Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we provide evidence that the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) acts as a mast cell chemoattractant through interactions with its receptor CXCR4 expressed on mast cell progenitors in the blood as well as on in vitro-developed and leukemic mast cells. We found expression of CXCR4 on cord blood-derived mast cells (CBMC) and on the human mast cell line HMC-1, analyzed by RNAse protection assay and flow cytometry. SDF-1alpha induced intracellular calcium mobilization in HMC-1 cells and was chemotactic for both HMC-1 cells and CBMC. The activity of SDF-1alpha was completely blocked by treating the cells with pertussis toxin, indicating the involvement of Gi-proteins in the signaling. By applying a transwell assay we could show that SDF-1alpha induces migration of a cell population in peripheral blood that is enriched for cells with the capacity to differentiate into mast cells. These findings thus suggest a mechanism by which human mast cell progenitors may be recruited from circulation into the tissue.
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PMID:The chemokine receptor CXCR4 is expressed within the mast cell lineage and its ligand stromal cell-derived factor-1alpha acts as a mast cell chemotaxin. 1116 4

We provide convergent and multiple evidence for a CD26/CXCR4 interaction. Thus, CD26 codistributes with CXCR4, and both coimmunoprecipitate from membranes of T (CD4(+)) and B (CD4(-)) cell lines. Upon induction with stromal cell-derived factor 1alpha (SDF-1alpha), CD26 is cointernalized with CXCR4. CXCR4-mediated down-regulation of CD26 is not induced by antagonists or human immunodeficiency virus (HIV)-1 gp120. SDF-1alpha-mediated down-regulation of CD26 is not blocked by pertussis toxin but does not occur in cells expressing mutant CXCR4 receptors unable to internalize. Codistribution and cointernalization also occurs in peripheral blood lymphocytes. Since CD26 is a cell surface endopeptidase that has the capacity to cleave SDF-1alpha, the CXCR4.CD26 complex is likely a functional unit in which CD26 may directly modulate SDF-1alpha-induced chemotaxis and antiviral capacity. CD26 anchors adenosine deaminase (ADA) to the lymphocyte cell surface, and this interaction is blocked by HIV-1 gp120. Here we demonstrate that gp120 interacts with CD26 and that gp120-mediated disruption of ADA/CD26 interaction is a consequence of a first interaction of gp120 with a domain different from the ADA binding site. SDF-1alpha and gp120 induce the appearance of pseudopodia in which CD26 and CXCR4 colocalize and in which ADA is not present. The physical association of CXCR4 and CD26, direct or part of a supramolecular structure, suggests a role on the function of the immune system and the pathophysiology of HIV infection.
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PMID:Comodulation of CXCR4 and CD26 in human lymphocytes. 1127 78

Stem cell homing into the bone microenvironment is the first step in the initiation of marrow-derived blood cells. It is reported that human severe combined immunodeficient (SCID) repopulating cells home and accumulate rapidly, within a few hours, in the bone marrow and spleen of immunodeficient mice previously conditioned with total body irradiation. Primitive CD34(+)CD38(-/low)CXCR4(+) cells capable of engrafting primary and secondary recipient mice selectively homed to the bone marrow and spleen, whereas CD34(-)CD38(-/low)Lin(-) cells were not detected. Moreover, whereas freshly isolated CD34(+)CD38(+/high) cells did not home, in vivo stimulation with granulocyte colony-stimulating factor as part of the mobilization process, or in vitro stem cell factor stimulation for 2 to 4 days, potentiated the homing capabilities of cytokine-stimulated CD34(+)CD38(+) cells. Homing of enriched human CD34(+) cells was inhibited by pretreatment with anti-CXCR4 antibodies. Moreover, primitive CD34(+)CD38(-/low)CXCR4(+) cells also homed in response to a gradient of human stromal cell-derived factor 1 (SDF-1), directly injected into the bone marrow or spleen of nonirradiated NOD/SCID mice. Homing was also inhibited by pretreatment of CD34(+) cells with antibodies for the major integrins VLA-4, VLA-5, and LFA-1. Pertussis toxin, an inhibitor of signals mediated by Galpha(i) proteins, inhibited SDF-1-mediated in vitro transwell migration but not adhesion or in vivo homing of CD34(+) cells. Homing of human CD34(+) cells was also blocked by chelerythrine chloride, a broad-range protein kinase C inhibitor. This study reveals rapid and efficient homing to the murine bone marrow by primitive human CD34(+)CD38(-/low)CXCR4(+) cells that is integrin mediated and depends on activation of the protein kinase C signal transduction pathway by SDF-1.
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PMID:Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice. 1134 60

Stromal cell-derived factor-1 (SDF-1), the ligand of the CXCR4 receptor, is a chemokine involved in chemotaxis and brain development that also acts as co-receptor for HIV-1 infection. We previously demonstrated that CXCR4 and SDF-1alpha are expressed in cultured type-I cortical rat astrocytes, cortical neurones and cerebellar granule cells. Here, we investigated the possible functions of CXCR4 expressed in rat type-I cortical astrocytes and demonstrated that SDF-1alpha stimulated the proliferation of these cells in vitro. The proliferative activity induced by SDF-1alpha in astrocytes was reduced by PD98059, indicating the involvement of extracellular signal-regulated kinases (ERK1/2) in the astrocyte proliferation induced by CXCR4 stimulation. This observation was further confirmed showing that SDF-1alpha treatment selectively activated ERK1/2, but not p38 or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). Moreover, both astrocyte proliferation and ERK1/2 phosphorylation, induced by SDF-1alpha, were inhibited by pertussis toxin (PTX) and wortmannin treatment indicating the involvement of a PTX sensitive G-protein and of phosphatidyl inositol-3 kinase in the signalling of SDF-1alpha. In addition, Pyk2 activation represent an upstream components for the CXCR4 signalling to ERK1/2 in astrocytes. To our knowledge, this is the first report demonstrating a proliferative effect for SDF-1alpha in primary cultures of rat type-I astrocytes, and showing that the activation of ERK1/2 is responsible for this effect. These data suggest that CXCR4/SDF-1 should play an important role in physiological and pathological glial proliferation, such as brain development, reactive gliosis and brain tumour formation.
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PMID:Stromal cell-derived factor-1alpha induces astrocyte proliferation through the activation of extracellular signal-regulated kinases 1/2 pathway. 1138 73

The dissemination of T cell hybridomas to multiple nonhematopoietic tissues is blocked by pertussis toxin, suggesting the involvement of a chemokine. To study whether this chemokine is SDF-1, we employed a strategy proposed previously for gene therapy of AIDS, whereby the SDF-1 receptor CXCR4 (also a coreceptor for HIV) is retained in the endoplasmic reticulum (ER) and fails to reach the cell surface. We transfected SDF-1, carrying an ER retention sequence, into a T cell hybridoma. This altered chemokine is retained in the ER, where it binds CXCR4 and prevents the latter protein from reaching the surface. These cells failed to migrate toward SDF-1 or to invade fibroblast monolayers, although they could still migrate toward thymus and activation-regulated chemokine (TARC) and invade TARC-treated monolayers. Furthermore, the ability of the transfected cells to disseminate to multiple organs upon intravenous injection into mice was abolished. This dissemination reflects the in vivo migration patterns of activated and memory T cells into nonhematopoietic tissues, which is thus likely to depend on CXCR4. Attempts to block CXCR4 function as a therapy for AIDS may affect this migration with consequences for T cell function. Our results also suggest a decisive role for CXCR4 in the dissemination of hematopoietic malignancies expressing this receptor.
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PMID:Retention of CXCR4 in the endoplasmic reticulum blocks dissemination of a T cell hybridoma. 1145 80

HIV infects and propagates into CD4+ T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.
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PMID:Cytokine and chemokine based control of HIV infection and replication. 1147 51

The chemokine SDF-1 alpha (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1 alpha both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1 alpha are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1 alpha are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through G(alpha i) activation. In conclusion, SDF-1 alpha plays a role in two important processes of granule cell maturation - proliferation and migration - assisting in the achievement of appropriate cell number and position in the cerebellar cortex.
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PMID:SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. 1149 20

Aminooxypentane (AOP)-RANTES is a potent inhibitor of nonsyncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) isolates. Although classical chemotactic responses are not induced in primary leukocytes by AOP-RANTES, recent studies suggest that a remnant of cell signaling occurs upon binding of receptor to this compound. We have detected a breakthrough of NSI/R5 replication from the inhibitory effects of high AOP-RANTES concentrations (<100 nM). A stimulation of different primary syncytium-inducing (SI), CXCR4-tropic (X4) HIV-1 isolates was also observed in the presence of AOP-RANTES. This stimulation was also observed after 110 h in PCR and RT-PCR for minus-strand strong-stop DNA and unspliced and multiply spliced RNA, respectively. However, there was significant variability between different SI/X4 or NSI/R5 HIV-1 isolates with regard to this AOP-RANTES-mediated stimulation or breakthrough, respectively. To further define the mechanism(s) responsible for this AOP-RANTES effect, we performed detailed retroviral replication studies with an NSI/R5 (B-92BR021) and SI/X4 (D-92UG021) HIV-1 isolate in the presence of the drug. Treatment of peripheral blood mononuclear cells with 125 nM AOP-RANTES and virus did not alter coreceptor expression, HIV-1 entry, reverse transcription, or mRNA transcription from the long terminal repeat, but it did result in increased HIV-1 integration. This AOP-RANTES-mediated increase in HIV-1 integration was diminished by treatment with pertussis toxin. Phosphorylation of the mitogen-activated protein kinase (MAPK) isoforms, extracellular signal-regulated kinase 1 (ERK1) and ERK2, was increased in a CD4(+) CCR5(+) U87 cell line treated with AOP-RANTES or with an NSI/R5 HIV-1 isolate. These findings suggest that AOP-RANTES may induce a MAPK/ERK signal transduction pathway upon binding to a G-protein-coupled receptor. MAPK/ERK1 and -2 appear to phosphorylate the HIV-1 preintegration complex, a step necessary for nuclear translocation and successful integration.
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PMID:Mechanisms involved in stimulation of human immunodeficiency virus type 1 replication by aminooxypentane RANTES. 1150 8

The major human immunodeficiency virus type 1 (HIV-1) coreceptors are the chemokine receptors CCR5 and CXCR4. The patterns of expression of the major coreceptors and their use by HIV-1 strains largely explain viral tropism at the level of entry. However, while virus infection is dependent upon the presence of CD4 and an appropriate coreceptor, it can be influenced by a number of factors, including receptor concentration, affinity between envelope gp120 and receptors, and potentially receptor conformation. Indeed, seven-transmembrane domain receptors, such as CCR5, can exhibit conformational heterogeneity, although the significance for virus infection is uncertain. Using a panel of monoclonal antibodies (MAbs) to CXCR4, we found that CXCR4 on both primary and transformed T cells as well as on primary B cells exhibited considerable conformational heterogeneity. The conformational heterogeneity of CXCR4 explains the cell-type-dependent ability of CXCR4 antibodies to block chemotaxis to stromal cell-derived factor 1 alpha and to inhibit HIV-1 infection. In addition, the MAb most commonly used to study CXCR4 expression, 12G5, recognizes only a subpopulation of CXCR4 molecules on all primary cell types analyzed. As a result, CXCR4 concentrations on these important cell types have been underestimated to date. Finally, while the factors responsible for altering CXCR4 conformation are not known, we found that they do not involve CXCR4 glycosylation, sulfation of the N-terminal domain of CXCR4, or pertussis toxin-sensitive G-protein coupling. The fact that this important HIV-1 coreceptor exists in multiple conformations could have implications for viral entry and for the development of receptor antagonists.
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PMID:Antigenically distinct conformations of CXCR4. 1153 59

In the present study we analysed expression of the chemokine receptors CCR5 and CXCR4 in human embryonic neurons. Both receptors were detected in neurons from primary cultures by immunofluorescence and confocal laser microscopy analysis. Both CCR5 and CXCR4 were mainly located inside the cell in the neuronal cell body and processes. In addition, neurons synthesised CCR5 and CXCR4 transcripts, as demonstrated by reverse transcription-polymerase chain reaction. Stimulation with the CCR5 and the CXCR4 agonists increased [Ca(2+)](i) in embryonic neurons, indicating that CXCR4 and CCR5 were functional at the neuronal surface. The inhibitory effect of pertussis toxin demonstrated that G(i)alpha protein is involved in chemokine receptor activation. The fact that chemokine receptors are expressed at embryonic stage in neurons reinforces the idea that chemokines might be cues for neuron pathfinding during brain ontogeny.
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PMID:Cellular expression of functional chemokine receptor CCR5 and CXCR4 in human embryonic neurons. 1156 89


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