UMLS:C0043167 - FACTA Search

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

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.
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PMID:Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor. 751 63

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

Low density lipoprotein (LDL) interactions with the endothelium are thought to play a major role in the development of atherosclerosis. The mechanism(s) involved are not fully understood, although several lines of evidence support the idea that oxidation of LDL increases its atherogenicity. In this study we report for the first time that native LDL (n-LDL) binding to the LDL receptor (100-700 mug/ml) triggers a rise in intracellular calcium which acts as a second messenger to induce vascular cell adhesion molecule-1 (VCAM-1) expression in human coronary artery (HCAEC) and pig aortic endothelial cells (PAEC) and VCAM-1 and E-selectin expression in human aortic (HAEC) endothelial cells. Preincubation of HCAEC with a monoclonal antibody (IgGC7) to the classical LDL receptor or pretreatment with pertussis toxin blocked the n-LDL-induced calcium transients. Preincubation of each of the endothelial cell lines with the calcium chelator 1,-2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetic acetomethyl ester (BAPTA/AM) prevented the expression of VCAM-1 and E-selectin. The increase in VCAM-1 by n-LDL results in increased monocyte binding to HCAEC which can be attenuated by inhibiting the intracellular calcium rise or by blocking the VCAM-1 binding sites. These studies in human and pig endothelial cells link calcium signaling conferred by n-LDL to mechanisms controlling the expression of endothelial cell adhesion molecules involved in atherogenesis.
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PMID:Native low density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. 948 77

We have used the Stamper-Woodruff frozen-section assay (FSA) to characterize the integrin and activation steps involved in adhesion of peripheral blood eosinophils and neutrophils to nasal polyp endothelium (NPE). Eosinophil and neutrophil adhesion was significantly inhibited by monoclonal antibodies (mAbs) against CD18 (beta2) and CD11a-c. Eosinophil adhesion was also inhibited to a lesser extent by mAbs against CD29 (beta1), CD49d (alpha4), and vascular cell adhesion molecule-1. The involvement of integrins raised the possibility of an activation step being involved in the adhesion process. Although stimulation of the cells with granulocyte macrophage colony-stimulating factor (GM-CSF) before the assay failed to modulate adhesion, binding was inhibited by up to 50% by treatment of the leukocytes with azide. In addition, neutrophil adhesion was completely abrogated by pertussis toxin (PT) and inhibited by about 50% by the platelet-activating factor antagonist WEB 2086 and antibodies against interleukin (IL)-8 and the two IL-8 receptors IL8RA and IL8RB (C-X-CR1 and -CR2). In contrast, eosinophil adhesion was unaffected by PT, WEB 2086, or anti-IL8R mAbs. mAbs against CCR-3, IL-3, IL-5, and GM-CSF also had no effect. This study demonstrates that eosinophil and neutrophil adhesion to NPE in the FSA conforms to the multistep paradigm for leukocyte adhesion and can be used to model the molecular basis for adhesion to endothelium in the context of chronic inflammatory disease. Using this assay, we have observed significant differences in integrin usage between eosinophils and neutrophils and a striking difference in the mechanism of integrin activation. These differences could explain, in part, the preferential accumulation of eosinophils in diseases such as asthma.
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PMID:Characterization of the integrin and activation steps mediating human eosinophil and neutrophil adhesion to chronically inflamed airway endothelium. 1034 Sep 44

Lysophosphatidic acid (LPA) is produced by a variety of activated cell types and acts as an intercellular mediator of processes associated with inflammation and repair including platelets aggregation, and smooth muscle and fibroblast proliferation. However no previous studies have examined the effects of LPA on endothelial cell leukocyte interactions. We have examined the ability of LPA to activate human aortic endothelial cells (HAEC) to bind monocytes, neutrophils, and HL60 cells (a neutrophil surrogate). Treatment of HAEC for 4 hours with 10 microM LPA caused an increase in the binding of monocytes, neutrophils, and HL60. LPA but not phosphatidic acid dose-dependently increased E-selectin and vascular cell adhesion molecule-1 (VCAM-1) cell surface expression. We performed several studies to characterize the receptor mediating the LPA effect. We demonstrate that at least five potential LPA receptors are expressed by HAEC: Edg-1, -3, -4, and -5 as well as PSP24. Cyclic phosphate-containing phosphatidic acid analogue, an agonist for the type 3 low affinity LPA receptor, was not effective in activating HAEC to bind leukocytes, excluding a role for this receptor. The selective receptor antagonists N-palmitoyl-serine and N-palmitoyl-tyrosine (which inhibits PSP24) completely inhibited LPA-induced VCAM expression; however these antagonists inhibited E-selectin expression by only 30%, suggesting a role for at least one additional LPA receptor mediating E-selectin expression. We propose that Edg-1 might be the second receptor, because this receptor, when expressed in HEK293 cells, similarly to the PSP24 receptor, caused ERK activation to nanomolar concentration of LPA. Exposure of HAEC to sphingosine-1-phosphate, another Edg-1 receptor agonist, increased surface expression of E-selectin and to a much smaller extent VCAM-1. The effects of both LPA and sphingosine-1-phosphate on the induction of both VCAM-1 and E-selectin expression was abolished by pretreatment with pertussis toxin suggesting that both LPA receptors in HAEC couple to a Gi pathway. These findings reveal an important and novel role for LPA and its receptors in inflammatory processes.
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PMID:Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction. 1053 86

Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and VCAM-1 play variably important roles in immune-mediated processes. They are induced by the proinflammatory cytokines IL-1 and TNF-alpha, and NF-kappaB is required for the regulated expression of all three genes. Regulators of this pathway could potentially be potent immune modulators. We studied the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on cytokine-induced expression of CAMs in HUVEC. Unexpectedly, pretreatment with simvastatin potentiated the induction of all three endothelial CAMs by IL-1 and TNF, but not LPS or PMA, as detected by flow cytometry. Northern blot analysis demonstrated an increase in steady state IL-1-induced E-selectin mRNA levels in cells pretreated with simvastatin. This was associated with an increase in nuclear translocation of NF-kappaB, as detected by EMSA. The effect of simvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate but not squalene, indicating that an inhibitory prenylated protein is involved in endothelial responses to proinflammatory cytokines. Pertussis toxin mimicked the effect of simvastatin, and the G protein activator NaF inhibited the cytokine-induced expression of endothelial CAMs, indicating that a Gialpha protein is involved. These results demonstrate that cytokine-mediated activation of the endothelium, and specifically CAM induction, can be modulated by a heterotrimeric G protein-coupled pathway. This may represent a "basal tone" of endothelial inactivation, which can either be disinhibited or amplified, depending on the stimulus.
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PMID:Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein. 1094 2

The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) and its G-protein-linked receptor CXCR4 are involved in hematopoietic progenitor cell and lymphocyte migration. The integrin VLA-4 is a cell adhesion receptor for CS-1/fibronectin and VCAM-1 and constitutes one of the main adhesion receptors mediating myeloma cell adhesion to bone marrow (BM) stroma in multiple myeloma (MM). It is shown here that MM CD38(hi)CD45RA(-) BM cells and myeloma-derived cell lines expressed CXCR4 and displayed a moderate chemotactic response to SDF-1alpha. Because cell migration in response to SDF-1alpha might require a dynamic regulation of integrin function, it was investigated whether SDF-1alpha can modulate VLA-4 function on myeloma cells. SDF-1alpha rapidly and transiently up-regulated VLA-4-mediated myeloma cell adhesion to both CS-1/fibronectin and VCAM-1, which was inhibited by pertussis toxin and cytochalasin D, indicating the involvement of G(i) protein downstream signaling and an intact cytoskeleton. Modulation of VLA-4-dependent myeloma cell adhesion by SDF-1alpha could contribute to the trafficking and localization of these cells in the BM microenvironment.
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PMID:Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1. 1115 7

B-cell accumulation and formation of ectopic germinal centers are characteristic changes in the diseased joints of patients with rheumatoid arthritis (RA). Earlier studies suggested that interactions between B lymphocytes and specialized synovial "nurse-like" cells peculiar to the RA synovium may be responsible for the homing and sustained survival of B cells in the synovium. However, in this study, we found that B cells spontaneously migrate beneath ordinary fibroblast-like synoviocytes (FLSs) and then experience prolonged survival. FLSs isolated from joints of patients with osteoarthritis also supported this activity, termed B-cell pseudoemperipolesis. We found that FLSs constitutively expressed the chemokine stromal cell-derived factor-1 (SDF-1), and that pertussis toxin or antibodies to the SDF-1 receptor (CXCR4) could inhibit B-cell pseudoemperipolesis. However, expression of SDF-1 is not sufficient, as dermal fibroblasts also expressed this chemokine but were unable to support B-cell pseudoemperipolesis unless previously stimulated with IL-4 to express CD106 (VCAM-1), a ligand for the alpha(4)beta(1) integrin, very-late-antigen-4 (VLA-4 or CD49d). Furthermore, mAb's specific for CD49d and CD106, or the synthetic CS1 fibronectin peptide, could inhibit B-cell pseudoemperipolesis. We conclude that ordinary FLSs can support B-cell pseudoemperipolesis via a mechanism dependent upon fibroblast expression of SDF-1 and CD106.
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PMID:Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. 1116 Jan 54

Stromal cell-derived factor-1alpha (SDF-1alpha) is a potent chemoattractant for hematopoietic progenitor cells (HPC), suggesting that it could play an important role during their migration within or to the bone marrow (BM). The integrin VLA-4 mediates HPC adhesion to BM stroma by interacting with CS-1/fibronectin and VCAM-1. It is required during hematopoiesis and homing of HPC to the BM. As HPC migration in response to SDF-1alpha might require dynamic regulation of integrin function, we investigated if SDF-1alpha could modulate VLA-4 function on BM CD34(hi) cells.CD34(hi) BM cells and hematopoietic cell lines were tested for the effect of SDF-1alpha on VLA-4-dependent adhesion to CS-1/fibronectin and VCAM-1, as well as to BM stroma. CD34(hi) BM cells that adhered to VLA-4 ligands after SDF-1alpha treatment were characterized in colony-forming and long-term culture-initiating cell (LTC-IC) assays.SDF-1alpha rapidly (1 minute) and transiently upregulated the adhesion of CD34(hi) BM cells and hematopoietic cell lines to both CS-1/fibronectin and VCAM-1, and to BM stromal cells. The upregulation of VLA-4-dependent cell adhesion by SDF-1alpha targeted primitive LTC-IC as well as committed CD34(hi) cells. SDF-1alpha-triggered enhancement in VLA-4 function was inhibited by pertussis toxin (PTx) and cytochalasin D, indicating the involvement of G(i) protein downstream signaling and an intact cytoskeleton. Instead, activation of p44/42 MAP kinases by SDF-1alpha did not functionally correlate with enhancement of VLA-4-dependent cell adhesion. Modulation of VLA-4-mediated CD34(hi) BM cell adhesion by SDF-1alpha could play a key role in their migration within and to the BM and therefore influence their proliferation and differentiation.
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PMID:Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells. 1127 63

IL-12, a cytokine produced by microglia, may regulate cellular immunity at a localized level in the CNS. To investigate this further, we examined the consequences of peripheral immune stimulation without specific autoantigen in wild-type or transgenic (termed GF-IL12) mice with astrocyte production of the bioactive IL-12 p75 heterodimer. Active immunization with CFA and pertussis toxin, a procedure known to stimulate a robust type 1-biased immune response, produced CNS immune pathology from which GF-IL12 but not wild-type mice developed signs of clinical disease consisting of loss of activity, piloerection, mild tremor, and motor change. All immunized mice had some degree of mononuclear cell infiltration into the brain; however, the severity of this was markedly increased in GF-IL12 mice where leukocytes accumulated in perivascular and parenchymal locations. Accumulating cells consisted of CD4(+) and CD8(+) T cells and macrophage/microglia. Moreover, expression of cytokines (IFN-gamma and TNF), chemokines (IFN-inducible protein-10 and RANTES), the immune accessory molecules, MHC class II, B7.2, ICAM-1 and VCAM-1, and NO synthase-2 was induced in the CNS of the GF-IL12 mice. Therefore, peripheral immunization of GF-IL12 but not wild-type mice can provoke active type 1 immunity in the brain-a process that does not require CNS-specific immunizing autoantigen. These findings indicate that the cytokine milieu of a tissue can dramatically influence the development of intrinsic immune responses and associated pathology.
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PMID:Induction of type 1 immune pathology in the brain following immunization without central nervous system autoantigen in transgenic mice with astrocyte-targeted expression of IL-12. 1167 69

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