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Query: UNIPROT:P06889 (Mol)
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The expression of CXCR4, a membrane protein which is involved in the entry of HIV-1, is down-modulated from the cell surface by Phorbol 12-myristate 13-acetate (PMA) and the Ca+ ionophore, Ionomycin. Inducible co-stimulator (ICOS), which contributes to lymphocyte proliferation, is up-regulated by PMA/Ionomycin. We examined the influence of S-nitrosoglutathione (SNG), an inhibitor of Vacuolar H+-ATPase (V-ATPase), on the expression of CXCR4 and ICOS in PMA/Ionomycin-treated peripheral mononuclear cells (PBMC), and of CXCR4 alone in lymphoid cell lines. In this report, we show that SNG interferes with both effects of PMA/Ionomycin, namely CXCR4 down-regulation and ICOS up-regulation. These studies imply opposing roles of V-ATPase in the regulation of CXCR4 and ICOS. The influence of SNG in modulating the susceptibility of T cells to HIV-1 and on their immune responses needs further investigation.
Cell Mol Biol Lett 2006
PMID:S-nitrosoglutathione modulates CXCR4 and ICOS expression. 1684 46

Stromal-derived factor (SDF)-1, an alpha-chemokine that binds to G protein-coupled seven transmembrane-spanning receptor, CXCR4, plays an important and unique role in regulating the trafficking of normal hematopoietic stem/progenitor cells and their homing/retention in bone marrow. The same axis also modulates several biological processes in more differentiated cells from the granulocyte-monocytic, erythroid, and megakaryocytic lineages. In this chapter, experimental details are described for the isolation of early human hematopoietic cells, such as CD34+ mononuclear cells, myeloblasts, erythroblasts, and megakaryoblasts. These cells can be used routinely for studying the role of the CXCR4-SDF-1 axis in normal human hematopoiesis.
Methods Mol Biol 2006
PMID:Biological role of the CXCR4-SDF-1 axis in normal human hematopoietic cells. 1687 87

CXCR4, the receptor for stromal cell-derived factor (SDF)-1, was expressed in Saccharomyces cerevisiae, coupled to the pheromone response pathway via a chimeric Galpha subunit. Engagement of CXCR4 by SDF-1 resulted in expression of reporter genes, HIS3 or lacZ, under the transcriptional control of a FUS1 promoter, which is pheromone-responsive. CXCR4 mutants with constitutive signaling activity were generated by random mutagenesis of receptor coding sequences and selection for complementation of histidine auxotrophy in the yeast strain by autonomous expression of the FUS1-HIS3 reporter gene. Linkage of CXCR4 to the pheromone response pathway in yeast provides a system that lends itself to screening of receptor antagonists. The use of constitutively active mutants to screen for inhibitors of the weak partial agonist and inverse agonist pharmacologic types offers a sensitive, efficient approach that is independent of ligand.
Methods Mol Biol 2006
PMID:Functional expression of CXCR4 in Saccharomyces cerevisiae in the development of powerful tools for the pharmacological characterization of CXCR4. 1687 88

Mobilized bone marrow stem cells (BMSC) exhibit high degree of plasticity and participate in the repair process in the event of myocardial damage. In this study, we verified the proportional contribution of recipient BMSC in the repair process and identified their specific surface markers. Wild-type (WT) donor female heart was transplanted into abdominal cavity of male rat (Group I). In some of recipient animals, infarction was created by LAD occlusion (Group II). Two weeks later, transplanted female hearts were harvested for histological analysis of the mobilized cells. C-kit, CD31, Ki67 and Y-chromosome were used as markers to identify mobilized cells in the female hearts. Y-chromosome positive cells were found in the donor female cardiac allografts. Acute myocardial infarction (AMI) of recipient heart induced migration of progenitor cells into the lesions of chronic rejection in the allograft. Donor ventricular mass reduction was more pronounced in Group I. Endothelial progenitor cells induced by AMI from male recipient extensively migrated into the cardiac allograft. SDF-1 mRNA levels significantly increased (peak level at 24 h after AMI) in recipient heart. CXCR4 was strongly expressed in the transplanted hearts around the perivascular area. Spontaneous mobilization of hematopoietic progenitor cells (HPCs) occurred in cardiac allografts after creating recipient heart AMI and was detectable until 2 weeks. These data suggests that CXCR4 overexpression enhances vascularization in the damaged myocardium and SDF-1/CXCR4 axis seems particularly important in progenitor cell chemotaxis, homing, engraftment and retention in damaged myocardium. In addition, BMSC attracted to the site of ischemic injury participate in cardiac repair.
J Mol Cell Cardiol 2006 Sep
PMID:Evidence for ischemia induced host-derived bone marrow cell mobilization into cardiac allografts. 1692 22

The chemokine SDF-1 is a secreted protein that plays a critical role in several aspects of neuron development through interaction with its unique receptor CXCR4. A key mechanism that controls neuron responsiveness to extracellular signals during neuronal growth is receptor endocytosis. Since we previously reported that SDF-1 regulates axon development without affecting the other neurites, we asked whether this could correlate with a compartment-selective trafficking of CXCR4. We thus studied CXCR4 behavior upon SDF-1 exposure in rat hippocampus slices and in transfected neuron cultures. A massive agonist-induced redistribution of CXCR4 in endosomes was observed in dendrites whereas no modification was evidenced in axons. Our data suggest that CXCR4 trafficking may play a role in mediating selective effects of SDF-1 on distinct neuronal membrane subdomains.
Mol Cell Neurosci 2006 Oct
PMID:Dendrite-selective redistribution of the chemokine receptor CXCR4 following agonist stimulation. 1695 64

Despite HAART, a significant number of HIV-1-infected patients develop neurological complications. However, the presence of specific neurotropic HIV-1 strains, the extent of viral replication in the brain, and the type of cells infected remain controversial issues. To address this controversy we have analyzed different V3 loop sequences of viral isolates from four vertically HIV-1-infected children who developed HIV-1-related encephalopathy. Moreover, we have determined that some biological and molecular properties of HIV-1 might contribute to AIDS neurological dysfunctions. We detected very different HIV-1 isolates (X4 and R5) in the brain despite no great differences in clinical, pathological, or immunological parameters. In vitro, no differences in replicative competence in glial or neuroblastoma cells were observed between virus isolated from the blood of children with or without clinical neurological symptoms. The expression of both CXCR4 and CCR5 RNAs was observed in the brain independently of HIV-1 infection and viral strain predominant in this location. Our results failed to show a particular phenotypic property of the HIV-1 virus that might explain its neurovirulence and/or neurotropism.
J Mol Neurosci 2006
PMID:Lack of association of HIV-1 biological or molecular properties with neurotropism for brain cells. 1695 3

The inflammatory response is critical to the development and progression of heart failure. Chemokines and their receptors are a distinct class of inflammatory modulators that may play a role in mediating myocardial dysfunction in heart failure. Levels of the chemokine CXCL12, also known as stromal cell-derived factor (SDF), and its receptor, CXCR4, are elevated in patients with heart failure, and we undertook this study to determine whether this chemokine system can directly affect cardiac function in the absence of leukocytes. Murine papillary muscles and adult rat cardiac myocytes treated with CXCL12, the only identified ligand of CXCR4, demonstrate blunted inotropic responses to physiologic concentrations of calcium. The negative inotropic effects on cardiac myocytes are accompanied by a proportional diminution of calcium transients. The effects are abrogated by AMD3100, a specific CXCR4 inhibitor. Overexpression of the receptor through adenoviral infection with a CXCR4 construct accentuates the negative inotropic effects of CXCL12 on cardiac myocytes during calcium stimulation. CXCR4 activation also attenuates beta-adrenergic-mediated increases in calcium mobilization and fractional shortening in cardiac myocytes. In electrophysiologic studies, CXCL12 decreases forskolin- and isoproterenol-induced voltage-gated L-type calcium channel activation. These studies demonstrate that activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function. The specific mechanism of action involves alterations of calcium channel activity on the membrane. The presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction.
J Mol Cell Cardiol 2006 Nov
PMID:CXCR4 modulates contractility in adult cardiac myocytes. 1701 Mar 72

Chemokine receptor CXCR4 (CD184) may play a role in cancer metastasis and is known to form homodimers. However, it is not clear how transmembrane regions (TM) of CXCR4 and receptor homotypic interactions affect the function of CXCR4 in living cells. Using confocal microscopy and flow cytometric analysis, we showed that high levels of CXCR4 are present in the cytoplasm, accompanied by lower expression on the cell surface in CXCR4 transfectants, tumor cells, and normal peripheral blood lymphocytes. CXCR4 homodimers were detected in tumor cells, both on the cell surface membrane and in the cytoplasm using fluorescence resonance energy transfer and photobleaching fluorescence resonance energy transfer to measure energy transfer between CXCR4-CFP and CXCR4-YFP constructs. Disruption of lipid rafts by depletion of cholesterol with methyl-beta-cyclodextrin reduced the interaction between CXCR4 molecules and inhibited malignant cell migration to CXCL12/SDF-1alpha. A synthetic peptide of TM4 of CXCR4 reduced energy transfer between molecules of CXCR4, inhibited CXCL12-induced actin polymerization, and blocked chemotaxis of malignant cells. TM4 also inhibited migration of normal monocytes toward CXCL12. Reduction of CXCR4 energy transfer by the TM4 peptide and methyl-beta-cyclodextrin indicates that interactions between CXCR4s may play important roles in cell migration and suggests that cell surface and intracellular receptor dimers are appropriate targets for control of tumor cell spread. Targeting chemokine receptor oligomerization and signal transduction for the treatment of cancer, HIV-1 infections, and other CXCR4 mediated inflammatory conditions warrants further investigation.
Mol Cancer Ther 2006 Oct
PMID:Dimerization of CXCR4 in living malignant cells: control of cell migration by a synthetic peptide that reduces homologous CXCR4 interactions. 1704 Oct 91

Expression of the chemokine receptor CXCR4 by tumor cells promotes metastasis, possibly by activating prosurvival signals that render cancer cells resistant to immune attack. Inhibition of CXCR4 with a peptide antagonist, T22, blocks metastatic implantation of CXCR4-transduced B16 (CXCR4-luc-B16) melanoma cells in lung, but not the outgrowth of established metastases, raising the question of how T22 can best be used in a clinical setting. Herein, whereas the treatment of CXCR4-luc-B16 cells in vitro with the CXCR4 ligand CXCL12 did not reduce killing induced by cisplatin or cyclophosphamide, CXCL12 markedly reduced Fas-dependent killing by gp100-specific (pmel-1) CD8(+) T cells. T22 pretreatment restored sensitivity of CXCR4-luc-B16 cells to pmel-1 killing, even in the presence of CXCL12. Two immune-augmenting regimens were used in combination with T22 to treat experimental lung metastases. First, low-dose cyclophosphamide treatment (100 mg/kg) on day 5 in combination with T22 (days 4-7) yielded a approximately 70% reduction of B16 metastatic tumor burden in the lungs compared with cyclophosphamide treatment alone (P < 0.001). Furthermore, whereas anti-CTL antigen 4 (CTLA4) monoclonal antibody (mAb; or T22 treatment) alone had little effect on established B16 metastases, pretreatment with T22 (in combination with anti-CTLA4 mAb) resulted in a 50% reduction in lung tumor burden (P = 0.02). Thus, in vitro, CXCR4 antagonism with T22 renders B16 cells susceptible to killing by antigen-specific T cells. In vivo, T22 synergizes with cyclophosphamide or anti-CTLA4 mAb in the treatment of established lung metastases, suggesting a novel strategy for augmenting the efficacy of immunotherapy.
Mol Cancer Ther 2006 Oct
PMID:Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases. 1704 Nov 4

Exposure of HIV-1 to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing B-lymphoblast Raji cells (Raji/DC-SIGN) but not to wild-type Raji/0 cells results in the capture of HIV-1 particles to the cells as measured by the quantification of cell-associated p24 antigen. Cocultivation of HIV-1-captured Raji/DC-SIGN cells with uninfected CD4+ T lymphocyte C8166 cells results in abundant formation of syncytia within 36 h after cocultivation. Short preexposure of HIV-1 to carbohydrate-binding agents (CBA) dose dependently prevents the Raji/DC-SIGN cells from efficiently binding the virus particles, and no syncytia formation occurs upon subsequent cocultivation with C8166 cells. Thus, the mannose-specific [i.e., the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Narcissus pseudonarcissus agglutinin; and Cymbidium agglutinin (CA); the procaryotic cyanovirin-N (CV-N); and the monoclonal antibody 2G12) and N-acetylglucosamine-specific (i.e., the plant lectin Urtica dioica agglutinin) CBAs efficiently abrogate the DC-SIGN-directed HIV-1 capture and subsequent transmission to T lymphocytes. In this assay, the CD4-down-regulating cyclotriazodisulfonamide derivative, the CXCR4 and CCR5 coreceptor antagonists 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl] - 1,4,8,11 - tetrazacyclotetradecane (AMD3100) and maraviroc, the gp41-binding enfuvirtide, and the polyanionic substances dextran sulfate (M(r) 5000), sulfated polyvinyl alcohol, and the naphthalene sulfonate polymer PRO-2000 were markedly less efficient or even completely ineffective. Similar observations were made in primary monocyte-derived dendritic cell cultures that were infected with HIV-1 particles that had been shortly pre-exposed to the CBAs CV-N, CA, HHA, and GNA and the polyanions DS-5000 and PRO-2000. The potential of CBAs, but not polyanions and other structural/functional classes of entry inhibitors, to impair DC-SIGN-expressing cells in their capacity of transmitting HIV to T lymphocytes might be an important property to be taken into consideration in the eventual choice to move microbicide candidate drugs to the clinical setting.
Mol Pharmacol 2007 Jan
PMID:Carbohydrate-binding agents efficiently prevent dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1 transmission to T lymphocytes. 1705 72


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