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Frederick Schatz - One of the best experts on this subject based on the ideXlab platform.
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zika virus infected Decidual Cells elicit a gestational age dependent innate immune response and exaggerate trophoblast zika permissiveness implication for vertical transmission
Journal of Immunology, 2020Co-Authors: Ozlem Guzeloglukayisli, Frederick Schatz, Nihan Semerci, Xiaofang Guo, Zhonghua Tang, Asli Ozmen, Kellie Larsen, Duygu Mutluay, Seth Guller, Umit A KayisliAbstract:Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term Decidual stromal Cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term Decidual Cells. ZIKV-infected Decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal Cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human Decidual Cells, are gestational age dependent, and Decidual Cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human Decidual Cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.
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regulation of cx3cl1 expression in human first trimester Decidual Cells implications for preeclampsia
Reproductive Sciences, 2019Co-Authors: Lynn Buchwalder, Frederick Schatz, Joseph S Huang, Chiepein Chen, Longzhu Piao, Chunyen Huang, Charles J. LockwoodAbstract:C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) Cells, monocytes, and T-Cells to endothelial/epithelial Cells. Aberrant numbers and/or activation of these Decidual immune Cells elicit preeclampsia development. Decidual macrophages and NK Cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and Decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester Decidual Cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16- NK Cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and Decidual Cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16- NK cell migration. In conclusion, the current study suggests that Decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.
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the role of Decidual Cells in uterine hemostasis menstruation inflammation adverse pregnancy outcomes and abnormal uterine bleeding
Human Reproduction Update, 2016Co-Authors: Frederick Schatz, Umit A Kayisli, Ozlem Guzeloglukayisli, Sefa Arlier, Charles J. LockwoodAbstract:BACKGROUND Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the Decidualized endometrium, modification of spiral arteries and post-partum processes. However, Decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of Decidual Cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. METHODS We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. RESULTS Progestin-induced Decidualization of estradiol-primed human endometrial stromal Cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in Decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester Decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to Decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate Decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. CONCLUSION Perivascular Decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.
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inflammatory gene networks in term human Decidual Cells define a potential signature for cytokine mediated parturition
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Sherrine Ibrahim, Frederick Schatz, Charles J. Lockwood, William E Ackerman, Taryn Summerfield, Douglas A KnissAbstract:Background Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood. Objective The principal goal of the work was to examine the inflammatory genomic profile of human Decidual Cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of Decidual stromal Cells. Study Design The effects of interleukin-1β exposure on mature microRNA expression were tested in human Decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time–polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions. Results Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate Conclusion Stimulation of Decidual Cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance.
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expression of interferon γ by Decidual Cells and natural killer Cells at the human implantation site implications for preeclampsia spontaneous abortion and intrauterine growth restriction
Reproductive Sciences, 2015Co-Authors: Chiepein Chen, Frederick Schatz, Charles J. Lockwood, R Masch, Longzhu Piao, Xilin Chen, Joseph S HuangAbstract:Human first-trimester Decidual Cells (FTDCs) chemoattract CXCR3-expressing circulating CD56brightCD16− natural killer (NK) Cells, which increase uteroplacental blood flow by remodeling spiral arter...
Charles J. Lockwood - One of the best experts on this subject based on the ideXlab platform.
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regulation of cx3cl1 expression in human first trimester Decidual Cells implications for preeclampsia
Reproductive Sciences, 2019Co-Authors: Lynn Buchwalder, Frederick Schatz, Joseph S Huang, Chiepein Chen, Longzhu Piao, Chunyen Huang, Charles J. LockwoodAbstract:C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) Cells, monocytes, and T-Cells to endothelial/epithelial Cells. Aberrant numbers and/or activation of these Decidual immune Cells elicit preeclampsia development. Decidual macrophages and NK Cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and Decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester Decidual Cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16- NK Cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and Decidual Cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16- NK cell migration. In conclusion, the current study suggests that Decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.
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the role of Decidual Cells in uterine hemostasis menstruation inflammation adverse pregnancy outcomes and abnormal uterine bleeding
Human Reproduction Update, 2016Co-Authors: Frederick Schatz, Umit A Kayisli, Ozlem Guzeloglukayisli, Sefa Arlier, Charles J. LockwoodAbstract:BACKGROUND Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the Decidualized endometrium, modification of spiral arteries and post-partum processes. However, Decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of Decidual Cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. METHODS We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. RESULTS Progestin-induced Decidualization of estradiol-primed human endometrial stromal Cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in Decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester Decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to Decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate Decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. CONCLUSION Perivascular Decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.
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inflammatory gene networks in term human Decidual Cells define a potential signature for cytokine mediated parturition
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Sherrine Ibrahim, Frederick Schatz, Charles J. Lockwood, William E Ackerman, Taryn Summerfield, Douglas A KnissAbstract:Background Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood. Objective The principal goal of the work was to examine the inflammatory genomic profile of human Decidual Cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of Decidual stromal Cells. Study Design The effects of interleukin-1β exposure on mature microRNA expression were tested in human Decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time–polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions. Results Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate Conclusion Stimulation of Decidual Cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance.
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expression of interferon γ by Decidual Cells and natural killer Cells at the human implantation site implications for preeclampsia spontaneous abortion and intrauterine growth restriction
Reproductive Sciences, 2015Co-Authors: Chiepein Chen, Frederick Schatz, Charles J. Lockwood, R Masch, Longzhu Piao, Xilin Chen, Joseph S HuangAbstract:Human first-trimester Decidual Cells (FTDCs) chemoattract CXCR3-expressing circulating CD56brightCD16− natural killer (NK) Cells, which increase uteroplacental blood flow by remodeling spiral arter...
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interferon γ protects first trimester Decidual Cells against aberrant matrix metalloproteinases 1 3 and 9 expression in preeclampsia
American Journal of Pathology, 2014Co-Authors: Charles J. Lockwood, Murat Basar, William Murk, R Masch, Umit A Kayisli, Ozlem Guzeloglukayisli, Jenny Wang, Nicole De Paz, John P Shapiro, Nihan SemerciAbstract:Human extravillous trophoblast (EVT) invades the decidua via integrin receptors and subsequently degrades extracellular matrix proteins. In preeclampsia (PE), shallow EVT invasion elicits incomplete spiral artery remodeling, causing reduced uteroplacental blood flow. Previous studies show that preeclamptic Decidual Cells, but not interstitial EVTs, display higher levels of extracellular matrix–degrading matrix metalloproteinase (MMP)-9, but not MMP-2. Herein, we extend our previous PE-related assessment of MMP-2 and MMP-9 to include MMP-1, which preferentially degrades fibrillar collagens, and MMP-3, which can initiate a local proteolytic cascade. In human first-trimester Decidual Cells incubated with estradiol, tumor necrosis factor-α (TNF-α) significantly enhanced MMP-1, MMP-3, and MMP-9 mRNA and protein levels and activity measured by real-time quantitative RT-PCR, ELISA, immunoblotting, and zymography, respectively. In contrast, interferon γ (IFN-γ) reversed these effects and medroxyprogesterone acetate elicited further reversal. Immunoblotting revealed that p38 mitogen-activated protein kinase signaling mediated TNF-α enhancement of MMP-1, MMP-3, and MMP-9, whereas IFN-γ inhibited p38 mitogen-activated protein kinase phosphorylation. Unlike highly regulated MMP-1, MMP-3, and MMP-9, MMP-2 mRNA and protein expression was constitutive in Decidual Cells. Because inflammation underlies PE-associated shallow EVT invasion, these results suggest that excess macrophage-derived TNF-α augments expression of MMP-1, MMP-3, and MMP-9 in Decidual Cells to interfere with normal stepwise EVT invasion of the decidua. In contrast, Decidual natural killer cell–derived IFN-γ reverses such TNF-α–induced MMPs to protect against PE.
Umit A Kayisli - One of the best experts on this subject based on the ideXlab platform.
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zika virus infected Decidual Cells elicit a gestational age dependent innate immune response and exaggerate trophoblast zika permissiveness implication for vertical transmission
Journal of Immunology, 2020Co-Authors: Ozlem Guzeloglukayisli, Frederick Schatz, Nihan Semerci, Xiaofang Guo, Zhonghua Tang, Asli Ozmen, Kellie Larsen, Duygu Mutluay, Seth Guller, Umit A KayisliAbstract:Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term Decidual stromal Cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term Decidual Cells. ZIKV-infected Decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal Cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human Decidual Cells, are gestational age dependent, and Decidual Cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human Decidual Cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.
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the role of Decidual Cells in uterine hemostasis menstruation inflammation adverse pregnancy outcomes and abnormal uterine bleeding
Human Reproduction Update, 2016Co-Authors: Frederick Schatz, Umit A Kayisli, Ozlem Guzeloglukayisli, Sefa Arlier, Charles J. LockwoodAbstract:BACKGROUND Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the Decidualized endometrium, modification of spiral arteries and post-partum processes. However, Decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of Decidual Cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. METHODS We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia. RESULTS Progestin-induced Decidualization of estradiol-primed human endometrial stromal Cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in Decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester Decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to Decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate Decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival. CONCLUSION Perivascular Decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.
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mechanisms of chorioamnionitis associated preterm birth interleukin 1β inhibits progesterone receptor expression in Decidual Cells
The Journal of Pathology, 2015Co-Authors: Ozlem Guzeloglukayisli, Murat Basar, Lynn Buchwalder, Umit A Kayisli, Nihan Semerci, Felice Arcuri, Irina A Buhimschi, Catalin S Buhimschi, Kellie LarsenAbstract:In chorioamnionitis (CAM), a major cause of preterm birth (PTB), maternal–fetal inflammation of the decidua and amniochorion cause the release of cytokines that elicit cervical ripening, fetal membrane rupture and myometrial activation. We posit that this inflammatory milieu triggers PTB by inhibiting progesterone receptor (PR) expression and increasing Decidual prostaglandin (PG) production. Immunohistochemical staining of decidua detected significantly lower PR levels in Decidual Cells (DCs) from CAM-complicated PTB. Incubation of DCs with IL-1β decreased PR expression and significantly increased PGE2 and PGF2α production and COX-2 expression. The addition of PGF2α to DC cultures also suppressed PR expression. However, the COX inhibitor, indomethacin, did not reverse IL-1β suppression of PR expression in DC cultures. Although IL-1β treatment activated the NF-KB, ERK1/2 and p38 MAPK signalling cascades in DCs, inhibition of ERK1/2 MAPK signalling alone was sufficient to completely reverse the suppression of PR levels by IL-1β. These findings suggest that CAM-associated PTB is induced at least in part by IL-1β-mediated functional progesterone withdrawal. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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interferon γ protects first trimester Decidual Cells against aberrant matrix metalloproteinases 1 3 and 9 expression in preeclampsia
American Journal of Pathology, 2014Co-Authors: Charles J. Lockwood, Murat Basar, William Murk, R Masch, Umit A Kayisli, Ozlem Guzeloglukayisli, Jenny Wang, Nicole De Paz, John P Shapiro, Nihan SemerciAbstract:Human extravillous trophoblast (EVT) invades the decidua via integrin receptors and subsequently degrades extracellular matrix proteins. In preeclampsia (PE), shallow EVT invasion elicits incomplete spiral artery remodeling, causing reduced uteroplacental blood flow. Previous studies show that preeclamptic Decidual Cells, but not interstitial EVTs, display higher levels of extracellular matrix–degrading matrix metalloproteinase (MMP)-9, but not MMP-2. Herein, we extend our previous PE-related assessment of MMP-2 and MMP-9 to include MMP-1, which preferentially degrades fibrillar collagens, and MMP-3, which can initiate a local proteolytic cascade. In human first-trimester Decidual Cells incubated with estradiol, tumor necrosis factor-α (TNF-α) significantly enhanced MMP-1, MMP-3, and MMP-9 mRNA and protein levels and activity measured by real-time quantitative RT-PCR, ELISA, immunoblotting, and zymography, respectively. In contrast, interferon γ (IFN-γ) reversed these effects and medroxyprogesterone acetate elicited further reversal. Immunoblotting revealed that p38 mitogen-activated protein kinase signaling mediated TNF-α enhancement of MMP-1, MMP-3, and MMP-9, whereas IFN-γ inhibited p38 mitogen-activated protein kinase phosphorylation. Unlike highly regulated MMP-1, MMP-3, and MMP-9, MMP-2 mRNA and protein expression was constitutive in Decidual Cells. Because inflammation underlies PE-associated shallow EVT invasion, these results suggest that excess macrophage-derived TNF-α augments expression of MMP-1, MMP-3, and MMP-9 in Decidual Cells to interfere with normal stepwise EVT invasion of the decidua. In contrast, Decidual natural killer cell–derived IFN-γ reverses such TNF-α–induced MMPs to protect against PE.
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abruption induced preterm delivery is associated with thrombin mediated functional progesterone withdrawal in Decidual Cells
American Journal of Pathology, 2012Co-Authors: Charles J. Lockwood, Lynn Buchwalder, William Murk, Umit A Kayisli, Emre Vatandaslar, Carlos Stocco, Frederick SchatzAbstract:Plasma progesterone levels remain elevated throughout human pregnancy, suggesting that reduced reproductive-tract progesterone receptor (PR) initiates labor. Placental abruption and excess thrombin generation elicit preterm delivery (PTD). PR, glucocorticoid receptor (GR), and total and p-ERK1/2 in Decidual Cells (DCs) and interstitial trophoblasts (IT) were assessed via immunohistochemical staining in abruption-associated PTD versus gestational-age matched control placentas, and in cultured DCs incubated with estradiol (E2) ± medroxyprogesterone acetate (MPA) ± thrombin. Immunostaining for PR was lower in DC nuclei in abruption versus control decidua and was absent from ITs; GR was higher in IT than DCs, with no abruption-related changes in either cell type; p-ERK1/2 was higher in DCs in abruption than control decidua, with total ERK 1/2 unchanged. Immunoblotting of cultured DCs demonstrated strong E2, weak MPA, and intermediate E2+MPA mediated elevation of PR-A and PR-B levels, with constitutive GR expression. In cultured DCs, thrombin inhibited PR but not GR mRNA levels, reduced PR binding to DNA and [3H]progesterone binding to PR, and enhanced phosphorylated but not total ERK1/2 levels. Coincubation with a specific p-ERK1/2 inhibitor reversed thrombin-enhanced p-ERK1/2 and lowered PR levels. Thus, abruption-associated PTD is initiated by functional progesterone withdrawal, as indicated by significantly reduced DC nuclear expression of PR-A and PR-B. Functional withdrawal of progesterone results in increased p-ERK1/2, and is thus one pathway initiating abruption-associated PTD.
Lynn Buchwalder - One of the best experts on this subject based on the ideXlab platform.
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regulation of cx3cl1 expression in human first trimester Decidual Cells implications for preeclampsia
Reproductive Sciences, 2019Co-Authors: Lynn Buchwalder, Frederick Schatz, Joseph S Huang, Chiepein Chen, Longzhu Piao, Chunyen Huang, Charles J. LockwoodAbstract:C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) Cells, monocytes, and T-Cells to endothelial/epithelial Cells. Aberrant numbers and/or activation of these Decidual immune Cells elicit preeclampsia development. Decidual macrophages and NK Cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and Decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester Decidual Cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16- NK Cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and Decidual Cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16- NK cell migration. In conclusion, the current study suggests that Decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.
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mechanisms of chorioamnionitis associated preterm birth interleukin 1β inhibits progesterone receptor expression in Decidual Cells
The Journal of Pathology, 2015Co-Authors: Ozlem Guzeloglukayisli, Murat Basar, Lynn Buchwalder, Umit A Kayisli, Nihan Semerci, Felice Arcuri, Irina A Buhimschi, Catalin S Buhimschi, Kellie LarsenAbstract:In chorioamnionitis (CAM), a major cause of preterm birth (PTB), maternal–fetal inflammation of the decidua and amniochorion cause the release of cytokines that elicit cervical ripening, fetal membrane rupture and myometrial activation. We posit that this inflammatory milieu triggers PTB by inhibiting progesterone receptor (PR) expression and increasing Decidual prostaglandin (PG) production. Immunohistochemical staining of decidua detected significantly lower PR levels in Decidual Cells (DCs) from CAM-complicated PTB. Incubation of DCs with IL-1β decreased PR expression and significantly increased PGE2 and PGF2α production and COX-2 expression. The addition of PGF2α to DC cultures also suppressed PR expression. However, the COX inhibitor, indomethacin, did not reverse IL-1β suppression of PR expression in DC cultures. Although IL-1β treatment activated the NF-KB, ERK1/2 and p38 MAPK signalling cascades in DCs, inhibition of ERK1/2 MAPK signalling alone was sufficient to completely reverse the suppression of PR levels by IL-1β. These findings suggest that CAM-associated PTB is induced at least in part by IL-1β-mediated functional progesterone withdrawal. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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abruption induced preterm delivery is associated with thrombin mediated functional progesterone withdrawal in Decidual Cells
American Journal of Pathology, 2012Co-Authors: Charles J. Lockwood, Lynn Buchwalder, William Murk, Umit A Kayisli, Emre Vatandaslar, Carlos Stocco, Frederick SchatzAbstract:Plasma progesterone levels remain elevated throughout human pregnancy, suggesting that reduced reproductive-tract progesterone receptor (PR) initiates labor. Placental abruption and excess thrombin generation elicit preterm delivery (PTD). PR, glucocorticoid receptor (GR), and total and p-ERK1/2 in Decidual Cells (DCs) and interstitial trophoblasts (IT) were assessed via immunohistochemical staining in abruption-associated PTD versus gestational-age matched control placentas, and in cultured DCs incubated with estradiol (E2) ± medroxyprogesterone acetate (MPA) ± thrombin. Immunostaining for PR was lower in DC nuclei in abruption versus control decidua and was absent from ITs; GR was higher in IT than DCs, with no abruption-related changes in either cell type; p-ERK1/2 was higher in DCs in abruption than control decidua, with total ERK 1/2 unchanged. Immunoblotting of cultured DCs demonstrated strong E2, weak MPA, and intermediate E2+MPA mediated elevation of PR-A and PR-B levels, with constitutive GR expression. In cultured DCs, thrombin inhibited PR but not GR mRNA levels, reduced PR binding to DNA and [3H]progesterone binding to PR, and enhanced phosphorylated but not total ERK1/2 levels. Coincubation with a specific p-ERK1/2 inhibitor reversed thrombin-enhanced p-ERK1/2 and lowered PR levels. Thus, abruption-associated PTD is initiated by functional progesterone withdrawal, as indicated by significantly reduced DC nuclear expression of PR-A and PR-B. Functional withdrawal of progesterone results in increased p-ERK1/2, and is thus one pathway initiating abruption-associated PTD.
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the implication of aberrant gm csf expression in Decidual Cells in the pathogenesis of preeclampsia
American Journal of Pathology, 2010Co-Authors: Joseph S Huang, Murat Basar, Erdogan Kocamaz, Hui Yang, Chiepein Chen, Felice Arcuri, Ana Claudia Zenclussen, Lynn BuchwalderAbstract:Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the Decidual implantation site, preeclampsia is accompanied by an excessive number of both macrophages and dendritic Cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony–stimulating factor is known to regulate the differentiation of both macrophages and dendritic Cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony–stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-α and interleukin-1 β, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human Decidual Cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic Cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony–stimulating factor as well as increased numbers of both macrophages and dendritic Cells when compared to control animals. Because granulocyte-macrophage colony–stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic Cells, these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia.
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regulation of interleukin 6 expression in human Decidual Cells and its potential role in chorioamnionitis
American Journal of Pathology, 2010Co-Authors: Charles J. Lockwood, Lynn Buchwalder, William Murk, Umit A Kayisli, Joseph S Huang, Felice Arcuri, Arun Gopinath, Frederick SchatzAbstract:Chorioamnionitis frequently precedes both genital tract and placental inflammation and is both a primary cause of maternal morbidity and a major antecedent of preterm premature rupture of the membranes (PPROM) as well as preterm delivery (PTD). In most cases of chorioamnionitis, neutrophils dominate the decidua. In a subset of these cases, a predominance of monocytes is uniquely associated with both neonatal intraventricular hemorrhage and death. The multifunctional cytokine, interleukin-6, promotes local monocyte dominance via several mechanisms. In this study, immunostaining of placental sections revealed significantly higher interleukin-6 HSCOREs in Decidual Cells (DCs) but not in interstitial trophoblasts, in chorioamnionitis versus gestational age-matched control placentas (P < 0.05). In confluent leukocyte-free term DCs, secreted interleukin-6 levels in incubations with estradiol-17β were increased 2500-fold by IL-1β (P < 0.05). This up-regulation was inhibited by more than 50% in parallel incubations that included medroxyprogesterone acetate (n = 12, P < 0.05). Western blotting data confirmed these enzyme-linked immunosorbent assay results; quantitative RT-PCR findings demonstrated corresponding changes in interleukin-6 mRNA levels. Specific inhibitors of signaling for both nuclear factor-κB activation and p38-mitogen-activated protein kinase, but not for protein kinase C, significantly decreased IL-1β-enhanced interleukin-6 expression levels in cultured DCs. In conclusion, in situ and in vitro results indicate that significantly enhanced interleukin-6 expression levels in DCs during chorioamnionitis could be pivotal in skewing Decidual monocyte differentiation to macrophages.
Joseph S Huang - One of the best experts on this subject based on the ideXlab platform.
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regulation of cx3cl1 expression in human first trimester Decidual Cells implications for preeclampsia
Reproductive Sciences, 2019Co-Authors: Lynn Buchwalder, Frederick Schatz, Joseph S Huang, Chiepein Chen, Longzhu Piao, Chunyen Huang, Charles J. LockwoodAbstract:C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) Cells, monocytes, and T-Cells to endothelial/epithelial Cells. Aberrant numbers and/or activation of these Decidual immune Cells elicit preeclampsia development. Decidual macrophages and NK Cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and Decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester Decidual Cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16- NK Cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and Decidual Cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16- NK cell migration. In conclusion, the current study suggests that Decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.
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modulation of Decidual macrophage polarization by macrophage colony stimulating factor derived from first trimester Decidual Cells implication in preeclampsia
American Journal of Pathology, 2016Co-Authors: Longzhu Piao, Chang-ching Yeh, R Masch, Joseph S Huang, Chiepein Chen, Chichang ChangAbstract:During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating-factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respectively. Previously, we observed the following: i) the preeclamptic decidua contains an excess of both macrophages and GM-CSF, ii) the preeclampsia-associated proinflammatory cytokines, IL-1β and tumor necrosis factor-α, markedly enhance GM-CSF and M-CSF expression in cultured leukocyte-free first-trimester Decidual Cells (FTDCs), iii) FTDC-secreted GM-CSF polarizes macrophages toward an M1 subtype. The microenvironment is a key determinant of macrophage phenotype. Thus, we examined proinflammatory stimulation of FTDC-secreted M-CSF and its role in macrophage development. Immunofluorescence staining demonstrated elevated M-CSF–positive Decidual cell numbers in preeclamptic decidua. In FTDCs, IL-1β and tumor necrosis factor-α signal through the NF-κB pathway to induce M-CSF production, which does the following: i) enhances differentiation of and elevates CD163 expression in macrophages, ii) increases macrophage phagocytic capacity, and iii) inhibits signal-regulatory protein α expression by macrophages. These findings suggest that FTDC-secreted M-CSF modulates the Decidual immune balance by inducing M2 macrophage polarization and phagocytic capacity in response to proinflammatory stimuli.
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expression of interferon γ by Decidual Cells and natural killer Cells at the human implantation site implications for preeclampsia spontaneous abortion and intrauterine growth restriction
Reproductive Sciences, 2015Co-Authors: Chiepein Chen, Frederick Schatz, Charles J. Lockwood, R Masch, Longzhu Piao, Xilin Chen, Joseph S HuangAbstract:Human first-trimester Decidual Cells (FTDCs) chemoattract CXCR3-expressing circulating CD56brightCD16− natural killer (NK) Cells, which increase uteroplacental blood flow by remodeling spiral arter...
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nfκb and jnk mapk activation mediates the production of major macrophage or dendritic cell recruiting chemokine in human first trimester Decidual Cells in response to proinflammatory stimuli
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Hui Yang, Joseph S HuangAbstract:Context: Preeclampsia is associated with elevated levels of proinflammatory cytokines, excess Decidual macrophages, and dendritic Cells. IL-1β- or TNF-α-stimulated leukocyte-free first trimester Decidual Cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua. Objective: The relative potency of IL-1β- or TNF-α-induced first trimester Decidual cell-secreted chemokines in chemoattracting macrophages or dendritic Cells and the signaling pathways involved in the expression of these chemokines were evaluated. Interventions and Main Outcome Measures: First trimester Decidual Cells were treated with estradiol + medroxyprogesterone acetate ± IL-1β or TNF-α. The chemotaxis assay was performed by incubating conditioned medium from first trimester Decidual Cells with neutralizing antibody for six chemokines. The activation of each signaling pathway was examined by Western blotting, flow cytometry, confocal microscopy, and ELISA with or without kinase and nuclea...
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the implication of aberrant gm csf expression in Decidual Cells in the pathogenesis of preeclampsia
American Journal of Pathology, 2010Co-Authors: Joseph S Huang, Murat Basar, Erdogan Kocamaz, Hui Yang, Chiepein Chen, Felice Arcuri, Ana Claudia Zenclussen, Lynn BuchwalderAbstract:Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the Decidual implantation site, preeclampsia is accompanied by an excessive number of both macrophages and dendritic Cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony–stimulating factor is known to regulate the differentiation of both macrophages and dendritic Cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony–stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-α and interleukin-1 β, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human Decidual Cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic Cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony–stimulating factor as well as increased numbers of both macrophages and dendritic Cells when compared to control animals. Because granulocyte-macrophage colony–stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic Cells, these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia.
