17 results on '"Gilder, Andrew"'
Search Results
2. Shedding of membrane-associated LDL receptor-related protein-1 from microglia amplifies and sustains neuroinflammation.
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Brifault, Coralie, Gilder, Andrew S., Laudati, Emilia, Banki, Michael, and Gonias, Steven L.
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LOW density lipoprotein receptors , *MICROGLIA , *NEURODEGENERATION , *GENE expression , *CYTOKINES , *MACROGLOBULINS - Abstract
In the CNS, microglia are activated in response to injury or infection and in neurodegenerative diseases. The endocytic and cell signaling receptor, LDL receptor-related protein-1 (LRP1), is reported to suppress innate immunity in macrophages and oppose microglial activation. The goal of this study was to identify novel mechanisms by which LRP1 may regulate microglial activation. Using primary cultures of microglia isolated from mouse brains, we demonstrated that LRP1 gene silencing increases expression of proinflammatory mediators; however, the observed response was modest. By contrast, the LRP1 ligand, receptor-associated protein (RAP), robustly activated microglia, and its activity was attenuated in LRP1-deficient cells. An important element of the mechanism by which RAP activated microglia was its ability to cause LRP1 shedding from the plasma membrane. This process eliminated cellular LRP1, which is anti-inflammatory, and generated a soluble product, shed LRP1 (sLRP1), which is potently proinflammatory. Purified sLRP1 induced expression of multiple proinflammatory cytokines and the mRNA encoding inducible nitric-oxide synthase in both LRP1-expressing and -deficient microglia. LPS also stimulated LRP1 shedding, as did the heat-shock protein and LRP1 ligand, calreticulin. Other LRP1 ligands, including β2-macroglobulin and tissue-type plasminogen activator, failed to cause LRP1 shedding. Treatment of microglia with a metalloproteinase inhibitor inhibited LRP1 shedding and significantly attenuated RAP-induced cytokine expression. RAP and sLRP1 both caused neuroinflammation in vivo when administered by stereotaxic injection into mouse spinal cords. Collectively, these results suggest that LRP1 shedding from microglia may amplify and sustain neuroinflammation in response to proinflammatory stimuli. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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3. Current Developments in Carbon & Climate Law: Africa.
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Gilder, Andrew and Rumble, Olivia
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CLIMATE change laws , *ENVIRONMENTAL law , *CARBON dioxide mitigation laws , *GREENHOUSE gas mitigation ,PARIS Agreement (2016) - Abstract
The article offers information on the developments in carbon emission & climate change laws in Africa. Topics discussed include the initiatives based on the Nationally Determined Contributions (NDCs) in accordance with the Paris Agreement; the National Greenhouse Gas Emissions Reduction Trajectory of South Africa; and the Earthlife Africa Johannesburg v Minister of Environmental Affairs and others court case of the South Africa's High Court.
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- 2017
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4. Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion.
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Gilder, Andrew S., Wang, Lei, Natali, Letizia, Karimi-Mostowfi, Nicki, Brifault, Coralie, and Gonias, Steven L.
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GLIOMA treatment , *PERTUSSIS toxin , *G protein coupled receptors , *CANCER cell culture , *CANCER cell migration , *CANCER invasiveness - Abstract
In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01–1.0 μg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor-supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion. [ABSTRACT FROM AUTHOR]
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- 2016
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5. The activities of LDL Receptor-related Protein-1 (LRP1) compartmentalize into distinct plasma membrane microdomains.
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Laudati, Emilia, Gilder, Andrew S., Lam, Michael S., Misasi, Roberta, Sorice, Maurizio, Gonias, Steven L., and Mantuano, Elisabetta
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CELL membranes , *LIPID rafts , *FUMONISINS , *CYCLODEXTRINS , *LOW density lipoprotein receptors , *PLASMINOGEN activators , *MACROGLOBULINS - Abstract
LDL Receptor-related Protein-1 (LRP1) is an endocytic receptor for diverse ligands. In neurons and neuron-like cells, ligand-binding to LRP1 initiates cell-signaling. Herein, we show that in PC12 and N2a neuron-like cells, LRP1 distributes into lipid rafts and non-raft plasma membrane fractions. When lipid rafts were disrupted, using methyl-β-cyclodextrin or fumonisin B 1, activation of Src family kinases and ERK1/2 by the LRP1 ligands, tissue-type plasminogen activator and activated α 2 -macroglobulin, was blocked. Biological consequences of activated LRP1 signaling, including neurite outgrowth and cell growth, also were blocked. The effects of lipid raft disruption on ERK1/2 activation and neurite outgrowth, in response to LRP1 ligands, were reproduced in experiments with cerebellar granule neurons in primary culture. Because the reagents used to disrupt lipid rafts may have effects on the composition of the plasma membrane outside lipid rafts, we studied the effects of these reagents on LRP1 activities unrelated to cell-signaling. Lipid raft disruption did not affect the total ligand binding capacity of LRP1, the affinity of LRP1 for its ligands, or its endocytic activity. These results demonstrate that well described activities of LRP1 require localization of this receptor to distinct plasma membrane microdomains. [ABSTRACT FROM AUTHOR]
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- 2016
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6. Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion.
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Gilder, Andrew S., Jones, Karra A., Jingjing Hu, Lei Wang, Chen, Clark C., Carter, Bob S., and Gonias, Steven L.
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EPIDERMAL growth factor receptors , *GLIOBLASTOMA multiforme , *GENE amplification , *XENOGRAFTS , *CELL migration - Abstract
Genomic heterogeneity is characteristic of glioblastoma (GBM). In many GBMs, the EGF receptor gene (EGFR) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII. EGFR gene amplification and EGFRvIII are associated with GBM progression, even when only a small fraction of the tumor cells express EGFRvIII. In this study, we show that EGFRvIII-positive GBM cells express significantly increased levels of cellular urokinase receptor (uPAR) and release increased amounts of soluble uPAR (suPAR). When mice were xenografted with human EGFRvIII-expressing GBM cells, tumor-derived suPAR was detected in the plasma, and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII-negative GBM cells. suPAR also was increased in plasma from patients with EGFRvIII-positive GBMs. Purified suPAR was biologically active when added to cultures of EGFRvIII-negative GBM cells, activating cell signaling and promoting cell migration and invasion. suPAR did not significantly stimulate cell signaling or migration of EGFRvIII-positive cells, probably because cell signaling was already substantially activated in these cells. The activities of suP AR were replicated by conditioned medium (CM) from EGFRvIII-positive GBM cells. When the CM was preincubated with uPAR-neutralizing antibody or when uPAR gene expression was silenced in cells used to prepare CM, the activity of the CM was significantly attenuated. These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII-positive GBMs, inducing an aggressive phenotype in tumor cells that are EGFRvIII-negative. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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7. Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1.
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Gilder, Andrew S., Chen, Yong-Bin, Jackson, Ramon J., Jiang, Jin, and Maher, Joseph F.
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APOPTOSIS , *UBIQUITINATION , *GENETIC transcription , *ZINC-finger proteins , *TRANSCRIPTION factors , *GENETIC regulation - Abstract
Highlights: [•] Fem1b binds, and promotes ubiquitylation of, the transcription factor Gli1. [•] Fem1b suppresses transcriptional activation and auto-regulation by Gli1. [•] Regulation of Gli1 by Fem1b requires a conserved VHL-box motif. [ABSTRACT FROM AUTHOR]
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- 2013
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8. To Tax or Trade (or Both or Neither)? The Confusing South African Status Quo on Carbon Taxation and Emissions Trading.
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Gilder, Andrew
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TAXATION of emissions trading , *CARBON taxes , *EMISSIONS (Air pollution) , *ENVIRONMENTAL impact charges - Abstract
South Africa has a rapidly evolving climate change policy environment, which is in keeping with the country's view of itself as a developing country leader in the climate change arena. Part of the policy environment includes attention to financial mechanisms that can be marshaled in support of the response to climate change. Flowing from the notion of using financial mechanisms in this manner, the South African National Treasury has taken initial steps towards the implementation of carbon taxation over emissions trading. While Treasury's progress towards carbon taxation is in keeping with its primary role in financial matters, a dichotomy exists between Treasury's view on how revenue raised from carbon taxation should be applied and the view of the Department of Environmental Affairs (which is the custodian of the national climate change policy). This article explores these and related issues with the purpose of giving a flavour and the status quo of the debate around carbon taxation and emissions trading in South Africa. [ABSTRACT FROM AUTHOR]
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- 2012
9. Country Profile: South Africa.
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du Toit, Louise and Gilder, Andrew
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GREENHOUSE gas mitigation , *CLIMATE change prevention , *CLIMATE change mitigation , *ENVIRONMENTAL law ,UNITED Nations Framework Convention on Climate Change (1992). Protocols, etc., 1997 December 11 - Abstract
The article presents the country profile of South Africa. It provides the background of its commitment to both the United Nations Framework Convention on Climate Change (UNFCCC) and the Kyoto Protocol. It highlights the country's greenhouse gas mitigation, along with emissions profile and strategy and objectives. It relates the launching of the Risk and Vulnerability Atlas by the Department of Science and Technology in response to climate change.
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- 2010
10. Editorial.
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Gilder, Andrew and Rumble, Olivia
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CLIMATE change laws , *CARBON pricing , *CLIMATE change , *CARBON taxes - Published
- 2019
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11. UNFCCC COP27 ∙ Coalitions in the UNFCCC: A Case Study of Egypt as Host of UNFCCC COP27.
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Mantlana, Brian, Rumble, Olivia, and Gilder, Andrew
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DECISION making in environmental policy , *COALITIONS , *PHYSIOLOGICAL adaptation , *GLOBAL environmental change ,DEVELOPING countries - Abstract
As the host of this year's Conference of the Parties (COP), Egypt will have to navigate an increasingly complex political landscape and skilfully address contentious negotiation points flowing from COP26. Challenges and Opportunities of Coalitions that Include Egypt Towards an Outcome at COP 2... Multilateral negotiations, such as those under the UNFCCC, are structured by coalitions and coalitions in the climate change negotiations have changed significantly over the past three decades of their existence. Egypt in Alliances with Other Countries in the UNFCCC Negotiations From the onset, it is important to point out that in the UNFCCC negotiations, Egypt belongs to at least four coalitions. The underlying point of departure is an acknowledgment that multilateral negotiations are associated with the formation and development of coalitions,[2] and coalitions remain central to understanding the dynamics in the climate change negotiations.[3] In our analysis we engage with the coalitions that have developed to date under the UNFCCC, and their relative merits and challenges. [Extracted from the article]
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- 2022
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12. PAI1 blocks effects of tissue-type plasminogen activator on cell-signaling and physiology mediated by the NMDA receptor.
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Gonias, Steven L., Banki, Michael A., Gilder, Andrew S., Azmoon, Pardis, Campana, Wendy M., and Mantuano, Elisabetta
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FIBRINOLYSIS , *TISSUE plasminogen activator - Abstract
The fibrinolysis proteinase, tissue-type plasminogen activator (tPA), triggers cell-signaling and regulates cell physiology. In PC12 cells, Schwann cells, and macrophages, the N-methyl-D-aspartate receptor (NMDA-R) mediates tPA-signaling. Plasminogen activator Inhibitor-1 (PAI1) is a rapid inhibitor of tPA enzyme activity. Although tPA-initiated cell-signaling is not dependent on its enzyme active site, we show that tPA-signaling is neutralized by PAI1. In PC12 cells, PAI1 blocked ERK1/2 activation by tPA and neurite outgrowth. In Schwann cells, PAI1 blocked tPA-mediated ERK1/2 activation and cell migration. In macrophages, PAI1 blocked the ability of tPA to inhibit IκBα phosphorylation and cytokine expression. The cell-signaling activity of tPA-PAI1 complex was rescued by forming the complex with PAI1R76→E, which binds to LRP1 with decreased affinity, by pre-treating cells with the LRP1 antagonist, Receptor-associated Protein, or by LRP1 gene-silencing. The inhibitory activity of LRP1 in tPA-PAI1 complex-initiated cell-signaling was unanticipated given the reported role of LRP1 as an NMDA-R co-receptor in signaling responses elicited by free tPA or α2-macroglobulin. We conclude that PAI1 functions as an inhibitor not only of the enzyme activity of tPA but also tPA receptor-mediated activities. [ABSTRACT FROM AUTHOR]
- Published
- 2018
13. mTORC2 activation is regulated by the urokinase receptor (uPAR) in bladder cancer.
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Hau, Andrew M., Leivo, Mariah Z., Gilder, Andrew S., Hu, Jing-Jing, Gonias, Steven L., and Hansel, Donna E.
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BLADDER cancer treatment , *TOR proteins , *UROKINASE regulation , *CANCER cell migration , *CANCER invasiveness , *CELLULAR signal transduction - Abstract
Mammalian target of rapamycin complex 2 (mTORC2) has been identified as a major regulator of bladder cancer cell migration and invasion. Upstream pathways that mediate mTORC2 activation remain poorly defined. Urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein and known activator of cell-signaling. We identified increased uPAR expression in 94% of invasive human bladder cancers and in 54–71% of non-invasive bladder cancers, depending on grade. Normal urothelium was uPAR-immunonegative. Analysis of publicly available datasets identified uPAR gene amplification or mRNA upregulation in a subset of bladder cancer patients with reduced overall survival. Using biochemical approaches, we showed that uPAR activates mTORC2 in bladder cancer cells. Highly invasive bladder cancer cell lines, including T24, J82 and UM-UC-3 cells, showed increased uPAR mRNA expression and protein levels compared with the less aggressive cell lines, UROtsa and RT4. uPAR gene-silencing significantly reduced phosphorylation of Serine-473 in Akt, an mTORC2 target. uPAR gene-silencing also reduced bladder cancer cell migration and Matrigel invasion. S473 phosphorylation was observed by immunohistochemistry in human bladder cancers only when the tumors expressed high levels of uPAR. S473 phosphorylation was not controlled by uPAR in bladder cancer cell lines that are PTEN-negative; however, this result probably did not reflect altered mTORC2 regulation. Instead, PTEN deficiency de-repressed alternative kinases that phosphorylate S473. Our results suggest that uPAR and mTORC2 are components of a single cell-signaling pathway. Targeting uPAR or mTORC2 may be beneficial in patients with bladder cancer. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Cajal-body formation correlates with differential coilin phosphorylation in primary and transformed cell lines.
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Hearst, Scoty M., Gilder, Andrew S., Negi, Sandeep S., Davis, Misty D., George, Eric M., Whittom, Angela A., Toyota, Cory G., Husedzinovic, Alma, Gruss, Oliver J., and Hebert, Michael D.
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PHOSPHORYLATION , *CELL lines , *ELECTROPHORESIS , *MESSENGER RNA , *NUCLEOPROTEINS , *GREEN fluorescent protein , *FLUORESCENT polymers - Abstract
Cajal bodies (CBs) are nuclear structures that are thought to have diverse functions, including small nuclear ribonucleoprotein (snRNP) biogenesis. The phosphorylation status of coilin, the CB marker protein, might impact CB formation. We hypothesize that primary cells, which lack CBs, contain different phosphoisoforms of coilin compared with that found in transformed cells, which have CBs. Localization, self-association and fluorescence recovery after photobleaching (FRAP) studies on coilin phosphomutants all suggest this modification impacts the function of coilin and may thus contribute towards CB formation. Two-dimensional gel electrophoresis demonstrates that coilin is hyperphosphorylated in primary cells compared with transformed cells. mRNA levels of the nuclear phosphatase PPM1G are significantly reduced in primary cells and expression of PPM1G in primary cells induces CBs. Additionally, PPM1G can dephosphorylate coilin in vitro. Surprisingly, however, expression of green fluorescent protein alone is sufficient to form CBs in primary cells. Taken together, our data support a model whereby coilin is the target of an uncharacterized signal transduction cascade that responds to the increased transcription and snRNP demands found in transformed cells. [ABSTRACT FROM AUTHOR]
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- 2009
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15. Expression of LDL receptor-related proteins (LRPs) in common solid malignancies correlates with patient survival.
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Gonias, Steven L., Karimi-Mostowfi, Nicki, Murray, Sarah S., Mantuano, Elisabetta, and Gilder, Andrew S.
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CANCER patients , *GENE expression , *LOW density lipoproteins , *MEMBRANE proteins , *CELLULAR signal transduction - Abstract
LDL receptor-related proteins (LRPs) are transmembrane receptors involved in endocytosis, cell-signaling, and trafficking of other cellular proteins. Considerable work has focused on LRPs in the fields of vascular biology and neurobiology. How these receptors affect cancer progression in humans remains largely unknown. Herein, we mined provisional databases in The Cancer Genome Atlas (TCGA) to compare expression of thirteen LRPs in ten common solid malignancies in patients. Our first goal was to determine the abundance of LRP mRNAs in each type of cancer. Our second goal was to determine whether expression of LRPs is associated with improved or worsened patient survival. In total, data from 4,629 patients were mined. In nine of ten cancers studied, the most abundantly expressed LRP was LRP1; however, a correlation between LRP1 mRNA expression and patient survival was observed only in bladder urothelial carcinoma. In this malignancy, high levels of LRP1 mRNA were associated with worsened patient survival. High levels of LDL receptor (LDLR) mRNA were associated with decreased patient survival in pancreatic adenocarcinoma. High levels of LRP10 mRNA were associated with decreased patient survival in hepatocellular carcinoma, lung adenocarcinoma, and pancreatic adenocarcinoma. LRP2 was the only LRP for which high levels of mRNA expression correlated with improved patient survival. This correlation was observed in renal clear cell carcinoma. Insights into LRP gene expression in human cancers and their effects on patient survival should guide future research. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Tissue-type plasminogen activator regulates macrophage activation and innate immunity.
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Mantuano, Elisabetta, Azmoon, Pardis, Brifault, Coralie, Banki, Michael A., Gilder, Andrew S., Campana, Wendy M., and Gonias, Steven L.
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PLASMINOGEN activators , *MACROPHAGE activation , *NATURAL immunity , *LOW density lipoprotein receptor-related proteins , *MITOGEN-activated protein kinases , *METHYL aspartate receptors , *FIBRINOLYSIS - Abstract
Tissue-type plasminogen activator (tPA) is the major intravascular activator of fibrinolysis and a ligand for receptors involved in cell signaling. In cultured macrophages, tPA inhibits the response to lipopolysaccharide (LPS) by a pathway that apparently requires low-density lipoprotein receptor-related protein-1 (LRP1). Herein, we show that the mechanism by which tPA neutralizes LPS involves rapid reversal of IkBa phosphorylation. tPA independently induced transient IkBa phosphorylation and extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages; however, these events did not trigger inflammatory mediator expression. ThetPA signaling responsewas distinguished from the signature of signaling events elicited by proinflammatory LRP1 ligands, such as receptor-associated protein (RAP), which included sustained IkBa phosphorylation and activation of all 3 MAP kinases (ERK1/2, c-Jun kinase, and p38 MAP kinase). Enzymatically active and inactive tPA demonstrated similar immune modulatory activity. Intravascular administration of enzymatically inactive tPA in mice blocked the toxicity of LPS. In mice not treated with exogenous tPA, the plasma concentration of endogenous tPA increased 3-fold in response to LPS, to 116±15 pM, but remained below the approximate threshold for eliciting anti-inflammatory cell signaling in macrophages (∼2.0 nM). This threshold is readily achieved in patients when tPA is administered therapeutically for stroke. In addition to LRP1, we demonstrate that the N-methyl-D-aspartic acid receptor (NMDA-R) is expressed by macrophages and essential for anti-inflammatory cell signaling and regulation of cytokine expression by tPA. The NMDA-R and Toll-like receptor-4 were not required for proinflammatory RAP signaling. By mediating the tPA response in macrophages, the NMDA-R provides a pathway by which the fibrinolysis system may regulate innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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17. LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response.
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Mantuano, Elisabetta, Brifault, Coralie, Lam, Michael S., Azmoon, Pardis, Gilder, Andrew S., and Gonias, Steven L.
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LOW density lipoproteins , *MICRORNA , *MACROPHAGES , *LIPOPOLYSACCHARIDES , *CYTOKINES , *CHEMOKINES , *LACTOFERRIN - Abstract
LDL receptor-related protein-1 (LRP1) is an endocytic and cellsignaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ERT fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1- expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α2-macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NF?B was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFa. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NF?B, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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