The Experts below are selected from a list of 4005 Experts worldwide ranked by ideXlab platform
Alessandro Fatatis - One of the best experts on this subject based on the ideXlab platform.
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interactions between chemokines regulation of Fractalkine cx3cl1 homeostasis by sdf cxcl12 in cortical neurons
Journal of Biological Chemistry, 2010Co-Authors: Anna Cook, Alessandro Fatatis, Randi L Hippensteel, Saori Shimizu, Jaclyn Nicolai, Olimpia MeucciAbstract:The soluble form of the chemokine Fractalkine/CX3CL1 regulates microglia activation in the central nervous system (CNS), ultimately affecting neuronal survival. This study aims to determine whether CXCL12, another chemokine constitutively expressed in the CNS (known as stromal cell-derived factor 1; SDF-1), regulates cleavage of Fractalkine from neurons. To this end, ELISA was used to measure protein levels of soluble Fractalkine in the medium of rat neuronal cultures exposed to SDF-1. Gene arrays, quantitative RT-PCR, and Western blot were used to measure overall Fractalkine expression in neurons. The data show that the rate of Fractalkine shedding in healthy cultures positively correlates with in vitro differentiation and survival. In analogy to non-neuronal cells, metalloproteinases (ADAM10/17) are involved in cleavage of neuronal Fractalkine as indicated by studies with pharmacologic inhibitors. Moreover, treatment of the neuronal cultures with SDF-1 stimulates expression of the inducible metalloproteinase ADAM17 and increases soluble Fractalkine content in culture medium. The effect of SDF-1 is blocked by an inhibitor of both ADAM10 and -17, but only partially affected by a more specific inhibitor of ADAM10. In addition, SDF-1 also up-regulates expression of the Fractalkine gene. Conversely, exposure of neurons to an excitotoxic stimulus (i.e. NMDA) inhibits α-secretase activity and markedly diminishes soluble Fractalkine levels, leading to cell death. These results, along with previous findings on the neuroprotective role of both SDF-1 and Fractalkine, suggest that this novel interaction between the two chemokines may contribute to in vivo regulation of neuronal survival by modulating microglial neurotoxic properties.
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cx3cr1 is expressed by prostate epithelial cells and androgens regulate the levels of cx3cl1 Fractalkine in the bone marrow potential role in prostate cancer bone tropism
Cancer Research, 2008Co-Authors: Whitney L. Jamieson, Olimpia Meucci, Saori Shimizu, Julia Dambrosio, Alessandro FatatisAbstract:We have previously shown that the chemokine Fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro . Thus, the interaction of Fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of Fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble Fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of Fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce Fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a Fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, Fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22]
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role of the chemokine Fractalkine cx3cl1 and its receptor cx3cr1 in skeletal metastasis from prostate cancer
Cancer Research, 2006Co-Authors: Whitney L. Jamieson, Julia A Fox, Alessandro FatatisAbstract:2407 Approximately 90% of patients with advanced prostate cancer develop skeletal metastasis. Despite many efforts, the cellular and molecular mechanisms regulating the location of migrating cancer cells to secondary organs are still poorly defined. It is likely that, in addition to vascular patterns, unique characteristics of the endothelial cells lining the capillary beds of the colonized tissues play a role in cancer organ-tropism. In addition - similarly to hematopoietic stem cells - cancer cells may migrate from the luminal side of the endothelial cells into the surrounding tissue in response to chemotactic molecules released by bone marrow stromal cells. We have previously shown that: 1) prostate cancer cells express CX3CR1 in vitro and this receptor mediates their adhesion - under dynamic flow conditions - to bone marrow endothelial cells, which constitutively express the chemokine Fractalkine/CX3CL1 on their surface; 2) human osteoblasts also express Fractalkine and release it in a soluble form, which attracts prostate cancer cells in vitro. In the present study we show that epithelial cells in frozen sections of human prostate glands - either normal or affected by adenocarcinoma - stain positive for CX3CR1. This ex vivo evidence further support our previous in vitro observations and indicates that the expression of CX3CR1 by prostate epithelial cells does not require the necessary intervention of a positive selective pressure for its exclusive expression in the malignant phenotype. This is in contrast to what reported by others for CXCR4, the receptor for the chemokine SDF-1 (CXCL12), both also implicated in prostate bone secondary tumors. We also found that, in addition to osteoblasts, human bone mesenchymal and stromal cells express membrane-bound Fractalkine and release its soluble, chemoattractant form. Consistently, high levels of soluble Fractalkine were detected by ELISA in human bone marrow aspirates from normal donors. Further experiments were conducted to investigate the modulation of Fractalkine cleavage and release in bone cells, with a particular focus on the role played by androgens in this process. Finally, silencing of CX3CR1, achieved using shRNA, was used to further define the role of this chemokine receptor in the adhesion of prostate cancer cells to bone marrow endothelial cells as well as their migration towards media conditioned by different types of bone cells. The long term goal of this study is to ascertain whether the chemokine Fractalkine and its specific receptor CX3CR1 can be considered molecular targets for therapeutic strategies aiming to prevent or significantly impair the colonization of the skeleton in patients with prostate adenocarcinoma
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expression of cx3cr1 chemokine receptors on neurons and their role in neuronal survival
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Olimpia Meucci, Alessandro Fatatis, Arthur A Simen, Richard J MillerAbstract:Recent in vitro and in vivo studies have shown that the chemokine Fractalkine is widely expressed in the brain and localized principally to neurons. Central nervous system expression of CX3CR1, the only known receptor for Fractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that Fractalkine regulates cellular communication between neurons (that produce Fractalkine) and microglia (that express its receptor). Here we show, for the first time, that hippocampal neurons also express CX3CR1. Receptor activation by soluble Fractalkine induces activation of the protein kinase Akt, a major component of prosurvival signaling pathways, and nuclear translocation of NF-κB, a downstream effector of Akt. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120IIIB, an effect blocked by anti-CX3CR1 antibodies. Experiments with two different inhibitors of the phosphatidylinositol 3-kinase, a key enzyme in the activation of Akt, and with a phospholipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of Fractalkine. These data show that neuronal CX3CR1 receptors mediate the neurotrophic effects of Fractalkine, suggesting that Fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.
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chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Olimpia Meucci, Patrick W. Gray, Alessandro Fatatis, Arthur A Simen, Trevor J Bushell, Richard J MillerAbstract:The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1α, RANTES, and Fractalkine, affect neuronal Ca signaling, suggesting that hippocampal neurons possess a wide variety of chemokine receptors. Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage-dependent Ca currents in the same neurons. Reverse transcription–PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX3CR1, as well as the chemokine Fractalkine in these neurons. Both Fractalkine and macrophage-derived chemokine (MDC) produced a time-dependent activation of extracellular response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-terminal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1α, activated the Ca- and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocampal neurons, both in the presence and absence of the glial feeder layer. These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity.
David R. Greaves - One of the best experts on this subject based on the ideXlab platform.
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Fractalkine: A Survivor's Guide Chemokines as Antiapoptotic Mediators
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Gemma E. White, David R. GreavesAbstract:Chemokines are a family of low-molecular-weight proteins essential to the directed migration of cells under homeostatic and pathological conditions. Fractalkine (CX3CL1) is an unusual chemokine that can act as either a soluble or membrane-bound mediator and signals through the G protein–coupled chemokine receptor CX3CR1, expressed on monocytes, natural killer cells, T cells, and smooth muscle cells. Accumulating evidence suggests that Fractalkine, in addition to its role in chemotaxis and adhesion of leukocytes, supports the survival of multiple cell types during homeostasis and inflammation. This review presents the evidence obtained from several disease models implying an antiapoptotic function for Fractalkine and shows how this is relevant to the pathology of atherosclerosis and other vascular diseases. We discuss whether the key role of Fractalkine, unlike other chemokines, is the promotion of cell survival and whether this has implications for vascular disease.
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the role of chemokines in atherosclerosis recent evidence from experimental models and population genetics
Current Opinion in Lipidology, 2004Co-Authors: Christina A Bursill, Keith M Channon, David R. GreavesAbstract:Purpose of review Atherosclerosis is an inflammatory disease process. This review discusses the recent genetic evidence from animal models and human populations that highlight the importance of chemokines in atherosclerosis. Recent findings CC-chemokine/CC-chemokine receptors (CCR), including CCR2/ MCP-1 (monocyte chemoattractant protein-1) and CCR5/RANTES (regulated on activation, normal T-cell expressed and secreted), have been shown in animal knockout and transgenic studies to have significant effects on atherosclerotic lesion size and macrophage recruitment. More recently Fractalkine (CX3C1) and its receptor (CX3CR1) have emerged as another important pathway in atherosclerosis. For example, Fractalkine is present in human atherosclerotic lesions and is able to stimulate platelet activation and adhesion. CX3CR1 is expressed on human aortic smooth muscle cells and CX3CR1/apolipoprotein E double knockout mice have significantly reduced atherosclerotic lesion size and macrophage recruitment. Human population genetic studies have tried to assess the importance of chemokines in human atherosclerosis. Currently, there is conflicting evidence regarding an association between polymorphisms in CCR2/MCP-1 and CCR5/RANTES and coronary artery disease. There is evidence, however, for an association between the Fractalkine receptor polymorphism (CX3CR1-I249) and coronary artery disease in both human population and function studies. Summary Recent transgenic and gene knockout studies in murine models of atherosclerosis have highlighted the importance of chemokines and their receptors in atherosclerosis. Genetic evidence for a role of chemokines and their receptors in human population studies remains under investigation. Identifying chemokine polymorphisms could help to determine pathways that are important in atherosclerosis disease pathology and that may suggest novel therapeutic targets.
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smooth muscle cells in human atherosclerotic plaques express the Fractalkine receptor cx3cr1 and undergo chemotaxis to the cx3c chemokine Fractalkine cx3cl1
Circulation, 2003Co-Authors: Andrew Lucas, Christina A Bursill, Tomasz J Guzik, Jerzy Sadowski, Keith M Channon, David R. GreavesAbstract:Background— Chemokines are important mediators of inflammatory cell recruitment that play a significant role in atherosclerosis. Fractalkine (CX3CL1) is an unusual membrane-bound chemokine that med...
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tumor necrosis factor alpha converting enzyme adam17 mediates the cleavage and shedding of Fractalkine cx3cl1
Journal of Biological Chemistry, 2001Co-Authors: Kyle J Garton, David R. Greaves, Peter J Gough, Carl P Blobel, Gillian Murphy, Peter J Dempsey, Elaine W RainesAbstract:Abstract Fractalkine (CX3CL1) is an unusual member of the chemokine family that is synthesized with its chemokine domain at the end of a mucin-rich, transmembrane stalk. This membrane-bound localization allows Fractalkine to function as an adhesion molecule for cells bearing its receptor, CX3CR1. In addition, Fractalkine can be proteolytically released from the cell surface, generating a soluble molecule that functions as a chemoattractant similar to the other members of the chemokine family. In this study, we have examined the mechanisms that regulate the conversion between these two functionally distinct forms of Fractalkine. We demonstrate that under normal conditions Fractalkine is synthesized as an intracellular precursor that is rapidly transported to the cell surface where it becomes a target for metalloproteinase-dependent cleavage that causes the release of a fragment containing the majority of the Fractalkine extracellular domain. We show that the cleavage of Fractalkine can be markedly enhanced by stimulating cells with phorbol 12-myristate 13-acetate (PMA), and we identify tumor necrosis factor-α converting enzyme (TACE; ADAM17) as the protease responsible for this PMA-induced Fractalkine release. In addition, we provide data showing that TACE-mediated Fractalkine cleavage occurs at a site distinct from the dibasic juxtamembrane motif that had been suggested previously based on protein sequence homologies. The identification of TACE as a major protease responsible for the conversion of Fractalkine from a membrane-bound adhesion molecule to a soluble chemoattractant will provide new information for understanding the physiological function of this chemokine.
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the transmembrane form of the cx3cl1 chemokine Fractalkine is expressed predominantly by epithelial cells in vivo
American Journal of Pathology, 2001Co-Authors: Andrew Lucas, Nicholas Chadwick, Bryan F Warren, D P Jewell, Siamon Gordon, Fiona Powrie, David R. GreavesAbstract:Fractalkine (CX3CL1) is synthesized as a type I transmembrane protein. Its unique CX3C chemokine domain is attached to a 241-amino acid mucin stalk, a 19-amino acid transmembrane domain, and a 37-amino acid intracellular domain of unknown function. A soluble form of Fractalkine can be generated by proteolytic cleavage at the base of the mucin stalk. Novel monoclonal and polyclonal antibodies that specifically recognize only the amino- or carboxyl-terminal ends of the human Fractalkine molecule have revealed that epithelial cells are the predominant cell type expressing transmembrane forms of Fractalkine in human skin, the tonsil, and the large intestine. Using these specific anti-Fractalkine reagents we do not detect high-level expression of Fractalkine on endothelial cells in normal or inflamed colon samples obtained from patients with Crohn’s disease or ulcerative colitis. In contrast to previous reports we do not detect Fractalkine expression by Langerhans cells or immature dendritic cells in mucosal-associated lymphoid tissues in vivo. We show that the reagent used in previous studies, an anti-Fractalkine N-terminal peptide antisera, cross-reacts with human CD84. Finally we discuss potential roles for Fractalkine in constitutive leukocyte trafficking based on its observed pattern of expression in epithelia.
Olimpia Meucci - One of the best experts on this subject based on the ideXlab platform.
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CX3CR1 Is Expressed by Prostate Epithelial Cells and Androgens Regulate the Levels of CX3CL1/Fractalkine in the Bone Marrow: Potential Role in Prostate Cancer Bone Tropism
2014Co-Authors: Whitney L. Jamieson, Olimpia Meucci, Saori Shimizu, Julia A. D’ambrosio, Ro FatatisAbstract:We have previously shown that the chemokine Fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro. Thus, the interaction of Fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of Fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble Fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of Fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce Fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a Fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, Fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22
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interactions between chemokines regulation of Fractalkine cx3cl1 homeostasis by sdf cxcl12 in cortical neurons
Journal of Biological Chemistry, 2010Co-Authors: Anna Cook, Alessandro Fatatis, Randi L Hippensteel, Saori Shimizu, Jaclyn Nicolai, Olimpia MeucciAbstract:The soluble form of the chemokine Fractalkine/CX3CL1 regulates microglia activation in the central nervous system (CNS), ultimately affecting neuronal survival. This study aims to determine whether CXCL12, another chemokine constitutively expressed in the CNS (known as stromal cell-derived factor 1; SDF-1), regulates cleavage of Fractalkine from neurons. To this end, ELISA was used to measure protein levels of soluble Fractalkine in the medium of rat neuronal cultures exposed to SDF-1. Gene arrays, quantitative RT-PCR, and Western blot were used to measure overall Fractalkine expression in neurons. The data show that the rate of Fractalkine shedding in healthy cultures positively correlates with in vitro differentiation and survival. In analogy to non-neuronal cells, metalloproteinases (ADAM10/17) are involved in cleavage of neuronal Fractalkine as indicated by studies with pharmacologic inhibitors. Moreover, treatment of the neuronal cultures with SDF-1 stimulates expression of the inducible metalloproteinase ADAM17 and increases soluble Fractalkine content in culture medium. The effect of SDF-1 is blocked by an inhibitor of both ADAM10 and -17, but only partially affected by a more specific inhibitor of ADAM10. In addition, SDF-1 also up-regulates expression of the Fractalkine gene. Conversely, exposure of neurons to an excitotoxic stimulus (i.e. NMDA) inhibits α-secretase activity and markedly diminishes soluble Fractalkine levels, leading to cell death. These results, along with previous findings on the neuroprotective role of both SDF-1 and Fractalkine, suggest that this novel interaction between the two chemokines may contribute to in vivo regulation of neuronal survival by modulating microglial neurotoxic properties.
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cx3cr1 is expressed by prostate epithelial cells and androgens regulate the levels of cx3cl1 Fractalkine in the bone marrow potential role in prostate cancer bone tropism
Cancer Research, 2008Co-Authors: Whitney L. Jamieson, Olimpia Meucci, Saori Shimizu, Julia Dambrosio, Alessandro FatatisAbstract:We have previously shown that the chemokine Fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro . Thus, the interaction of Fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of Fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble Fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of Fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce Fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a Fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, Fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22]
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expression of cx3cr1 chemokine receptors on neurons and their role in neuronal survival
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Olimpia Meucci, Alessandro Fatatis, Arthur A Simen, Richard J MillerAbstract:Recent in vitro and in vivo studies have shown that the chemokine Fractalkine is widely expressed in the brain and localized principally to neurons. Central nervous system expression of CX3CR1, the only known receptor for Fractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that Fractalkine regulates cellular communication between neurons (that produce Fractalkine) and microglia (that express its receptor). Here we show, for the first time, that hippocampal neurons also express CX3CR1. Receptor activation by soluble Fractalkine induces activation of the protein kinase Akt, a major component of prosurvival signaling pathways, and nuclear translocation of NF-κB, a downstream effector of Akt. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120IIIB, an effect blocked by anti-CX3CR1 antibodies. Experiments with two different inhibitors of the phosphatidylinositol 3-kinase, a key enzyme in the activation of Akt, and with a phospholipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of Fractalkine. These data show that neuronal CX3CR1 receptors mediate the neurotrophic effects of Fractalkine, suggesting that Fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.
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chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Olimpia Meucci, Patrick W. Gray, Alessandro Fatatis, Arthur A Simen, Trevor J Bushell, Richard J MillerAbstract:The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1α, RANTES, and Fractalkine, affect neuronal Ca signaling, suggesting that hippocampal neurons possess a wide variety of chemokine receptors. Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage-dependent Ca currents in the same neurons. Reverse transcription–PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX3CR1, as well as the chemokine Fractalkine in these neurons. Both Fractalkine and macrophage-derived chemokine (MDC) produced a time-dependent activation of extracellular response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-terminal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1α, activated the Ca- and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocampal neurons, both in the presence and absence of the glial feeder layer. These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity.
Whitney L. Jamieson - One of the best experts on this subject based on the ideXlab platform.
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CX3CR1 Is Expressed by Prostate Epithelial Cells and Androgens Regulate the Levels of CX3CL1/Fractalkine in the Bone Marrow: Potential Role in Prostate Cancer Bone Tropism
2014Co-Authors: Whitney L. Jamieson, Olimpia Meucci, Saori Shimizu, Julia A. D’ambrosio, Ro FatatisAbstract:We have previously shown that the chemokine Fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro. Thus, the interaction of Fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of Fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble Fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of Fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce Fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a Fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, Fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22
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cx3cr1 is expressed by prostate epithelial cells and androgens regulate the levels of cx3cl1 Fractalkine in the bone marrow potential role in prostate cancer bone tropism
Cancer Research, 2008Co-Authors: Whitney L. Jamieson, Olimpia Meucci, Saori Shimizu, Julia Dambrosio, Alessandro FatatisAbstract:We have previously shown that the chemokine Fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro . Thus, the interaction of Fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of Fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble Fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of Fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce Fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a Fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, Fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22]
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role of the chemokine Fractalkine cx3cl1 and its receptor cx3cr1 in skeletal metastasis from prostate cancer
Cancer Research, 2006Co-Authors: Whitney L. Jamieson, Julia A Fox, Alessandro FatatisAbstract:2407 Approximately 90% of patients with advanced prostate cancer develop skeletal metastasis. Despite many efforts, the cellular and molecular mechanisms regulating the location of migrating cancer cells to secondary organs are still poorly defined. It is likely that, in addition to vascular patterns, unique characteristics of the endothelial cells lining the capillary beds of the colonized tissues play a role in cancer organ-tropism. In addition - similarly to hematopoietic stem cells - cancer cells may migrate from the luminal side of the endothelial cells into the surrounding tissue in response to chemotactic molecules released by bone marrow stromal cells. We have previously shown that: 1) prostate cancer cells express CX3CR1 in vitro and this receptor mediates their adhesion - under dynamic flow conditions - to bone marrow endothelial cells, which constitutively express the chemokine Fractalkine/CX3CL1 on their surface; 2) human osteoblasts also express Fractalkine and release it in a soluble form, which attracts prostate cancer cells in vitro. In the present study we show that epithelial cells in frozen sections of human prostate glands - either normal or affected by adenocarcinoma - stain positive for CX3CR1. This ex vivo evidence further support our previous in vitro observations and indicates that the expression of CX3CR1 by prostate epithelial cells does not require the necessary intervention of a positive selective pressure for its exclusive expression in the malignant phenotype. This is in contrast to what reported by others for CXCR4, the receptor for the chemokine SDF-1 (CXCL12), both also implicated in prostate bone secondary tumors. We also found that, in addition to osteoblasts, human bone mesenchymal and stromal cells express membrane-bound Fractalkine and release its soluble, chemoattractant form. Consistently, high levels of soluble Fractalkine were detected by ELISA in human bone marrow aspirates from normal donors. Further experiments were conducted to investigate the modulation of Fractalkine cleavage and release in bone cells, with a particular focus on the role played by androgens in this process. Finally, silencing of CX3CR1, achieved using shRNA, was used to further define the role of this chemokine receptor in the adhesion of prostate cancer cells to bone marrow endothelial cells as well as their migration towards media conditioned by different types of bone cells. The long term goal of this study is to ascertain whether the chemokine Fractalkine and its specific receptor CX3CR1 can be considered molecular targets for therapeutic strategies aiming to prevent or significantly impair the colonization of the skeleton in patients with prostate adenocarcinoma
Toshio Imai - One of the best experts on this subject based on the ideXlab platform.
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E6130, a Novel CX3C Chemokine Receptor 1 (CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR1+ Leukocyte Trafficking in Mice with Colitis.
Molecular Pharmacology, 2017Co-Authors: Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi, Toshio ImaiAbstract:The chemokine Fractalkine (CX3C chemokine ligand 1; CX3CL1) and its receptor CX3CR1 are involved in the pathogenesis of several diseases, including inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, rheumatoid arthritis, hepatitis, myositis, multiple sclerosis, renal ischemia, and atherosclerosis. There are no orally available agents that modulate the Fractalkine/CX3CR1 axis. [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl)benzyl]-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetic acid (2S)-hydroxy(phenyl)acetate (E6130) is an orally available highly selective modulator of CX3CR1 that may be effective for treatment of inflammatory bowel disease. We found that E6130 inhibited the Fractalkine-induced chemotaxis of human peripheral blood natural killer cells (IC50 4.9 nM), most likely via E6130-induced down-regulation of CX3CR1 on the cell surface. E6130 had agonistic activity via CX3CR1 with respect to guanosine 5′-3-O-(thio)triphosphate binding in CX3CR1-expressing Chinese hamster ovary K1 (CHO-K1) membrane and had no antagonistic activity. Orally administered E6130 ameliorated several inflammatory bowel disease–related parameters in a murine CD4+CD45RBhigh T-cell-transfer colitis model and a murine oxazolone-induced colitis model. In the CD4+CD45RBhigh T-cell transfer model, E6130 inhibited the migration of CX3CR1+ immune cells and decreased the number of these cells in the gut mucosal membrane. These results suggest that E6130 is a promising therapeutic agent for treatment of inflammatory bowel disease.
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Fractalkine cx3cl1 in rheumatoid arthritis
Modern Rheumatology, 2017Co-Authors: Toshihiro Nanki, Toshio Imai, Shinichi KawaiAbstract:Fractalkine is a CX3C chemokine that exists in both membrane-bound and soluble forms. Interaction between Fractalkine and its unique receptor (CX3CR1) induces cell adhesion, chemotaxis, crawling, "accessory cell" activity, and survival. The serum level of Fractalkine is elevated in patients with rheumatoid arthritis (RA) and is correlated with disease activity. Peripheral blood CD16+ monocytes and a subset of T cells express CX3CR1, while Fractalkine is expressed on fibroblast-like synoviocytes and endothelial cells in the synovial tissue of patients with RA. Fractalkine expression is enhanced by tumor necrosis factor-α and interferon-γ, and it promotes the migration of monocytes, T cells, and osteoclast precursors into RA synovial tissue. Fractalkine also induces the production of inflammatory mediators by macrophages, T cells, and fibroblast-like synoviocytes. Moreover, Fractalkine promotes angiogenesis and osteoclastogenesis. In an animal model of RA, arthritis was improved by the abrogation of Fractalkine. Recently, a clinical trial of an anti-Fractalkine monoclonal antibody for the treatment of RA commenced in Japan. We review the multiple roles of Fractalkine in the pathogenesis of RA and its potential as a therapeutic target for this disease.
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Fractalkine in vascular biology from basic research to clinical disease
Arteriosclerosis Thrombosis and Vascular Biology, 2004Co-Authors: Hisanori Umehara, Yutaka Nagano, Eda T. Bloom, Toshiro Okazaki, Osamu Yoshie, Toshio ImaiAbstract:Fractalkine (now also called CX3CL1) is a unique chemokine that functions not only as a chemoattractant but also as an adhesion molecule and is expressed on endothelial cells activated by proinflammatory cytokines, such as interferon-γ and tumor necrosis factor-α. The Fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes, which contain high levels of intracellular perforin and granzyme B, and on macrophages. Soluble Fractalkine causes migration of NK cells, cytotoxic T lymphocytes, and macrophages, whereas the membrane-bound form captures and enhances the subsequent migration of these cells in response to secondary stimulation with other chemokines. Furthermore, stimulation through membrane-bound Fractalkine activates NK cells, leading to increased cytotoxicity and interferon-γ production. Recently, accumulating evidence has shown that Fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection, and rheumatoid arthritis. In addition, polymorphisms in CX3CR1, which reduce its binding activity to Fractalkine, have been reported to increase the risk of HIV disease and to reduce the risk of coronary artery disease. This review will examine new concepts underlying Fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of Fractalkine in various clinical conditions, especially in atherosclerosis and vascular injury.
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dual functions of Fractalkine cx3c ligand 1 in trafficking of perforin granzyme b cytotoxic effector lymphocytes that are defined by cx3cr1 expression
Journal of Immunology, 2002Co-Authors: Miyuki Nishimura, Osamu Yoneda, Hisanori Umehara, Osamu Yoshie, Kunio Hieshima, Mayumi Kakizaki, Takashi Nakayama, Naochika Dohmae, Toshio ImaiAbstract:Fractalkine/CX3C ligand 1 and its receptor CX3CR1 are known to mediate both cell adhesion and cell migration. Here we show that CX3CR1 defines peripheral blood cytotoxic effector lymphocytes commonly armed with intracellular perforin and granzyme B, which include NK cells, gammadelta T cells, and terminally differentiated CD8(+) T cells. In addition, soluble Fractalkine preferentially induced migration of cytotoxic effector lymphocytes. Furthermore, interaction of cytotoxic effector lymphocytes with membrane-bound Fractalkine promoted subsequent migration to the secondary chemokines, such as macrophage inflammatory protein-1beta/CC ligand 4 or IL-8/CXC ligand 8. Thus, Fractalkine expressed on inflamed endothelium may function as a vascular regulator for cytotoxic effector lymphocytes, regardless of their lineage and mode of target cell recognition, through its ability to capture them from blood flow and to promote their emigration in response to other chemokines.
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cx3cr1 tyrosine sulfation enhances Fractalkine induced cell adhesion
Journal of Biological Chemistry, 2002Co-Authors: Alan M Fong, Toshio Imai, Munir S Alam, Bodduluri Haribabu, Dhavalkumar D PatelAbstract:Fractalkine is a unique CX3C chemokine/mucin hybrid molecule that functions like selectins in inducing the capture of receptor-expressing cells. Because of the importance of tyrosine sulfation for ligand binding of the selectin ligand PSGL1, we tested the role of tyrosine sulfation for CX3CR1 function in cell adhesion. Tyrosine residues 14 and 22 in the N terminus of CX3CR1 were mutated to phenylalanine and stably expressed on K562 cells. Cells expressing CX3CR1-Y14F were competent in signal transduction but defective in capture by and firm adhesion to immobilized Fractalkine under physiologic flow conditions. In static binding assays, CX3CR1-Y14F mutants had a 2–4-fold decreased affinity to Fractalkine compared with wild type CX3CR1. By surface plasmon resonance measurements of Fractalkine binding to biosensor chip-immobilized cell membranes, CX3CR1-Y14F mutants had a 100-fold decreased affinity to Fractalkine. CX3CR1-expressing cell membranes treated with arylsulfatase to desulfate tyrosine residues also showed a 100-fold decreased affinity for Fractalkine. Finally, synthesized, sulfated N-terminal CX3CR1 peptides immobilized on biosensor chips showed a higher affinity for Fractalkine than non-sulfated peptides. Thus, we conclude that sulfation of tyrosine 14 enhances the function of CX3CR1 in cell capture and firm adhesion. Further, tyrosine sulfation may represent a general mechanism utilized by molecules that function in the rapid capture of circulating leukocytes.
