gab3 KO NK cells with IL-2 or IL-15 by assessing phosphorylation of STAT5 (JAK/STAT pathway), Akt, p70 S6K, mTORc1, S6 ribosomal protein, and ERK, JNK and p38 (MAPK pathway) at various time points. Both IL-2 and IL-15 induced robust and normal activation of STAT5, Akt and p70 S6 kinase in WT, Gab3 R27C and Gab3 KO NK cells (Fig.3a-c). In contrast, both Gab3 R27C and Gab3 KO NK cells showed a profound defect in activation of the MAPK pathways i.e. pERK, pJNK and P-p38 ( Fig.3e-g). ...
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... IL-2 and IL-15 induced robust and normal activation of STAT5, Akt and p70 S6 kinase in WT, Gab3 R27C and Gab3 KO NK cells (Fig.3a-c). In contrast, both Gab3 R27C and Gab3 KO NK cells showed a profound defect in activation of the MAPK pathways i.e. pERK, pJNK and P-p38 ( Fig.3e-g). Importantly, the Gab3 R27C displayed a partial reduction while the Gab3 KO exhibited a near complete lack of MAPK activation, confirming the Gab3 R27C allele to behave as a hypomorphic allele. ...
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... these studies also revealed a partial yet significant reduction in the phosphorylation of the Ribosomal protein S6 (RpS6) (Fig.3d) in Gab3 R27C and Gab3 KO NK cells. RpS6 is a key component of the 40S ribosomal subunit required for RNA translation and cell growth and previous studies revealed that phosphorylation of RpS6 is can be mediated by both the PI3K and ERK pathway (34,35). ...
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... studies thus identify a critical and selective role for Gab3 in the activation of the MAPK pathway downstream of the IL-2/IL-15R, while Gab3 is dispensable for the JAK/ STAT-and PI3K-pathways (Fig.3h). ...
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... enrichment analyses (ToppFun) identified gene sets with reduced expression in Gab3 KO uNK cells that were involved in 1) Eukaryotic Translation, 2) Citric Acid and respiratory electron transport, and 3) Natural killer cell mediated cytotoxicity (Fig.S5c-f). The reduced expression of gene sets in translation/elongation and metabolism are consistent with the signaling defects and reduced Rps6 phosphorylation observed in IL-15-stimulated NK cells (Fig.3d), and suggest a reduced uNK cell growth/expansion in the DB. ...
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... we assessed development of NK cells in the bone marrow by flow cytometry as previously described (20). Consistent with the normal peripheral NK cell numbers, no changes were observed in the frequency of NK-committed progenitors or NK1.1 + NK cells in the bone marrow (Fig.S3a,b). ...
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... NK cells from both Gab3 R27C and Gab3 KO mice showed markedly reduced proliferation as assessed by Cell Trace Violet dilution and Ki67 expression (Fig.2d) while no apparent loss of NK cell viability was observed. Consistent with the survival, we observed a normal induction of Mcl-1, a critical survival factor induced by IL-2 or IL-15 (27), in Gab R27C and Gab3 KO NK cells compared to WT (Fig.S3c). Finally, we investigated cell cycle progression using EDU incorporation in conjunction with 7-AAD staining during IL-2 and IL-15 expansion. ...
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... investigated downstream signaling in WT, Gab3 R27C and Gab3 KO NK cells with IL-2 or IL-15 by assessing phosphorylation of STAT5 (JAK/STAT pathway), Akt, p70 S6K, mTORc1, S6 ribosomal protein, and ERK, JNK and p38 (MAPK pathway) at various time points. Both IL-2 and IL-15 induced robust and normal activation of STAT5, Akt and p70 S6 kinase in WT, Gab3 R27C and Gab3 KO NK cells (Fig.3a-c). In contrast, both Gab3 R27C and Gab3 KO NK cells showed a profound defect in activation of the MAPK pathways i.e. pERK, pJNK and P-p38 ( Fig.3e-g). ...
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... IL-2 and IL-15 induced robust and normal activation of STAT5, Akt and p70 S6 kinase in WT, Gab3 R27C and Gab3 KO NK cells (Fig.3a-c). In contrast, both Gab3 R27C and Gab3 KO NK cells showed a profound defect in activation of the MAPK pathways i.e. pERK, pJNK and P-p38 ( Fig.3e-g). Importantly, the Gab3 R27C displayed a partial reduction while the Gab3 KO exhibited a near complete lack of MAPK activation, confirming the Gab3 R27C allele to behave as a hypomorphic allele. ...
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... these studies also revealed a partial yet significant reduction in the phosphorylation of the Ribosomal protein S6 (RpS6) (Fig.3d) in Gab3 R27C and Gab3 KO NK cells. RpS6 is a key component of the 40S ribosomal subunit required for RNA translation and cell growth and previous studies revealed that phosphorylation of RpS6 is can be mediated by both the PI3K and ERK pathway (34,35). ...
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... studies thus identify a critical and selective role for Gab3 in the activation of the MAPK pathway downstream of the IL-2/IL-15R, while Gab3 is dispensable for the JAK/ STAT-and PI3K-pathways (Fig.3h). ...
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... enrichment analyses (ToppFun) identified gene sets with reduced expression in Gab3 KO uNK cells that were involved in 1) Eukaryotic Translation, 2) Citric Acid and respiratory electron transport, and 3) Natural killer cell mediated cytotoxicity (Fig.S5c-f). The reduced expression of gene sets in translation/elongation and metabolism are consistent with the signaling defects and reduced Rps6 phosphorylation observed in IL-15-stimulated NK cells (Fig.3d), and suggest a reduced uNK cell growth/expansion in the DB. ...
Citations
... Researchers observed the failure of spiral arterial remodeling in uNK knockout mice, there is an observed failure in spiral arterial remodeling, which also results in a limitation of uNK expansion, indicating its essential role in embryo development (103, 104). Notably, Anna Sliz et al. creatively identified the Gab family members Gab3 as a key determinant of NK cell expansion, while loss of Gab3 resulted in impaired IL-2 and IL-15-induced NK cell priming and expansion due to a selective impairment in MAPK signaling (104). For the first week of pregnancy, uNK cells infiltrate and aggregate around the spiral artery ( Figure 4A), but their total amount does not change significantly as the embryo develops. ...
Female fertility decline is an accumulative consequence caused by complex factors, among them, the disruption of the immune profile in female reproduction stands out as a crucial contributor. Presently, the effects of immune microenvironment (IME) on the female reproductive process have attracted increasing attentions for their dynamic but precisive roles. Immunocytes including macrophages, dendritic cells, T cells, B cells and neutrophils, with diverse subpopulations as well as high plasticity functioned dynamically in the process of female reproduction through indirect intercellular communication via specific cytokine release transduced by molecular signal networks or direct cell-cell contact to maintain the stability of the reproductive process have been unveiled. The immune profile of female reproduction in each stage has also been meticulously unveiled. Especially, the application of single-cell sequencing (scRNA-seq) technology in this process reveals the distribution map of immune cells, which gives a novel insight for the homeostasis of IME and provides a research direction for better exploring the role of immune cells in female reproduction. Here, we provide an all-encompassing overview of the latest advancements in immune modulation within the context of the female reproductive process. Our approach involves structuring our summary in accordance with the physiological sequence encompassing gonadogenesis, folliculogenesis within the ovaries, ovulation through the fallopian tubes, and the subsequent stages of embryo implantation and development within the uterus. Our overarching objective is to construct a comprehensive portrayal of the immune microenvironment (IME), thereby accentuating the pivotal role played by immune cells in governing the intricate female reproductive journey. Additionally, we emphasize the pressing need for heightened attention directed towards strategies that focus on immune interventions within the female reproductive process, with the ultimate aim of enhancing female fertility.
... This approach identified more than half the genes (17/27) in these BRCA samples that have recently been recognised for their tumour-suppressive capacities in a range of sporadic cancers, with others apparently underexplored (Table S1, Tab#2). Several prime examples are functionally linked to metabolism: monoamine oxidase A (MAOA) inhibits aerobic glycolysis and immunity in lung cancer [49]; Integral Membrane Protein 2A (ITM2A) in BRCA induces PD-1 and higher tumour infiltrating lymphocyte (TIL) infiltration [50]; and GRB2-associated binding protein 3 (GAB3) drives natural killer cell priming and expansion [51]. ...
Ubiquitous to normal female human somatic cells, X-chromosome inactivation (XCI) tightly regulates the transcriptional silencing of a single X chromosome from each pair. Some genes escape XCI, including crucial tumour suppressors. Cancer susceptibility can be influenced by the variability in the genes that escape XCI. The mechanisms of XCI dysregulation remain poorly understood in complex diseases, including cancer. Using publicly available breast cancer next-generation sequencing data, we show that the status of the major tumour suppressor TP53 from Chromosome 17 is highly associated with the genomic integrity of the inactive X (Xi) and the active X (Xa) chromosomes. Our quantification of XCI and XCI escape demonstrates that aberrant XCI is linked to poor survival. We derived prognostic gene expression signatures associated with either large deletions of Xi; large amplifications of Xa; or abnormal X-methylation. Our findings expose a novel insight into female cancer risks, beyond those associated with the standard molecular subtypes.
... Recently, a GRB2-associated binding protein 3 knockout (Gab3 -/-) mouse model showed reduced decidual depth in mouse placentas and the spiral artery walls appeared to be heavily invaded by TGCs at approximately E12.5 (74). On E18.5, Gab3 -/mice showed a significant expansion of trophoblasts in the labyrinth and JZ in placentas, leading to an overall increase in the depth of the labyrinth, JZ, and uterine wall (74). ...
... Recently, a GRB2-associated binding protein 3 knockout (Gab3 -/-) mouse model showed reduced decidual depth in mouse placentas and the spiral artery walls appeared to be heavily invaded by TGCs at approximately E12.5 (74). On E18.5, Gab3 -/mice showed a significant expansion of trophoblasts in the labyrinth and JZ in placentas, leading to an overall increase in the depth of the labyrinth, JZ, and uterine wall (74). GRB2-associated binding (Gab) family proteins, including Gab1-3, are involved in the assembly of intracellular activation signaling complexes by acting as scaffolds to perform docking functions (79,80). ...
... GRB2-associated binding (Gab) family proteins, including Gab1-3, are involved in the assembly of intracellular activation signaling complexes by acting as scaffolds to perform docking functions (79,80). As a regulator, Gab3 is essential for NK cells to perform their functions, including uterine NK (uNK) cells (74). uNK cells are predominantly located in the decidua and High stability theoretically, non-invasive, pinpoint the role of specific gene in PAS progress ...
Placenta accreta spectrum disorder (PAS) is a kind of disease of placentation defined as abnormal trophoblast invasion of part or all of the placenta into the myometrium, even penetrating the uterus. Decidual deficiency, abnormal vascular remodeling in the maternal-fetal interface, and excessive invasion by extravillous trophoblast (EVT) cells contribute to its onset. However, the mechanisms and signaling pathways underlying such phenotypes are not fully understood, partly due to the lack of suitable experimental animal models. Appropriate animal models will facilitate the comprehensive and systematic elucidation of the pathogenesis of PAS. Due to the remarkably similar functional placental villous units and hemochorial placentation to humans, the current animal models of PAS are based on mice. There are various mouse models induced by uterine surgery to simulate different phenotypes of PAS, such as excessive invasion of EVT or immune disturbance at the maternal-fetal interface, which could define the pathological mechanism of PAS from the perspective of the "soil." Additionally, genetically modified mouse models could be used to study PAS, which is helpful to exploring the pathogenesis of PAS from the perspectives of both "soil" and "seed," respectively. This review details early placental development in mice, with a focus on the approaches of PAS modeling. Additionally, the strengths, limitations and the applicability of each strategy and further perspectives are summarized to provide the theoretical foundation for researchers to select appropriate animal models for various research purposes. This will help better determine the pathogenesis of PAS and even promote possible therapy.
... Both C57BL/6 wild type (WT) and Gab3 -/mice were used in this study. Gab3 -/mice were bred in-house from a breed pair generously provided by Dr. Helen Jones at the University of Cincinnati [15,24]. A total of 9 WT mice and 3 ...
Introduction: Placenta accreta spectrum (PAS) occurs when the placenta is pathologically adherent to the myometrium. An intact retroplacental clear space (RPCS) is a marker of normal placentation, but visualization with conventional imaging techniques is a challenge. In this study, we investigate use of an FDA-approved iron oxide nanoparticle, ferumoxytol, for contrast-enhanced magnetic resonance imaging of the RPCS in mouse models of normal pregnancy and PAS. We then demonstrate the translational potential of this technique in human patients presenting with severe PAS (FIGO Grade 3C), moderate PAS (FIGO Grade 1), and no PAS.
Methods: A T1-weighted gradient recalled echo (GRE) sequence was used to determine the optimal dose of ferumoxytol in pregnant mice. Pregnant Gab3-/- mice, which demonstrate placental invasion, were then imaged at day 16 of gestation alongside wild-type (WT) pregnant mice which do not demonstrate invasion. Signal-to-noise ratio (SNR) was computed for placenta and RPCS for all fetoplacental units (FPUs) with ferumoxytol-enhanced magnetic resonance imaging (Fe-MRI) and used for the determination of contrast-to-noise ratio (CNR). Fe-MRI was also performed in 3 pregnant subjects using standard T1 and T2 weighted sequences and a 3D magnetic resonance angiography (MRA) sequence. RPCS volume and relative signal were calculated in all three subjects.
Results: Ferumoxytol administered at 5 mg/kg produced strong T1 shortening in blood and led to strong placental enhancement in Fe-MRI images. Gab3-/- mice demonstrated loss of hypointense region characteristic of the RPCS relative to WT mice in T1w Fe-MRI. CNR between RPCS and placenta was lower in FPUs of Gab3-/- mice compared to WT mice, indicating higher degrees of vascularization and interruptions throughout the space. In human patients, Fe-MRI at a dose of 5 mg/kg enabled high uteroplacental vasculature signal and quantification of the volume and signal profile in severe and moderate invasion of the placenta relative to a non-PAS case.
Discussion: Ferumoxytol, an FDA-approved iron oxide nanoparticle formulation, enabled visualization of abnormal vascularization and loss of uteroplacental interface in a murine model of PAS. The potential of this non-invasive visualization technique was then further demonstrated in human subjects. Diagnosis of placental invasion using Fe-MRI may provide a sensitive method for clinical detection of PAS.
... Both ULBP1 and 2 are upregulated in the senescent human fibroblast IMR-90 [77]. Moreover, uNK cells can activate angiogenesis during implantation via IL15 secreted by decidualized ESCs [78]. The interaction of Ulbp1 and NKG2D was mainly observed between ESC 3/DEC ESCs and uNK cells/CD8 + T cells. ...
The decidualization of endometrial stromal cells (ESCs) is an essential process facilitating embryo implantation. However, the roles of non-decidualized and decidualized ESCs in regulating the microenvironment of a receptive endometrium remain unclear. We investigated single-cell transcriptomic changes in the uterus of a CD-1 mouse model at the post-implantation stage. The implantation and inter-implantation sites of the uteruses of pregnant mice at 4.5 and 5.5 days post-coitum were dissected for single-cell RNA sequencing. We identified eight cell types: epithelial cells, stromal cells, endothelial cells, mesothelial cells, lymphocytes, myocytes, myeloids, and pericytes. The ESC transcriptome suggests that the four ESC subtypes are involved in the extracellular remodeling during implantation. The trajectory plot of ESC subtypes indicates embryo implantation that involves a differentiation pathway from undifferentiated ESCs (ESC 1) to decidualized ESCs (DEC ESCs), with distinct signaling pathways between the ESC subtypes. Furthermore, the ligand-receptor analysis suggests that ESCs communicate with epithelial cells and immune cells through nectin and ICAM signaling. Collectively, both decidualized and non-decidualized ESCs may regulate the endometrial microenvironment for optimal endometrial receptivity and immune tolerance. This study provides insights on the molecular and cellular characteristics of mouse ESCs in modulating the epithelial and lymphocyte functions during early embryo implantation.
... However, mature NK cells have multiple disadvantages such as short lifespan and poor in vivo persistence [1,34]. It's noteworthy that Sliz and the colleagues recently reported the pivotal role of Gab3 in IL-2 and IL-15-mediated NK cell priming and expansion, together with the elimination and recognition of "missing-self " and antitumor responses, which indicated the possibility of lifespan intervention of ex vivo expanded NK cells [35]. Above all, we systematically and meticulously dissected the similarities and differences of UC-NKs and P-NKs in biological signatures, gene expression profiling and the recommended cytotoxic activity assessment for the first time. ...
Background
Perinatal blood including umbilical cord blood and placental blood are splendid sources for allogeneic NK cell generation with high cytotoxicity of combating pathogenic microorganism and malignant tumor. Despite the generation of NK cells from the aforementioned perinatal blood, yet the systematical and detailed information of the biological and transcriptomic signatures of UC-NKs and P-NKs before large-scale clinical applications in disease remodeling is still largely obscure.
Methods
Herein, we took advantage of the “3IL”-based strategy for high-efficient generation of NK cells from umbilical cord blood and placental blood (UC-NKs and P-NKs), respectively. On the one hand, we conducted flow cytometry (FCM) assay and coculture to evaluate the subpopulations, cellular vitality and cytotoxic activity of the aforementioned NK cells. On the other hand, with the aid of RNA-SEQ and multiple bioinformatics analyses, we further dissected the potential diversities of UC-NKs and P-NKs from the perspectives of transcriptomes.
Results
On the basis of the “3IL” strategy, high-efficient NKs were generated from mononuclear cells (MNCs) in perinatal blood. P-NKs revealed comparable ex vivo expansion but preferable activation and cytotoxicity upon K562 cells over UC-NKs. Both of the two NKs showed diversity in cellular vitality and transcriptome including apoptotic cells, cell cycle, gene expression profiling and the accompanied multifaceted biological processes.
Conclusions
Our data revealed the multifaceted similarities and differences of UC-NKs and P-NKs both at the cellular and molecular levels. Our findings supply new references for allogeneic NK cell-based immunotherapy in regenerative medicine and will benefit the further exploration for illuminating the underlying mechanism as well.
... 85,86 During early pregnancy, NK cells are the most abundant innate immune cells in the decidua and crucial for spiral artery remodeling. [87][88][89] Decidual NK (dNK) cells were elevated at maternal-fetal interface in PE when compared with normal pregnancies. 90,91 Elevated NK cells and cytolytic activation were observed in peripheral blood from women with PE as well as Reduced Uterine Perfusion Pressure (RUPP) rat model. ...
The contribution of immune cells in the initiation and maintenance of hypertension is undeniable. Several studies have established the association between hypertension, inflammation, and immune cells from the innate and adaptive immune systems. Here we provide an update to our 2017 American Journal of Hypertension review on the overview of the cellular immune responses involved in hypertension. Further, we discuss the activation of immune cells and their contribution to the pathogenesis of hypertension in different in vivo models. We also highlight existing gaps in the field of hypertension that need attention. The main goal of this review is to provide a knowledge base for translational research to develop therapeutic strategies that can improve cardiovascular health in humans.
... A comparison of scaffold protein Grb2-associated binding protein 3 (Gab3) knockout mice and wild-type mice showed that CD49a + Eomes + tissue-resident uNK cells were selectively decreased in the former on gestational day 8.5, with trophoblasts found to invade the labyrinth and junctional zone of the placenta in pregnant Grb2 −/− mice. Transfusion of wild-type spleen NK Mice [63,64] cells could rescue uncontrolled invasion of trophoblasts in pregnant Grb2 −/− mice [64], therefore, indicating that mouse uNK cells could inhibit trophoblast invasion by secreting IFNγ (Table 2). ...
... A comparison of scaffold protein Grb2-associated binding protein 3 (Gab3) knockout mice and wild-type mice showed that CD49a + Eomes + tissue-resident uNK cells were selectively decreased in the former on gestational day 8.5, with trophoblasts found to invade the labyrinth and junctional zone of the placenta in pregnant Grb2 −/− mice. Transfusion of wild-type spleen NK Mice [63,64] cells could rescue uncontrolled invasion of trophoblasts in pregnant Grb2 −/− mice [64], therefore, indicating that mouse uNK cells could inhibit trophoblast invasion by secreting IFNγ (Table 2). ...
During pregnancy, maternal decidual tissue interacts with fetal trophoblasts. They constitute the maternal-fetal interface responsible for supplying nutrition to the fetus. Uterine natural killer (uNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy and play critical roles throughout pregnancy. This review provides current knowledge about the functions of uNK cells. uNK cells have been shown to facilitate remodeling of the spiral artery, control the invasion of extravillous trophoblast (EVT) cells, contribute to the induction and maintenance of immune tolerance, protect against pathogen infection, and promote fetal development. Pregnancy-trained memory of uNK cells improves subsequent pregnancy outcomes. In addition, this review describes the distinct functions of three uNK cell subsets: CD27−CD11b−, CD27+ and CD27−CD11b+ uNK cells.
... The target genes include PI3K-AKT and MAPK signaling pathway-associated molecules, which leads to different phenotypes of different cells [17]. In immune cells, previous studies demonstrated that IL-15-IL-15R complex stimulated NK cells and T cells proliferation and reduced apoptosis by activing the JAK/STAT signaling pathway [29]. ...
Background
Interleukin-15 (IL-15), a member of the ‘four α-helix bundle’ cytokine family, has been associated with many inflammatory and metabolic diseases. Abnormal expression of IL-15 has been linked to the occurrence and development of obesity and diabetes. However, there is a paucity of research on the involvement of IL-15 in Gestational Diabetes Mellitus (GDM). This study aims at investigating the role of IL-15 in the pathogenesis of GDM.
Results
IL-15 was consistently expressed in the placenta throughout pregnancy and dynamically changed with pregnancy progress. Trophoblasts have been identified as the major source of IL-15 in the placenta. Expression of IL-15 was significantly increased in the placenta of GDM and in the trophoblasts cultured with high glucose (HG). In our study, expression of IL-15 in the placenta was positively correlated with blood glucose concentration of 75 g Oral Glucose Tolerance Test (OGTT), and was inversely correlated with weight of newborns. Further investigations in vitro showed that exogenous addition of IL-15 promoted trophoblasts proliferation, improved invasion and tube formation ability by activating the JAK/STAT signaling pathway, which be blocked by JAK inhibitors.
Conclusion
Our results demonstrated that IL-15 expression in the placenta was dynamically changing during pregnancy, and it was upregulated in the placenta of GDM patients. Furthermore, IL-15 altered the biological behavior of trophoblasts through JAK/STAT signaling pathway in vitro, and may contributed to the placental pathology of GDM. Our findings provide a new direction for studying the pathophysiological changes of placenta in GDM.
... Recent studies have also shed new light on how uNK interpret signals from IL-15 to carry out numerous functions essential to pregnancy, such as the release of angiogenic factors and growth factors, driving spiral artery remodeling, and shaping trophoblast invasion [59][60][61]. Sliz showed that the scaffolding protein GRB2-associated binding protein 3 (Gab3) was required for expansion of NK cells in response to both IL-15 (and IL-2) through CD122/γc [62]. Gab3-deficient NK cells stimulated with IL-15 exhibited major defects in phosphorylation of the mitogen-activated protein (MAP) kinases extracellular signalrelated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) but phosphorylated signal transducer and activator of transcription 5 (STAT5) and Akt normally (Figure 1). ...
Interleukin-15 (IL-15) is a pleiotropic cytokine that classically acts to support the development, maintenance, and function of killer lymphocytes. IL-15 is abundant in the uterus prior to and during pregnancy, but it is subject to tight spatial and temporal regulation. Both mouse models and human studies suggest that homeostasis of IL-15 is essential for healthy pregnancy. Dysregulation of IL-15 is associated with adverse outcomes of pregnancy. Herein, we review producers of IL-15 and responders to IL-15, including non-traditional responders in the maternal uterus and fetal placenta. We also review regulation of IL-15 at the maternal–fetal interface and propose mechanisms of action of IL-15 to facilitate additional study of this critical cytokine in the context of pregnancy.
