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1.
Int J Biol Sci ; 16(6): 957-969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32140065

RESUMO

Pregnancy constitutes a major challenge to the maternal immune system, which must tolerate fetal alloantigen encoded by paternal genes. In addition to their role in inducing maternal-fetal immune tolerance, accumulating evidence indicates that decidual immune cells are involved in several processes required for a successful pregnancy, including trophoblast invasion as well as tissue and spiral artery remodeling. Innate lymphoid cells (ILCs), an important branch of the innate immune system, which has expanded rapidly in recent years, are strong actors in mucosal immunity, tissue homeostasis and metabolism regulation. With the recent identification of ILCs in the human decidua, the role of ILCs at the maternal-fetal interface raises concern. Herein, we review the presence and characterization of ILCs in the human decidua, as well as their function in normal pregnancy and pathological pregnancy, including reproductive failure, preeclampsia and others.

2.
J Reprod Immunol ; 138: 103090, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32014721

RESUMO

OBJECTIVES: Endometriosis (EMS) is a benign disease that is related to estrogen, immune disorders and inflammation. The purpose of this research was to determine the expression of CD200 in EMS and to clarify its role in the pathogenesis of the disease. METHODS: The levels of serum CD200 in patients with and without EMS were determined by ELISA. Furthermore, the expression of CD200 in normal eutopic endometrium and ectopic endometrium was detected by immunohistochemistry and western blotting. The CD200 receptor (CD200R) in macrophages in peritoneal fluid (pMØ) obtained from controls and patients with EMS was examined by western blotting. CD200 expression in human endometrial stromal cells (HESCs) stimulated with 17ß-estradiol (E2) was measured by western blotting. Furthermore, macrophages were stimulated with different concentrations of CD200 and the effect on phagocytosis was analyzed. RESULTS: The plasma CD200 levels of patients with EMS was significantly increased compared with controls (P = 0.0173, 95%CI [18.75, 159.6]). Compared with normal eutopic endometrium, the expression of CD200 was significantly increased in ectopic endometrial tissues. The CD200R expression in pMØ obtained from patients with EMS was increased compared with the controls (P = 0.0244). CD200 expression in HESCs stimulated with E2 was up-regulated. As the levels of CD200 increased, macrophage phagocytosis in vitro gradually decreased. CONCLUSIONS: CD200 is an estrogen-induced molecule that impairs macrophage phagocytosis and may contribute to the immune escape of ectopic lesions in EMS.

3.
Reprod Sci ; 27(1): 233-245, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32046372

RESUMO

Lipid metabolism-associated molecule abhydrolase domain containing 5 (ABHD5) has been reported to have a role in insulin-mediated glucose uptake, the deregulation of it is associated with gestational diabetes mellitus (GDM). However, whether ABHD5 participates in glucose metabolism disorders in GDM patients has remained elusive. The present study aimed to clarify the role of ABHD5 in regulating insulin signaling in placentae during GDM. Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) analysis was used for detecting the levels of ABHD5 and AMP kinase (AMPK), the insulin signaling molecules insulin receptor (INSR), INSR substrate (IRS1, IRS2), phosphoinositide 3-kinase (PI3K) and AKT, as well as the glucose transporter type 4 (GLUT-4) in placentae and the trophoblast cell line HTR-8/SVneo, while the protein level of ABHD5 was determined by western blotting. Pearson correlation analysis was performed to assess the correlation between the levels of ABHD5 and AMPK in placentae. In addition, ABHD5 overexpression in HTR-8/SVneo cells was achieved using plasmid vectors. The results indicated that the expression of ABHD5 and AMPK was dampened in placental tissues of females with GDM, and the levels of ABHD5 were positively correlated with AMPK. High-glucose (HG) treatment suppressed the expression of ABHD5, AMPK, GLUT-4, INSR, IRS, PI3K, and AKT in HTR-8/SVneo cells, and the overexpression of ABHD5 caused an elevation of the expression of these genes under normal and HG conditions in vitro. In conclusion, HG conditions induce insulin resistance of HTR-8/SVneo cells through downregulating ABHD5, which may account for impaired insulin signaling of placental tissues in GDM women.

4.
Am J Reprod Immunol ; 83(4): e13223, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972050

RESUMO

The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of a series of cytokines and immune cells. Chemokines are a type of special cytokine those were originally described as having a role in leukocyte trafficking. CXC chemokine ligand (CXCL) 16 is a member of the chemokine family, and CXC chemokine receptor (CXCR) 6 is its sole receptor. Emerging evidence has shown that CXCL16/CXCR6 is expressed at the maternal-fetal interface, by cell types that include trophoblast cells, decidual stroma cells, and decidual immune cells (eg, monocytes, γδT cells, and natural killer T (NKT) cells). The regulation of expression of CXCL16 is quite complex, and this process involves a multitude of factors. CXCL16 exerts a critical role in the establishment of a successful pregnancy through a series of molecular interactions at the maternal-fetal interface. However, an abnormal expression of CXCL16 is associated with certain pathological states associated with pregnancy, including recurrent miscarriage, pre-eclampsia, and gestational diabetes mellitus (GDM). In the present review, the expression and pleiotropic roles of CXCL16 under conditions of physiological and pathological pregnancy are systematically discussed.

5.
Mol Hum Reprod ; 26(2): 88-100, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-31977025

RESUMO

During gestation, excess palmitate (PA) is enriched in decidua. Both excess PA and decidual dysfunctions are associated with numerous adverse pregnancy outcomes such as gestational diabetes, preeclampsia and preterm birth and intrauterine growth restriction. Here, mRNA data about the effects of PA were collected from multiple databases and analyzed. Human decidual tissues were obtained from clinically normal pregnancies, terminated for non-medical reasons, during the first trimester, and decidual stromal cells (DSCs) were isolated and exposed to PA, alone or together with the inhibitors of Toll-like receptor 4 (TLR4), Jun N-terminal kinase (JNK), nuclear factor-kappa-gene binding (NF-kB) or glutamine (GLN) oxidation. Furthermore, DSCs were transfected with lentiviral particles overexpressing human TLR4. We demonstrate that excess PA interacting with its receptor TLR4 disturbs DSC hemostasis during the first trimester. Specifically, high PA signal induced DSC apoptosis and formed an inflammatory program (elevated interleukin-1 beta and decreased interleukin-10) via the activation of TLR4/JNK/NF-kB pathways. A complexed cross-talk was found between TLR4/JNK/NF-kB signals and PA deposition in DSCs. Besides, under an excess PA environment, GLN oxidation was significantly enhanced in DSCs and the suppression of GLN oxidation further augmented PA-mediated DSC apoptosis and inflammatory responses. In conclusion, excess PA induces apoptosis and inflammation in DSCs via the TLR4/JNK/NF-kB pathways, which can be augmented by the suppression of GLN oxidation.

6.
Am J Reprod Immunol ; 83(2)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650642

RESUMO

PROBLEM: Decidual natural killer (dNK) cells play key roles in maternal-fetal immune regulation, trophoblast invasion, and vascular remodeling, and most dNK cell populations are CD56bright CD16- NK cells. However, the enrichment and redistribution of dNK cells in the local decidua have not been clarified yet. METHOD OF STUDY: A total of 45 women with normal pregnancies and 8 unexplained recurrent spontaneous abortion (RSA) patients were included. We isolated primary human dNK (n = 53) and peripheral blood NK (pNK) cells (n = 5) from specimen and analyzed CD56, CD82, and CD29 by flow cytometry (FCM). We assessed their adhesion ability by cell counts of NK cells adhered to decidual stromal cells (DSCs) in a co-culture system. RESULTS: We found that RSA patients had more CD56dim dNK cells with lower CD82 and higher CD29 than women with normal pregnancies. There were negative correlations of CD82 to CD29 on CD56dim and CD56+ dNK cells. In normal pregnancies, dNK cells had lower CD82 and higher CD29 expression with a stronger adhesion ability than pNK cells. Blocking CD82 on dNK cells increased the adhesive ability and CD29 expression, while blocking CD29 decreased the adhesive ability. Co-culturing dNK cells with trophoblast cells decreased CD82 expression and increased the adhesive ability of dNK cells and the percentage of CD56bright NK cells, while blocking trophoblast-derived CXCL12 increased CD82 expression, decreased CD29 expression, and impaired the adhesive ability of NK cells. CONCLUSION: Trophoblast cells enhance the adhesive ability of NK cells to DSCs via the CXCL12/CD82/CD29 signaling pathway and contribute to CD56bright NK cell enrichment in the uterus.

7.
Reproduction ; 159(3): 251-260, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31869309

RESUMO

Immune cells and cytokines have important roles in the pathogenesis of endometriosis. However, the production and role of cytokines of T helper type 1 (Th1) and Th2 cells in the progress of endometriosis have remained to be fully elucidated. The present study reported that the interferon (IFN)-γ levels and the percentage of IFN-γ+CD4+ cells were significantly increased in the peritoneal fluid (PF) at the early stage and maintained at a higher level at the advanced stage of endometriosis; furthermore, interleukin (IL)-10 and IL-10+CD4+ cells were elevated in the advanced stage of endometriosis. In addition, IL-2 levels in the PF at the advanced stage of endometriosis were elevated and negatively associated with IFN-γ expression. In a co-culture system of ectopic endometrial stromal cells (ESCs) and macrophages, elevated IL-2 was observed, and treatment with cytokines IL-2 and transforming growth factor-ß led to upregulation of the ratio of IL-2+ macrophages. IL-27-overexpressing ESCs and macrophages were able to induce a higher ratio of IL-10+CD4+ T cells. Blocking of IL-2 with anti-IL-2 neutralizing antibody led to upregulation of the ratio of IFN-γ+CD4+ T cells in the co-culture system in vitro. Recombinant human IL-10 and IFN-γ promoted the viability, invasiveness and transcription levels of matrix metalloproteinase (MMP)2, MMP9, and prostaglandin-endoperoxide synthase 2 of ESCs, particularly combined treatment with IL-10 and IFN-γ. These results suggest that IL-2 and IL-27 synergistically promote the growth and invasion of ESCs by modulating the balance of IFN-γ and IL-10 and contribute to the progress of endometriosis.

8.
Int J Biol Sci ; 15(13): 2783-2797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31853218

RESUMO

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.

9.
Cell Commun Signal ; 17(1): 99, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429768

RESUMO

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

10.
Reproduction ; 158(3): 257-266, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31299634

RESUMO

Endometriosis (EMS) is a chronic inflammatory disease characterized by the presence of extrauterine endometrial tissues. It has been previously reported that the refluxed blood containing viable endometrial tissues and the defective elimination of peritoneal macrophages in the pelvic cavity may involve in EMS pathogenesis. However, the mechanism by which macrophages exhibit attenuated phagocytic capability in EMS remains undetermined. Herein, we found that heme, the byproduct of lysed erythrocytes, accumulated abnormally in the peritoneal fluid (PF) of patients with EMS (14.22 µmol/L, 95% confidence interval (CI): 12.54-16.71), compared with the EMS-free group (9.517 µmol/L, 95% CI: 8.891-10.1053). This abnormal accumulation was not associated with the color of PF, phase of the menstrual cycle or severity of the disease. The reduced phagocytic ability of peritoneal macrophages (pMφs) was observed in the EMS group. Consistently, a high-concentration (30 µmol/L) heme treatment impaired EMS-pMφs phagocytosis more than a low-concentration (10 µmol/L) heme treatment. A similar phenomenon was observed in the EMS-free control pMφs (Ctrl-pMφs) and the CD14+ peripheral monocytes (CD14+ Mos). These results indicated that a high heme concentration exhibits a negative effect on macrophage phagocytosis, which supplements the mechanism of impaired scavenger function of pMφs in EMS.

11.
Am J Reprod Immunol ; 82(4): e13166, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295376

RESUMO

PROBLEM: During endometriosis, there is an increase in the number of dysfunctional macrophages; however, the mechanisms underlying macrophage recruitment are not well understood. The aim of the present study was to determine the role of natural killer (NK) cell-mediated secretion of chemokine (C-C motif) ligand 2 (CCL2) from endometrial stromal cells (ESCs) in the recruitment of macrophages. METHOD OF STUDY: Normal ESCs (nESC) and ectopic ESCs (eESCs) were separately co-cultured with NK cells for a macrophage chemotaxis assay, and the number of chemotactic macrophages was counted. The expression of interleukin-22 (IL-22) and IL-22 receptors was detected by ELISA and flow cytometry, respectively. eESCs were treated with 0.01, 0.1, and 1 ng/mL recombinant human IL-22 (rhIL-22) to determine the most effective concentration for stimulating CCL2 production. Following treatment with 1 ng/mL rhIL-22, secretion of CCL2 was detected from both the eESC monoculture and the eESC/NK co-culture. RESULTS: Compared with the eESC monoculture, the eESC/NK co-culture recruited a significantly higher number of chemotactic macrophages. There was also an increase in the levels of IL-22 and CCL2 secreted when eESCs were co-cultured compared with the monoculture. Treatment with rhIL-22 resulted in an increase in the levels of CCL2 secreted by eESCs, and the IL-22-induced CCL2 secretion was reversed by the IL-22 antagonist, αIL-22. Increased expression of IL-22 resulted in an increase in the number of chemotactic macrophages, but was reversed by αIL-22 and CCL2 antagonist (αCCL2). CONCLUSION: Interleukin-22 and CCL2 secretion by eESCs stimulated by NK cells contributes to the induction of macrophage recruitment and is thus implicated in the development of endometriosis.

12.
J Orthop Surg Res ; 14(1): 114, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036018

RESUMO

BACKGROUND: Several approaches to spring ligament reconstruction have been reported. However, a comparative study of nonanatomic and anatomic techniques with respect to biomechanical responses, such as kinematics and contact characteristics, has not been previously performed via a finite element analysis. The purpose of this study was to evaluate the biomechanical results of such spring ligament reconstructions via a finite element analysis. METHODS: A three-dimensional finite element model of the foot was developed and validated, and four reconstruction methods were simulated. The talonavicular dorsiflexion and abduction, hindfoot valgus, and contact characteristics in the Chopart joints were quantified in each model. RESULTS: Nonanatomic reconstructions corrected the talonavicular and hindfoot deformities to a greater extent than the anatomic reconstructions. The anatomic techniques also corrected the abduction and dorsiflexion deformities, although they presented insufficient power to correct for hindfoot valgus. None of the procedures restored the contact characteristics of the talonavicular and calcaneocuboid joints to those of a normal condition. CONCLUSION: Nonanatomic reconstruction of the spring ligament complex provided the greatest correction for midfoot and hindfoot misalignments in flatfoot. Severe deformities with large amounts of midfoot pronation and hindfoot valgus may be better treated with nonanatomic reconstruction methods. The spring ligament reconstruction method may mitigate the need for nonanatomic bony procedures associated with complications and allows for the preservation of the triple joint complex.


Assuntos
Análise de Elementos Finitos , Pé/anatomia & histologia , Pé/fisiologia , Imagem Tridimensional , Ligamentos Articulares/anatomia & histologia , Ligamentos Articulares/fisiologia , Adulto , Fenômenos Biomecânicos/fisiologia , Pé/diagnóstico por imagem , Humanos , Imagem Tridimensional/métodos , Ligamentos Articulares/diagnóstico por imagem , Masculino
13.
Curr Mol Med ; 19(7): 494-505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31109274

RESUMO

BACKGROUND: An increasing number of studies have described the pathological changes of placenta tissues in gestational diabetes mellitus (GDM), although the underlying mechanisms involved in this process remain uncertain. The aim of the present study was to verify the possible role of microRNA-137 (miR)-137 and FNDC5 in regulating the biological function of trophoblasts in high glucose (HG) conditions during the GDM period. METHODS: Expression levels of miR-137 and FNDC5 were measured in placenta specimens, the HG-treated trophoblast cell line HTR-8/SVneo and miR-137- overexpressing HTR-8/SVneo cells using reverse transcription quantitative-PCR or western blotting. The viability of HTR-8/SVneo cells was tested using a Cell Counting kit- 8 (CCK8) assay, with cell migration assessed using scratch and transwell assays. RESULTS: It was observed that the expression levels of miR-137 were increased and the expression levels of FNDC5 were decreased in the placenta tissues of women with severe GDM and in HG-exposed HTR-8/SVneo cells. In addition, upregulating miR-137 in HTR-8/SVneo cells downregulated the expression levels of FNDC5. The viability and migration of HTR-8/SVneo cells were suppressed by increased miR-137 expression levels, and upregulating FNDC5 in miR-137-overexpressing HTR-8/SVneo cells resulted in the reversal of all these effects. CONCLUSIONS: The data from the present study suggest that miR-137 suppresses the viability and migration of trophoblasts via downregulating FNDC5 in GDM, which may contribute to the pathology of placenta tissues and occurrence of adverse pregnancy outcomes.

14.
Cell Death Dis ; 10(3): 223, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833572

RESUMO

Recurrent spontaneous abortion (RSA) refers to the unintentional termination of two or more consecutive pregnancies that severely threatens human reproductive health. Our previous study has shown that miR-184 is expressed more highly in RSA than in normal pregnancy, whether in the villus or decidua. In this study, compared with normal pregnant women, the expression of miR-184 in decidual stromal cells (DSCs) and decidual immune cells (DICs), as well as in peripheral blood, from RSA patients was enhanced similarly. Moreover, we found miR-184 could promote the apoptosis and repress the proliferation of trophoblast cells. Further exploration indicated that miR-184 upregulated the expression of Fas by targeting WIG1 thus inducing cell apoptosis. Finally, after miR-184 overexpression in vivo, the embryo resorption rate in pregnant mice was increased significantly. Therefore, our study outlines the pivotal role of miR-184 in maintaining successful pregnancy, providing a new diagnostic and therapeutic target for RSA.

15.
Cell Mol Life Sci ; 76(11): 2111-2132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30826860

RESUMO

Although the pathogenesis of endometriosis is not fully understood, it is often considered to be an inflammatory disease. An increasing number of studies suggest that differential expression of anti-inflammatory cytokines (e.g., interleukin-4 and -10, and transforming growth factor-ß1) occurs in women with endometriosis, including in serum, peritoneal fluid and ectopic lesions. These anti-inflammatory cytokines also have indispensable roles in the progression of endometriosis, including by promoting survival, growth, invasion, differentiation, angiogenesis, and immune escape of the endometriotic lesions. In this review, we provide an overview of the expression, origin, function and regulation of anti-inflammatory cytokines in endometriosis, with brief discussion and perspectives on their future clinical implications in the diagnosis and therapy of the disease.


Assuntos
Endometriose/imunologia , Endométrio/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Células Estromais/imunologia , Fator de Crescimento Transformador beta1/imunologia , Progressão da Doença , Endometriose/genética , Endometriose/patologia , Endométrio/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-10/genética , Interleucina-4/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Transdução de Sinais , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Fator de Crescimento Transformador beta1/genética
16.
Am J Reprod Immunol ; 81(6): e13110, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30903677

RESUMO

PROBLEM: Decidual stromal cells (DSCs) are important origins of cytokines to modulate maternal-fetal immunotolerance and provide a feasible environment for embryo implantation and development. Interleukin (IL)-24 is a multifunctional cancer killing cytokine and a pleiotropic immunoregulator with complex potency according to tissue or cell types. Its role in establishment and maintenance of normal pregnancy is largely unknown. The aim of our study was to investigate the function and significance of IL-24 and its receptor in the coordination between DSCs and natural killer cells (NK) in early pregnancy. METHOD OF STUDY: The levels of IL-24 in DSC, endometrial stromal cell (ESC), peripheral blood NK cells (pNK), or decidual NK cells (dNK) culture supernatants were detected by enzyme-linked immunosorbent assay (ELISA), and the levels of IL-24 receptors were determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry assays. The effect of IL-24 on the functions of decidual NK cells was analyzed by flow cytometry assays in vitro. RESULTS: The concentration of IL-24 in culture supernatant of DSCs was significantly higher than that of ESCs. Both eNK (endometrial NK cells) and dNK highly expressed IL-24 receptors (IL-20R1 and IL-22R1), especially on CD56dim eNK. However, there were extremely low levels of IL-20R1 and IL-22R1 on pNK. Recombinant human IL-24 or DSCs-secreted IL-24 downregulated the levels of CD16, Granzyme B, perforin, and interferon (IFN)-γ and upregulated the levels of inhibitory receptors killer-cell immunoglobulin-like receptor (KIR)2DL1 and KIR3DL1, or immunotolerant or angiogenic cytokines (eg, transforming growth factor (TGF)-ß, IL-10, and IL-8), and elevated the percentage of CD56bright CD16- dNK in vitro. CONCLUSION: These data suggest that DSCs promote the differentiation of CD56bright CD16- NK with high levels of inhibitory receptors, immunotolerant, and angiogenic cytokines by secreting IL-24 during decidualization in early pregnancy.

17.
Cell Death Dis ; 10(2): 113, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737372

RESUMO

ABSTACT: Decidual Î³Î´Τ (dγδΤ) cells play an essential role during successful pregnancy; however, the residence and polarization of Î³Î´Τ cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-κ B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on dÎ³Î´Τ cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of peripheral blood Î³Î´Τ (pγδΤ) and dÎ³Î´Τ cells to Foxp3 + Î³Î´Τ cells, and upregulate the expression of transforming growth factor (TGF)-ß1. This process is mediated through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, RANKL promotes the adhesion of dÎ³Î´Τ cells to DSCs in vitro, which is associated with the upregulation of ICAM-1 and VCAM-1 on DSCs and integrins on dÎ³Î´Τ cells. RANKL knockout leads to the decreased numbers of uterus total Î³Î´Τ cells, Foxp3+Î³Î´Τ cells and the expression of TGF-ß1, and the increased pregnancy loss in mice. These results suggest that RANKL is a pivotal regulator of maternal-fetal tolerance by triggering the polarization and residence of TGF-ß1-producing Foxp3+Î³Î´Τ cells in early pregnancy. The abnormal low level of RANKL/RANK results in pregnancy loss because of the dialogue disorder between DSCs and dÎ³Î´Τ cells. This observation provides a scientific basis on which a potential marker can be detected to early warning of pregnancy loss.

18.
Reproduction ; 157(3): 273-282, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30620718

RESUMO

Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. The aim of this study was to determine the role of chemokine CXCL16 and its receptor CXCR6 in the decidualization during pregnancy. Here, the expression of CXCL16 was investigated in endometrial tissues, decidua and placenta in this study. Compared with endometrial tissue, protein expression of CXCL16 was significantly higher in tissues from the fertile control samples, especially in villus. Meanwhile, the primary trophoblast cells and decidual stromal cells (DSCs) secreted more CXCL16 and expressed higher CXCR6 compared to endometrial stromal cells (ESCs) in vitro. Stimulation with the inducer of decidualization (8-bromoadenosine 3',5'-cyclic with medroxyprogesterone acetate, 8-Br-cAMP plus MPA) significantly upregulated the expression of CXCL16 and CXCR6 in ESCs in vitro. After treatment with exogenous recombinant human CXCL16 (rhCXCL16) or trophoblast-secreted CXLC16, decidualised ESCs showed a significant decidual response, mainly characterised by increased prolactin (PRL) secretion. Simultaneously, PI3K/PDK1/AKT/Cyclin D1 pathway in decidualised ESCs were activated by rhCXCL16, and AKT inhibitor GS 690693 abolished the PRL secretion of ESCs that was triggered by rhCXCL16. Finally, the impaired CXCL16/CXCR6 expression could be observed at the maternal-foetal interface from patients who have experienced spontaneous abortion. This study suggests that the CXCL16/CXCR6 axis contributes to the progression of ESC decidualization by activating PI3K/PDK1/AKT/Cyclin D1 pathway. It unveils a new paradigm at the maternal-foetal interface in which CXCL16 is an initiator for the molecular crosstalk that enhances decidualization of ESCs.

19.
Reprod Sci ; 26(4): 532-542, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29909746

RESUMO

BACKGROUND: Decidual γδ T cells are known to regulate the function of trophoblasts at the maternal-fetal interface; however, little is known about the molecular mechanisms of cross talk between trophoblast cells and decidual γδ T cells. METHODS: Expression of chemokine C-X-C motif ligand 6 (CXCL16) and its receptor CXCR6 was evaluated in first-trimester human villus and decidual tissues by immunohistochemistry. γδ T cells were isolated from first-trimester human deciduae and cocultured with JEG3 trophoblast cells. Cell proliferation and apoptosis-related molecules, together with cytotoxicity factor and cytokine production, were measured by flow cytometry analysis. RESULTS: Expression of CXCL16 and CXCR6 was reduced at the maternal-fetal interface in patients who experienced unexplained recurrent spontaneous abortion as compared to healthy pregnancy women. With the administration of pregnancy-related hormones or coculture with JEG3 cells, CXCR6 expression was upregulated on decidual γδ T cells. CXCL16 derived from JEG3 cells caused a decrease in granzyme B production of decidual γδ T cells. In addition, decidual γδ T cells educated by JEG3-derived CXCL16 upregulated the expression of Bcl-xL in JEG3 cells. CONCLUSION: This study suggested that the CXCL16/CXCR6 axis may contribute to maintaining normal pregnancy by reducing the secretion of cytotoxic factor granzyme B of decidual γδ T cells and promoting the expression of antiapoptotic marker Bcl-xL of trophoblasts.


Assuntos
Quimiocina CXCL16/metabolismo , Decídua/metabolismo , Granzimas/metabolismo , Trofoblastos/metabolismo , Proteína bcl-X/metabolismo , Sobrevivência Celular , Células Cultivadas , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Receptores CXCR6/metabolismo
20.
Int J Mol Med ; 43(2): 945-955, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569127

RESUMO

Angiogenesis is an essential process involved in various physiological, including placentation, and pathological, including cancer and endometriosis, processes. Melatonin (MLT), a well­known natural hormone secreted primarily in the pineal gland, is involved in regulating neoangiogenesis and inhibiting the development of a variety of cancer types, including lung and breast cancer. However, the specific mechanism of its anti­angiogenesis activity has not been systematically elucidated. In the present study, the effect of MLT on viability and angiogenesis of human umbilical vein endothelial cells (HUVECs), and the production of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS), under normoxia or hypoxia was analyzed using Cell Counting kit 8, tube formation, flow cytometry, ELISA and western blot assays. It was determined that the secretion of VEGF by HUVECs was significantly increased under hypoxia, while MLT selectively obstructed VEGF release as well as the production of ROS under hypoxia. Furthermore, MLT inhibited the viability of HUVECs in a dose­dependent manner and reversed the increase in cell viability and tube formation that was induced by hypoxia/VEGF/H2O2. Additionally, treatment with an inhibitor of hypoxia inducible factor (HIF)­1α (KC7F2) and MLT synergistically reduced the release of ROS and VEGF, and inhibited cell viability and tube formation of HUVECs. These observations demonstrate that MLT may serve dual roles in the inhibition of angiogenesis, as an antioxidant and a free radical scavenging agent. MLT suppresses the viability and angiogenesis of HUVECs through the downregulation of HIF­1α/ROS/VEGF. In summary, the present data indicate that MLT may be a potential anticancer agent in solid tumors with abundant blood vessels, particularly combined with KC7F2.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Melatonina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia
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