Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-formyl-methionyl-leucyl-phenylalanine (fMLP) is a major chemotactic factor produced by Escherichia coli and other Gram-negative bacteria. The prototypal human fMLP receptor 1 (FPR1) was cloned in 1990 from a differentiated HL-60 myeloid leukemia cell cDNA library. In transfected cells, FPR1 binds fMLP with high affinity and is activated by picomolar to low nanomolar concentrations of fMLP in chemotaxis and calcium ion mobilization assays. Two additional human genes, designated FPR-like 1 (FPRL1) and FPR-like 2 (FPRL2), were later isolated by low-stringency hybridization using FPR1 cDNA as a probe, and these were shown to cluster with FPR1 on chromosome 19q13.3. In avian models the fMLP effects and the possible expression of FPRs have been poorly investigated. In this study we demonstrated that stimulation with fMLP of cultured cells isolated from the 10-day chick embryo brain causes superoxide anion and nitric oxide release and protein phosphorylation at serine, threonine, and tyrosine residues. These effects were abrogated by pretreatment with pertussis toxin, suggesting the involvement of a G-protein-coupled receptor (GPCR). Although specific N-formyl peptide receptors have so far been demonstrated only in mammals, a specific polyclonal antihuman-FPR1 antibody proved to bind to the membrane of both neurons and glial cells isolated from the chick brain. Immunoblot analysis revealed a single band corresponding to 60 kDa ca. A BLAST search and aa sequence alignments demonstrated that a number of avian 7-transmembrane (7TM) GPCRs share some homologies with the human FPR1. Furthermore, the CXCR4 ligand, SDF-1alpha, seems to compete with the antihuman-FPR1 polyclonal antibody used in our experiments. We thus advance the hypothesis that in birds one (or more) of the expressed 7TM GPCRs, most probably chemokine receptors belonging to the CXCR4 subfamily, also may act as fMLP receptors.
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PMID:Formyl peptide receptor expression in birds. 1746 63

The CXCR4 chemokine receptor and the delta opioid receptor (DOR) are pertussis toxin-sensitive G protein-coupled receptors (GPCR). Both are widely distributed in brain tissues and immune cells, and have key roles in inflammation processes and in pain sensation on proximal nerve endings. We show that in immune cells expressing CXCR4 and DOR, simultaneous addition of their ligands CXCL12 and [D-Pen2, D-Pen5]enkephalin does not trigger receptor function. This treatment does not affect ligand binding or receptor expression, nor does it promote heterologous desensitization. Our data indicate that CXCR4 and DOR form heterodimeric complexes that are dynamically regulated by the ligands. This is compatible with a model in which GPCR oligomerization leads to suppression of signaling, promoting a dominant negative effect. Knockdown of CXCR4 and DOR signaling by heterodimerization might have repercussions on physiological and pathological processes such as inflammation, pain sensation and HIV-1 infection.
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PMID:Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. 1820 36

HIV-1 infection results in an increased risk of malignancy as well as immune suppression. However, analyses of cancer incidence in chronically immunosuppressed transplant recipients and HIV-infected person have demonstrated an unexpected low incidence of certain types of cancer, such as breast cancers, and the mechanism behind this remains unclarified. In this study, we show that most breast cancer cell lines express CXCR4 but are not susceptible to HIV-1 infection. The apoptosis of breast cancer cells is induced by HIV-1 in a viral-dose- and time-dependent manner without productive infection. The apoptosis is induced by R5X4 and X4 HIV-1 but not by R5 HIV-1, and is inhibited by an anti-CXCR4 antibody, an anti-gp120 antibody, AMD3100, or pertussis toxin. The apoptosis is mediated via CXCR4 in breast cancer cells that exhibit conformational heterogeneity in comparison with CXCR4 in T-cells. Furthermore, the gp120 mutant (E370R) with a low CD4 binding ability can specifically induce apoptosis in breast cancer cells but not in T-cells. Taken together, these results indicate that HIV-1 and gp120 can induce breast cancer cell apoptosis through gp120-CXCR4 interaction without a CD4-induced conformational change of gp120, and may lead to a novel HIV-1-based therapy for breast cancer.
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PMID:Human immunodeficiency virus-induced apoptosis of human breast cancer cells via CXCR4 is mediated by the viral envelope protein but does not require CD4. 1828 73

In humans, 10(11) neutrophils are released from the bone marrow per day, and these cells have a half-life in the blood of only approximately 6.5 h. Although it is generally believed that neutrophils are cleared from the circulation via the liver and spleen, in this study using (111)In-labeled senescent neutrophils, we show that in mice, 32% of neutrophils are cleared from the circulation via the bone marrow. We have previously shown that senescent neutrophils home to the bone marrow in a CXCR4-dependent manner, and we show here that pretreatment of neutrophils with pertussis toxin significantly inhibits neutrophil clearance via the bone marrow (75%), consistent with a role for chemokines in this process. By labeling senescent neutrophils with inert fluorescent microspheres, we have tracked their fate and shown that in vivo, they are ultimately phagocytosed by bone marrow stromal macrophages. Finally, we show that under noninflammatory conditions, circulating levels of neutrophils are regulated by granulocyte-colony stimulating factor (G-CSF), but not interleukin-17. Interestingly, we report that the uptake of apoptotic neutrophils by bone marrow macrophages stimulates their production of G-CSF in vitro. Taken together, these data provide evidence that the bone marrow represents a major site of neutrophil clearance in mice.
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PMID:The role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse. 1850 99

The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) binds to the chemokine receptor CXCR4 that couples to pertussis toxin-sensitive G-proteins of the G(i)/G(o)-family. CXCR4 plays a role in the pathogenesis of autoimmune diseases, human immunodeficiency virus infection and various tumors, fetal development as well as endothelial progenitor and T-cell recruitment. To this end, most CXCR4 studies have focused on the cellular level. The aim of this study was to establish a reconstitution system for the human CXCR4 that allows for the analysis of receptor/G-protein coupling at the membrane level. We wished to study specifically constitutive CXCR4 activity and the G-protein-specificity of CXCR4. We co-expressed N- and C-terminally epitope-tagged human CXCR4 with various G(i)/G(o)-proteins and regulator of G-protein signaling (RGS)-proteins in Sf9 insect cells. Expression of CXCR4, G-proteins, and RGS-proteins was verified by immunoblotting. CXCR4 coupled more effectively to Galpha(i1) and Galpha(i2) than to Galpha(i3) and Galpha(o) and insect cell G-proteins as assessed by SDF-1alpha-stimulated high-affinity steady-state GTP hydrolysis. The RGS-proteins RGS4 and GAIP enhanced SDF-1alpha-stimulated GTP hydrolysis. SDF-1alpha stimulated [(35)S]guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) binding to Galpha(i2). RGS4 did not enhance GTPgammaS binding. Na(+) salts of halides did not reduce basal GTPase activity. The bicyclam, 1-[[1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100), acted as CXCR4 antagonist but was devoid of inverse agonistic activity. Halides reduced the maximum SDF-1alpha-stimulated GTP hydrolysis in the order of efficacy I(-) > Br(-) > Cl(-). In addition, salts reduced the potency of SDF-1alpha at activating GTP hydrolysis. From our data, we conclude the following: (1) Sf9 cells are a suitable system for expression of functionally intact human CXCR4; (2) Human CXCR4 couples effectively to Galpha(i1) and Galpha(i2); (3) There is no evidence for constitutive activity of CXCR4; (4) RGS-proteins enhance agonist-stimulated GTP hydrolysis, showing that GTP hydrolysis becomes rate-limiting in the presence of SDF-1alpha; (5) By analogy to previous observations made for the beta(2)-adrenoceptor coupled to G(s), the inhibitory effects of halides on agonist-stimulated GTP hydrolysis may be due to increased GDP-affinity of G(i)-proteins, reducing the efficacy of CXCR4 at stimulating nucleotide exchange.
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PMID:Functional reconstitution of the human chemokine receptor CXCR4 with G(i)/G (o)-proteins in Sf9 insect cells. 1852 57

Neutrophil retention in and release from the bone marrow is a critical process that remains incompletely understood. Previous work has implicated the CXCR4/stromal derived factor-1 (SDF-1) chemokine axis in the marrow retention of neutrophils, yet the adhesion pathways responsible for this retention are unknown. Because alpha(4)beta(1) integrin (VLA-4) and its ligand VCAM-1 play a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether this integrin might be involved in marrow neutrophil retention and release. In this study, we show that VLA-4 is expressed on murine marrow neutrophils and decreases with maturation, whereas blockade of this integrin leads to the release of marrow neutrophils. Marrow neutrophils adhere via VLA-4 to VCAM-1, which is expressed on marrow endothelium and stroma, and inhibition of VCAM-1 causes release of marrow neutrophils. Furthermore, SDF-1 (CXCL12) signaling through neutrophil CXCR4 augments VLA-4 adhesion to VCAM-1 in vitro, an effect that is blocked by preincubation with pertussis toxin. In vivo blockade of both CXCR4 and alpha(4) causes synergistic release of marrow neutrophils, showing that cross-talk between CXCR4 and VLA-4 modulates marrow retention of these cells. Taken together, these results indicate that the VLA-4/VCAM adhesion pathway is critical in the retention and maturation-controlled release of neutrophils from the marrow, while providing an important link between the CXCR4/SDF-1 signaling axis and the adhesion events that govern this process.
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PMID:Crosstalk between CXCR4/stromal derived factor-1 and VLA-4/VCAM-1 pathways regulates neutrophil retention in the bone marrow. 1910 94

CXCL12, a ligand for the chemokine receptor CXCR4, is well known in mediating neural progenitor cell (NPC) migration during neural development. However, the effects of CXCL12 on human NPC proliferation and its associated signaling pathways remain unclear. The transcription factor, FOXO3a, a downstream target of Akt-1, is critical for cell cycle control and may also play an important role in regulating NPC proliferation. In this study, we found that CXCL12 promotes human NPC proliferation as determined by the proliferation marker Ki67 and BrdU incorporation. This CXCL12-mediated NPC proliferation was associated with an increase in Akt-1 and FOXO3a phosphorylation in a time- and dose-dependent manner. The CXCR4 antagonist (T140) or inhibitors for G proteins (Pertussis toxin) and phosphoinositide 3-kinase (PI3K) (LY294002) abolished CXCL12-mediated NPC proliferation and phosphorylation of Akt-1 and FOXO3a. The roles of Akt-1 and FOXO3a in CXCL12-mediated NPC proliferation were further investigated by using adenoviral over-expression in NPCs. Over-expression of dominant-negative Akt-1 or wild-type FOXO3a in NPC abrogated CXCL12-mediated proliferation. These data suggest that CXCL12-mediated NPC proliferation is reliant upon the phosphorylation of Akt-1 and FOXO3a and gives insight to an essential role of CXCL12 in neurogenesis. Understanding this mechanism may facilitate the development of novel therapeutic targets for NPC proliferation during neurogenesis.
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PMID:CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway. 1930 76

Glioblastoma is the most malignant and common brain tumor. To promote their growth, these glioma cells secrete a variety of soluble factors including plasminogen activator inhibitor-1 (PAI-1), which functions as an inhibitor of plasminogen activators. We report here with the basis of microarray gene expression analysis that CXCR4 expressing glioma cells are capable of expressing PAI-1 mRNA and protein upon CXCL12 stimulation. Pretreatment with U0126, an inhibitor of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2, abrogated CXCL12-induced PAI-1 expression. Pertussis toxin (PTX), an inhibitor of Galpha(i) proteins, also had inhibitory effects, indicating that the activation of Galpha(i) and ERK MAPK are required for this response. Interestingly, CXCL12 showed additive effects with another PAI-1 inducers, tumor necrosis factor (TNF)-alpha and/or tumor growth factor (TGF)-beta1, in increasing PAI-1 expression. These results indicate that CXCL12/CXCR4 signaling in glioma cells may be another mechanism for these cells to express PAI-1, which may be involved in angiogenesis and tumor invasion in brain tumors.
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PMID:CXCL12-mediated induction of plasminogen activator inhibitor-1 expression in human CXCR4 positive astroglioma cells. 1933 86

Pertussis toxin (PTx) has been shown to exert a variety of effects on immune cells independent of its ability to ADP-ribosylate G proteins. Of these effects, the binding subunit of PTx (PTxB) has been shown to block signaling via the chemokine receptor CCR5, but the mechanism involved in this process is unknown. Here, we show that PTxB causes desensitization of a related chemokine receptor, CXCR4, and explore the mechanism by which this occurs. CXCR4 is the receptor for the chemokine stromal cell-derived factor 1alpha (SDF-1alpha) and elicits a number of biological effects, including stimulation of T cell migration. PTxB treatment causes a decrease in CXCR4 surface expression, inhibits G protein-associated signaling, and blocks SDF-1alpha-mediated chemotaxis. We show that PTxB mediates these effects by activating the TCR signaling network, as the effects are dependent on TCR and ZAP70 expression. Additionally, the activation of the TCR with anti-CD3 mAb elicits a similar set of effects on CXCR4 activity, supporting the idea that TCR signaling leads to cross-desensitization of CXCR4. The inhibition of CXCR4 by PTxB is rapid and transient; however, the catalytic activity of PTx prevents CXCR4 signaling in the long term. Thus, the effects of PTx holotoxin on CXCR4 signaling can be divided into two phases: short term by the B subunit, and long term by the catalytic subunit. These data suggest that TCR crosstalk with CXCR4 is likely a normal cellular process that leads to cross-desensitization, which is exploited by the B subunit of PTx.
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PMID:Pertussis toxin signals through the TCR to initiate cross-desensitization of the chemokine receptor CXCR4. 1938 Aug 20

Neurodegenerative and neuroinflammatory disorders are commonly associated with local chemokine release. In other way, emerging data indicate that the prostaglandin E2 (PGE(2)), one of the major prostaglandins produced in the brain, play a central role in several pathological diseases. In this study, we investigated the relationship between CXCL12, cyclooxygenase (COX)-2 and PGE(2) in human brain cells. CXCL12 induced COX-2 and secretion of PGE(2) in a dose-dependent manner in human astrocytes. This induction was abolished by treatment with pertussis toxin and AMD3100, confirming the role of CXCR4 signaling. The nuclear factor-kappaB involvement was confirmed by using pyrrolidine dithiocarbamate, and with transient transfection assays. Over-expression of inhibitory proteins of nuclear factor-kappaB abrogated COX-2 induction, and CXCL12 induced p65/relA translocation. Culture supernatants from CXCL12-treated astrocytes reduced viability of neuroblastoma cells, and COX inhibitors abrogated this toxicity. Therefore, the relationship between chemokines and PGs could differentially influence the pathogenic network responsible for neurodegeneration.
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PMID:Nuclear factor-kappaB activation regulates cyclooxygenase-2 induction in human astrocytes in response to CXCL12: role in neuronal toxicity. 2018 Aug 83


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