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1
Hickstein, DD, E. Grunvald, G. Shumaker, DM Baker, AL Back, LJ Embree, E. Yee, and KA Gollahon. "Transfected leukocyte integrin CD11b/CD18 (Mac-1) mediates phorbol ester-activated, homotypic cell:cell adherence in the K562 cell line." Blood 82, no. 8 (October 15, 1993): 2537–45. http://dx.doi.org/10.1182/blood.v82.8.2537.2537.
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Abstract The CD11b/CD18 leukocyte integrin molecule mediates diverse neutrophil adherence-related functions, including cell:cell and cell:extracellular matrix attachments. To study the individual role of this leukocyte integrin in cell adherence in hematopoietic cells, we expressed the CD11b/CD18 complex on the surface of K562 cells, a cell line derived from an individual with chronic myelogenous leukemia in blast crisis. We used an amphotrophic retroviral vector designated LCD18SN, harboring the complete coding sequence for the CD18 subunit, to transfer the CD18 cDNA into K562 cells and select stable cell lines. The CD11b subunit in the expression plasmid pREP4 was transfected into these K562/CD18 cells by electroporation and stable cell clones were selected. These K562 cells possessed RNA and intracellular protein for each subunit, and they expressed the CD11b/CD18 heterodimer on the cell surface. When CD11b/CD18 expressing K562 cells were stimulated with phorbol myristate acetate (50 ng/mL) for 24 to 48 hours, these K562 cells formed dense cell:cell aggregates. This homotypic aggregation required both activation of the CD11b/CD18 complex and the induction of the counter- receptor for CD11b/CD18 on the conjugate cell. This cell line will (1) enable the structure-function relationships between cell activation and homotypic adherence to be assessed, (2) provide the opportunity to identify accessory molecules required for activation of the CD11b/CD18 complex, and (3) facilitate the identification of novel ligands for the CD11b/CD18 complex.
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Hickstein, DD, E. Grunvald, G. Shumaker, DM Baker, AL Back, LJ Embree, E. Yee, and KA Gollahon. "Transfected leukocyte integrin CD11b/CD18 (Mac-1) mediates phorbol ester-activated, homotypic cell:cell adherence in the K562 cell line." Blood 82, no. 8 (October 15, 1993): 2537–45. http://dx.doi.org/10.1182/blood.v82.8.2537.bloodjournal8282537.
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The CD11b/CD18 leukocyte integrin molecule mediates diverse neutrophil adherence-related functions, including cell:cell and cell:extracellular matrix attachments. To study the individual role of this leukocyte integrin in cell adherence in hematopoietic cells, we expressed the CD11b/CD18 complex on the surface of K562 cells, a cell line derived from an individual with chronic myelogenous leukemia in blast crisis. We used an amphotrophic retroviral vector designated LCD18SN, harboring the complete coding sequence for the CD18 subunit, to transfer the CD18 cDNA into K562 cells and select stable cell lines. The CD11b subunit in the expression plasmid pREP4 was transfected into these K562/CD18 cells by electroporation and stable cell clones were selected. These K562 cells possessed RNA and intracellular protein for each subunit, and they expressed the CD11b/CD18 heterodimer on the cell surface. When CD11b/CD18 expressing K562 cells were stimulated with phorbol myristate acetate (50 ng/mL) for 24 to 48 hours, these K562 cells formed dense cell:cell aggregates. This homotypic aggregation required both activation of the CD11b/CD18 complex and the induction of the counter- receptor for CD11b/CD18 on the conjugate cell. This cell line will (1) enable the structure-function relationships between cell activation and homotypic adherence to be assessed, (2) provide the opportunity to identify accessory molecules required for activation of the CD11b/CD18 complex, and (3) facilitate the identification of novel ligands for the CD11b/CD18 complex.
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Thylén, P., E. Fernvik, J. Lundahl, J. Hed, and S. H. Jacobson. "Modulation of CD11b/CD18 on Monocytes and Granulocytes following Hemodialysis Membrane Interaction in vitro." International Journal of Artificial Organs 19, no. 3 (March 1996): 156–63. http://dx.doi.org/10.1177/039139889601900304.
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We studied the generation of CD11b/CD18 mobilizing factors in serum after incubation with dialysis membrane fragments of different chemical composition. We also evaluated the relative importance of the alternative and classical pathways of the complement system in the generation of such factors. Monocytes and granulocytes from healthy blood donors were incubated in normal human serum (NHS) and in NHS that had been preincubated with Cuprophan (CU) membrane (NHS-CU), Hemophan (HE) (NHS-HE) or polysulfone (PS) (NHS-PS). NHS-CU caused the highest up-regulation of the CD11b/CD18 receptor on monocytes and granulocytes. The rank in capacity to mobilize CD11b/CD18 on granulocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.001). The rank in capacity to mobilize CD11b/CD18 on monocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.01). NHS-PS induced a lower up-regulation of CD11b/CD18 compared to NHS which indicates that serum factors with the ability to mobilize the CD11b/CD18 receptor on monocytes and granulocytes are deposited on or adsorbed by PS. In order to study the relative contribution of the alternative and classical pathways of the complement system in the generation of CD11b/CD18 mobilizing factors in serum, three different serum preparations (1. both pathways intact. 2. only the alternative intact and 3. only the classical pathway intact) were used. The CU membrane activated the classical pathway to a larger extent than the PS membrane (p<0.01). When only the alternative pathway was intact no difference in the generation of CD11b/CD18 mobilizing factors between the CU and PS membranes was observed. These studies show that CD11b/CD18 mobilizing serum factors are generated after incubation with CU membranes and that such factors are probably adsorbed by PS. The classical pathway of complement activation seems to contribute to the generation of CD11b/CD18 mobilizing factors in serum.
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Simms, H. H., and R. D′Amico. "Hypoxemia regulates effect of lipopolysaccharide on polymorphonuclear leukocyte CD11b/CD18 expression." Journal of Applied Physiology 76, no. 4 (April 1, 1994): 1657–63. http://dx.doi.org/10.1152/jappl.1994.76.4.1657.
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Expression of the receptor CD11b/CD18 on the polymorphonuclear leukocyte (PMN) surface is important for several aspects of PMN function during endotoxemia. The mechanisms underlying regulation of CD11b/CD18 expression during hypoxemia and endotoxemia, however, are less clear. We investigated the effects of exposure of whole blood PMNs to lipopolysaccharide (LPS) during hypoxemia. During hypoxemia (10–30% O2 saturation), LPS reduced CD11b/CD18 expression. Both kinetic assays and experiments with microfilament stabilizers (phalloidin, cytochalasin B) demonstrated that this was most likely due to receptor shedding. Incubation of whole blood PMNs with an anti-CD14 monoclonal antibody (MEM18) largely prevented the LPS-induced reduction of CD11b/CD18 expression. Decreased CD11b/CD18 expression reduced PMN functional capability, as the binding of its ligand (erythrocytes opsonized with the 3rd component of complement Cbi) and intracellular H2O2 production were reduced. After exposure to LPS, N-formyl-methionyl-leucyl-phenylalanine could rapidly induce new CD11b/CD18 receptors to the cell surface, and this was not inhibited by actinomycin D or cycloheximide. After reoxygenation (> 90% O2 saturation), CD11b/CD18 expression was restored, and this was abrogated by exposure to cytochalasin B. Lipid A was able to reproduce the effects of LPS during hypoxemia and hypoxemia-reoxygenation but required a 10-fold greater concentration to do so. These results demonstrate that during hypoxemia an important pathophysiological property of LPS is to reduce CD11b/CD18 expression. This results in diminished PMN functional capability, which would contribute to the pathogenicity of LPS during acute infectious states.
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Lo, S. K., P. A. Detmers, S. M. Levin, and S. D. Wright. "Transient adhesion of neutrophils to endothelium." Journal of Experimental Medicine 169, no. 5 (May 1, 1989): 1779–93. http://dx.doi.org/10.1084/jem.169.5.1779.
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Fluorescently labeled polymorphonuclear leukocytes (PMN) were used to measure adhesion to human umbilical vein endothelial cells (EC) cultured in vitro. Stimulation of PMN with phorbol dibutyrate (PDB), TNF, or C5a caused an increase in adhesion followed by a return to prestimulation levels of adhesion of longer times of incubation. Maximal adhesion of PMN to EC occurred rapidly in response to C5a (5 min) and more slowly with TNF or PDB (15 min). PMN stimulated to adhere with C5a detached from EC by 15 min. PMN from CD11/CD18-deficient patients and PMN incubated with anti-CD18 mAbs failed to bind to EC despite maximal stimulation. Anti-CD11a/CD18 and anti-CD11b/CD18 each partially inhibited adhesion, and a combination of these two reagents completely blocked adhesion. The adhesion we measured was therefore completely dependent on CD11/CD18, and CD11a/CD18 and CD11b/CD18 each contributed to adhesion. Stimuli that enhanced adhesion of PMN to EC also enhanced expression of CD11b/CD18 on the cell surface, but the time course of expression correlated poorly with changes in adhesivity. To determine if changes in the expression of CD11b/CD18 are necessary for the changes in adhesivity, we used enucleate cytoplasts that did not increase expression of CD11b/CD18. Cytoplasts showed a normal rise and fall in adhesivity in response to PDB. We conclude that the transient adhesion of stimulated PMN to naive EC is regulated by changes in the nature of existing CD11/CD18 molecules on the PMN surface. Changes in expression of CD11b/CD18 may contribute to enhancement of adhesivity, but a definite role for this phenomenon has yet to be established.
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Hajishengallis, George, Min Wang, Evlambia Harokopakis, Martha Triantafilou, and Kathy Triantafilou. "Porphyromonas gingivalis Fimbriae Proactively Modulate β2 Integrin Adhesive Activity and Promote Binding to and Internalization by Macrophages." Infection and Immunity 74, no. 10 (October 2006): 5658–66. http://dx.doi.org/10.1128/iai.00784-06.
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ABSTRACT In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the β2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this “inside-out” proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-β-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates β2 integrin adhesive activity for intracellular uptake.
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Forsyth, Christopher B., and Herbert L. Mathews. "Lymphocyte Adhesion to Candida albicans." Infection and Immunity 70, no. 2 (February 2002): 517–27. http://dx.doi.org/10.1128/iai.70.2.517-527.2002.
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ABSTRACT Adherence of lymphocytes to the fungus is the first step in the direct lymphocyte-mediated antifungal effect against Candida albicans. In this study we identified macrophage-1 antigen (Mac-1) (CD11b/CD18, αM/β2) as the lymphocyte surface structure responsible for the adhesion of activated lymphocytes to the hyphal form of the fungus. Antibodies specific for epitopes of the α-subunit (CD11b) and the β2-subunit (CD18) of Mac-1 were shown to completely eliminate lymphocyte adhesion to C. albicans hyphae. Lymphocyte adhesion to C. albicans was also inhibited significantly by known ligands of Mac-1, including the extracellular matrix proteins laminin and fibrinogen, as well as engineered peptides containing arginine-glycine-aspartic acid sequences and the disintegrin echistatin. N-Acetyl-d-glucosamine and β-glucan, which inhibit Mac-1-mediated adhesion to the yeast, blocked lymphocyte adhesion to hyphae. NIH 3T3 fibroblast transfectants expressing human CD11b/CD18 bound to C. albicans, and their binding was inhibited by antibodies specific for CD11b/CD18. Finally, antibodies specific for CD11b/CD18 effectively inhibited the capacity of activated lymphocytes to have an antifungal effect against hyphae. Our results clearly identify Mac-1 (CD11b/CD18) as the lymphocyte surface structure that mediates activated lymphocyte adhesion to C. albicans and the resultant antifungal effect of the lymphocytes.
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Detmers, P. A., S. K. Lo, E. Olsen-Egbert, A. Walz, M. Baggiolini, and Z. A. Cohn. "Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils." Journal of Experimental Medicine 171, no. 4 (April 1, 1990): 1155–62. http://dx.doi.org/10.1084/jem.171.4.1155.
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The cytokine NAP-1/IL-8 is produced by a variety of different cells in response to inflammatory stimuli and elicits several biological responses from PMN. Experiments presented here demonstrate that PMN exposed to NAP-1/IL-8 expressed increased amounts of CD11b/CD18, as well as CD11c/CD18 and CR1, on their cell surface, while expression of Fc gamma RIII and HLA-A,B,C remained essentially unchanged. Increased CD11b/CD18 and CD11c/CD18 appears to correspond with the release of specific granules by NAP-1/IL-8. NAP-1/IL-8 was also a potent stimulator of several of the binding activities of CD11b/CD18. Ligation of EC3bi by CD11b/CD18 was rapidly enhanced by NAP-1/IL-8, but phagocytosis of the ligated particles was not induced by the agonist. In addition, enhanced binding of EC3bi was observed in the absence of an increase in receptor expression as shown with PMN cytoplasts. NAP-1/IL-8 promoted additional adhesive interactions between CD11b/CD18 and the biosynthetic precursor of LPS, lipid IVa, fibrinogen, and endothelial cells, suggesting that NAP-1/IL-8 may promote leukocyte adhesion in vivo that could lead to recruitment of PMN to sites of tissue inflammation.
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Li, R., J. Xie, C. Kantor, V. Koistinen, D. C. Altieri, P. Nortamo, and C. G. Gahmberg. "A peptide derived from the intercellular adhesion molecule-2 regulates the avidity of the leukocyte integrins CD11b/CD18 and CD11c/CD18." Journal of Cell Biology 129, no. 4 (May 15, 1995): 1143–53. http://dx.doi.org/10.1083/jcb.129.4.1143.
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beta 2 integrin (CD11a,b,c/CD18)-mediated cell adhesion is required for many leukocyte functions. Under normal circumstances, the integrins are nonadhesive, and become adhesive for their cell surface ligands, the intercellular adhesion molecules (ICAMs), or soluble ligands such as fibrinogen and iC3b, when leukocytes are activated. Recently, we defined a peptide derived from ICAM-2, which specifically binds to purified CD11a/CD18. Furthermore, this peptide strongly induces T cell aggregation mainly mediated by CD11a/CD18-ICAM-1 interaction, and natural killer cell cytotoxicity. In the present study, we show that the same ICAM-2 peptide also avidly binds to purified CD11b/CD18, but not to CD11c/CD18. This binding can be blocked by the CD11b antibody OKM10. The peptide strongly stimulates CD11b/CD18-ICAM-1-mediated cell aggregations of the monocytic cell lines THP-1 and U937. The aggregations are energy and divalent cation-dependent. The ICAM-2 peptide also induces CD11b/CD18 and CD11c/CD18-mediated binding of THP-1 cells to fibrinogen and iC3b coated on plastic. These findings indicate that in addition to induction of CD11a/CD18-mediated cell adhesion, the ICAM-2 peptide may also serve as a "trigger" for high avidity ligand binding of other beta 2 integrins.
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Zen, Ke, Markus Utech, Yuan Liu, Illena Soto, Asma Nusrat, and Charles A. Parkos. "Association of BAP31 with CD11b/CD18." Journal of Biological Chemistry 279, no. 43 (August 4, 2004): 44924–30. http://dx.doi.org/10.1074/jbc.m402115200.
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Sheikh, S., and GB Nash. "Continuous activation and deactivation of integrin CD11b/CD18 during de novo expression enables rolling neutrophils to immobilize on platelets." Blood 87, no. 12 (June 15, 1996): 5040–50. http://dx.doi.org/10.1182/blood.v87.12.5040.bloodjournal87125040.
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In an in vitro flow model, unstimulated neutrophils rolled steadily over a surface coated with platelets, until superfusion of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP) caused a dose-dependent (10(-11) to 10(-7) mol/L) transition from rolling to stationary attachment in seconds, followed more slowly by neutrophil shape change and spreading on the surface, However, at low concentrations of Ca2+ and Mg2+ (0.1 mmol/L and 0.05 mmol/L, respectively, rather than physiologic 1 mmol/L and 0.5 mmol/L), neutrophils first halted but then started to roll again and to detach from the surface over 5 to 10 minutes. At the low cation concentration, stopping was largely inhibited by antibodies to the neutrophil integrins CD18 or CD11b, but not CD11a. When neutrophils were pretreated with antibodies to CD11b or CD18 in 1 mmol/L Ca2+ 0.5 mmol/L Mg2+, stopping was not prevented but delayed. However, if antibodies were also included with the superfused fMLP, stopping was inhibited, and detachment followed. This indicates that CD11b/CD18 was newly expressed during shape change and mediated the second phase of neutrophil immobilization and spreading in a cation-dependent manner. Prestimulated neutrophils also bound to platelets and spread, but immobilization was blocked if they were perfused with antibody to CD18 or CD11b or with low Ca2+ and Mg2+. Examining the cation-dependence further, it was evident that the presence of Mg2+ was essential for integrin-mediated adhesion and that the Mg2+ concentration determined whether immobilization could be maintained or was transient. Continuous superfusion of fMLP was also essential for maintenance of stable adhesion and spreading. Thus, activation of constitutive CD11b/CD18 rapidly and reversibly converted rolling to stationary attachment, whereas maintenance of adhesion and neutrophil spreading required continual expression of additional CD11b/CD18 that was only functional at physiologic Mg2+. Continual activation and deactivation of CD11b/CD18 during de novo expression could mediate immobilization and onward migration of neutrophils in vivo, and activated platelets appear capable of supporting this process as well as endothelial cells.
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Papayannopoulou, T., and M. Brice. "Integrin expression profiles during erythroid differentiation." Blood 79, no. 7 (April 1, 1992): 1686–94. http://dx.doi.org/10.1182/blood.v79.7.1686.1686.
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Abstract To study the expression of integrins at the erythroid progenitor level we isolated selected populations of cells from human fetal liver after immunoadherence to anti-beta 2 integrin (CD18) coated plates. These CD18 adherent cells (CD18-Ad), in contrast to CD18 nonadherent cells (CD18-NAd), have a blastlike cell morphology and are highly enriched in all progenitor types (14% to 37% progenitors). By several criteria progenitor cells present in CD18-Ad cells appear to have a higher proliferative potential and diversity than the ones found in CD18-NAd, which were mostly later erythroid progenitors. Positivity of CD18-Ad cells with the common beta 2 integrin (CD18) is largely attributable to expression of alpha L (CD11a) chain, rather than alpha M (CD11b). CD11a is present in all types of progenitors, but it is selectively lost at later stages of erythroid differentiation/maturation. By contrast, CD11b appears to be virtually absent from all progenitors but it has an enhanced expression during granulomonocytic differentiation/maturation. In addition to beta 2 integrins, CD18-Ad cells express several other cytoadhesion molecules (VLA-4, VLA-5, I-CAM, H-CAM) as well as other progenitor cell antigens (CD34, HLA-DR, CD38). Cells expressing all these antigens were selectively enriched in CD18-Ad cells. Our data add new information on the regulation of CD11a and CD11b molecules in hematopoiesis and on the composite profile of integrin expression at several stages of erythroid differentiation.
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Papayannopoulou, T., and M. Brice. "Integrin expression profiles during erythroid differentiation." Blood 79, no. 7 (April 1, 1992): 1686–94. http://dx.doi.org/10.1182/blood.v79.7.1686.bloodjournal7971686.
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To study the expression of integrins at the erythroid progenitor level we isolated selected populations of cells from human fetal liver after immunoadherence to anti-beta 2 integrin (CD18) coated plates. These CD18 adherent cells (CD18-Ad), in contrast to CD18 nonadherent cells (CD18-NAd), have a blastlike cell morphology and are highly enriched in all progenitor types (14% to 37% progenitors). By several criteria progenitor cells present in CD18-Ad cells appear to have a higher proliferative potential and diversity than the ones found in CD18-NAd, which were mostly later erythroid progenitors. Positivity of CD18-Ad cells with the common beta 2 integrin (CD18) is largely attributable to expression of alpha L (CD11a) chain, rather than alpha M (CD11b). CD11a is present in all types of progenitors, but it is selectively lost at later stages of erythroid differentiation/maturation. By contrast, CD11b appears to be virtually absent from all progenitors but it has an enhanced expression during granulomonocytic differentiation/maturation. In addition to beta 2 integrins, CD18-Ad cells express several other cytoadhesion molecules (VLA-4, VLA-5, I-CAM, H-CAM) as well as other progenitor cell antigens (CD34, HLA-DR, CD38). Cells expressing all these antigens were selectively enriched in CD18-Ad cells. Our data add new information on the regulation of CD11a and CD11b molecules in hematopoiesis and on the composite profile of integrin expression at several stages of erythroid differentiation.
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Senft, Albert P., Thomas R. Korfhagen, Jeffrey A. Whitsett, and Ann Marie LeVine. "Surfactant protein D regulates the cell surface expression of alveolar macrophage β2-integrins." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L469—L475. http://dx.doi.org/10.1152/ajplung.00297.2006.
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The β2-integrin receptors (CD11a/CD18, CD11b/CD18, and CD11c/CD18) are expressed on the surface of alveolar macrophages and are important for the phagocytic clearance of pathogens. In the present study, we demonstrate that surfactant protein D (SP-D) modulates surface expression of CD11b and CD11c, but not CD11a or CD18, on alveolar macrophages. While cell surface receptors were reduced, CD11b and CD11c mRNAs were increased by SP-D deficiency. CCSP-rtTA+/(tetO)7-rSPD+/SP-D−/−mice, which conditionally express SP-D in the lung, were used to study the kinetics and reversibility of β2-integrin receptors in response to changes in alveolar SP-D. Surface CD11b and CD11c were reduced on the alveolar macrophages within 3 days of SP-D deficiency and were restored with 3 days for CD11b and 7 days for CD11c of repletion of SP-D. SP-D deficiency caused a loss of cellular CD11b and CD11c content, indicating that the decrease in total cell content of the receptors was related to degradation rather than to redistribution of the receptor within the macrophage. CD11b and CD11c staining colocalized with Lamp-1 during SP-D deficiency, supporting the concept that reduced macrophage receptor levels resulted from increased lysosomal trafficking. Hydroxychloroquine, a lysomotropic agent, prevented the reduction of cellular and surface CD11b and CD11c. SP-D regulates surface CD11b and CD11c levels on the alveolar macrophage by modulating receptor trafficking, providing a mechanism by which SP-D mediates phagocytic activity in the alveolar macrophage.
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Zeltser, David, Vadim G. Karepov, and Natan M. Bornstein. "Lack of an Increased Expression of the CD11b/CD18 Antigen on the Surface of Peripheral Blood Circulating Pool of Leukocytes in Patients with an Acute Neurological Ischemic Event." Stroke 32, suppl_1 (January 2001): 322–23. http://dx.doi.org/10.1161/str.32.suppl_1.322-d.
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37 OBJECTIVE: To reveal the intensity of the surface expression of the adhesion molecules (CD11b/CD18) on monocytes and neutrophils in the peripheral blood of patients with an acute brain ischemia compared to healthy individuals who served as controls. BACKGROUND: The Leukocyte Integrin CD11b/CD18 is an important receptor that is involved in the modulation of leukocyte to endothelial interactions and is expressed in increased amounts during cell activation. It has been previously suggested that activated white blood cells, mainly polymorphonuclear leukocytes and monocytes, participate in the development of ischemic vascular disorders by virtue of their capability to obstruct the microvasculature and enhance tissue damage. DESIGN/METHODS: Cellular surface expression of the adhesion molecules CD11b/CD18 on the neutrophils and monocytes in the peripheral blood was measured by a direct immunotechnique of flow cytometry in two groups: patients who had transient ischemic attacks (TIA) or ischemic stroke (confirmed by CT scans, within 24 hours from onset of symptoms), and healthy individuals who served as controls. Analysis was done by ANOVA test. RESULT: Seventy-one patients and 150 controls were included in the study. The respective mean fluorescence intensity for CD11b/CD18 being 161±76, 155±87 for polymorphonuclear leukocytes and 231±99, 203±79 for monocytes. No statistically significant difference was noted between the groups. CONCLUSIONS: The results of the present study show that patients with acute cerebral ischemic event do not present increased amount of the CD11b/CD18 antigen on the surface of the peripheral blood polymorphonuclear or monocytes compared to control. Our data do not support the hypothesis that the white blood cells participate in the development of acute cerebral ischemia by the mechanism of activation of the adhesion molecule CD11b/CD18.
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Folkesson, Hans G., and Michael A. Matthay. "Inhibition of CD18 or CD11b attenuates acute lung injury after acid instillation in rabbits." Journal of Applied Physiology 82, no. 6 (June 1, 1997): 1743–50. http://dx.doi.org/10.1152/jappl.1997.82.6.1743.
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Folkesson, Hans G., and Michael A. Matthay. Inhibition of CD18 or CD11b attenuates acute lung injury after acid instillation in rabbits. J. Appl. Physiol. 82(6): 1743–1750, 1997.—Acid-induced lung injury is mediated primarily by activated neutrophils. Although a prior study demonstrated that acid-induced neutrophil influx into the air spaces was not CD18 dependent, we hypothesized that either a neutralizing anti-CD18 monoclonal antibody (MHM23) or a neutrophil inhibitory factor (NIF), NIF (CD11b,18), might attenuate acid-induced lung injury in rabbits by interfering with neutrophil activation. This hypothesis derived from in vitro studies that reported that anti-CD18 therapy prevented tumor necrosis factor-α-induced neutrophil activation. Hydrochloric acid (pH = 1.5 in one-third normal saline) or one-third normal saline (4 ml/kg) was instilled into the lungs of ventilated, anesthetized rabbits. The rabbits were studied for 6 h. In acid-instilled rabbits without the anti-CD18 monoclonal antibody or NIF (CD11b,18), severe lung injury developed. In acid-instilled rabbits, pretreatment (5 min before acid) with the anti-CD18 monoclonal antibody (2 mg/kg iv) or pretreatment with the NIF (anti-CD11b,18, 10 mg/kg iv) prevented 50–70% of acid-induced abnormalities in oxygenation, the increase in extravascular lung water, and extravascular protein accumulation. The anti-CD18 monoclonal antibody was associated with a significant increase in air space neutrophils by bronchoalveolar lavage, suggesting that the neutrophils respond normally to chemotactic stimuli but that the neutrophils did not injure the lung even though they accumulated in the air spaces. In summary, neutralization of CD18 attenuates the acute lung injury after acid instillation without reducing the number of neutrophils in the air spaces, suggesting that anti-CD18 therapy may be beneficial because of its capacity to reduce neutrophil activation.
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Yong, KL, PM Rowles, KG Patterson, and DC Linch. "Granulocyte-macrophage colony-stimulating factor induces neutrophil adhesion to pulmonary vascular endothelium in vivo: role of beta 2 integrins." Blood 80, no. 6 (September 15, 1992): 1565–75. http://dx.doi.org/10.1182/blood.v80.6.1565.1565.
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Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) causes upregulation of neutrophil surface CD11b/CD18 expression, and enhances the adhesion of neutrophils to cultured human endothelial cells in vitro. Systemic administration of GM-CSF results in a rapid, transient decrease in circulating phagocyte numbers. Using a nonhuman primate model (Cynomolgus), we provide histologic evidence that this transient leukopenia is associated with the margination of neutrophils in the pulmonary microcirculation. In four animals receiving 2 to 15 micrograms/kg recombinant human GM-CSF (rhGM-CSF), light microscopic sections of lung contained 36 +/- 8, 17 +/- 7, 21 +/- 6, and 15 +/- 8 (mean +/- SD, n = 20) neutrophils within a graticule grid, as compared with two control animals receiving saline injections whose lung sections contained 2.1 +/- 1.6 and 3.1 +/- 2.1 (mean +/- SD, n = 20) neutrophils within the same grid. Scanning electron microscopy shows activated leukocytes adherent to pulmonary vascular endothelium, but no morphologic evidence of endothelial damage, and no migration of cells into the extravascular space. Margination is associated with an increase in surface expression of CD11b/CD18 on circulating phagocytes, which could contribute to the adhesion to capillary endothelial cells, but CD11b/CD18 levels remain elevated even when demargination is complete. In vitro, monoclonal antibodies (MoAbs) to CD18 and CD11b were able to inhibit neutrophil aggregation and adhesion to endothelium. FMLP-induced neutrophil aggregation was inhibited by 39.8% +/- 11.5% and 44.8% +/- 12.3%, respectively, by MoAbs to CD18 and CD11b (P less than .0005, n = 4 for both); a similar effect was demonstrated on TPA-induced aggregation. MoAb CD18 reduced the adhesion of unstimulated neutrophils to endothelium by 44% (P less than .01, n = 7), and inhibited the amount of GM-CSF-stimulated adhesion by 74% (P less than .001, n = 7), while MoAb to CD11b produced a reduction of unstimulated neutrophil adhesion by 30%, and of GM-CSF-stimulated adhesion by 40% (P less than .01, n = 5, for both). However, when administered in vivo, MoAb CD18 produced only a small, albeit significant, amelioration of GM-CSF-induced margination in vivo, while MoAb CD11b was without effect. These results show that GM-CSF-induced transient leukopenia is associated with enhanced neutrophil adherence to pulmonary vascular endothelium, but suggest that the beta 2 leukocyte integrins CD11/CD18 play only a minor role in this process.
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Yong, KL, PM Rowles, KG Patterson, and DC Linch. "Granulocyte-macrophage colony-stimulating factor induces neutrophil adhesion to pulmonary vascular endothelium in vivo: role of beta 2 integrins." Blood 80, no. 6 (September 15, 1992): 1565–75. http://dx.doi.org/10.1182/blood.v80.6.1565.bloodjournal8061565.
Full textAbstract:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) causes upregulation of neutrophil surface CD11b/CD18 expression, and enhances the adhesion of neutrophils to cultured human endothelial cells in vitro. Systemic administration of GM-CSF results in a rapid, transient decrease in circulating phagocyte numbers. Using a nonhuman primate model (Cynomolgus), we provide histologic evidence that this transient leukopenia is associated with the margination of neutrophils in the pulmonary microcirculation. In four animals receiving 2 to 15 micrograms/kg recombinant human GM-CSF (rhGM-CSF), light microscopic sections of lung contained 36 +/- 8, 17 +/- 7, 21 +/- 6, and 15 +/- 8 (mean +/- SD, n = 20) neutrophils within a graticule grid, as compared with two control animals receiving saline injections whose lung sections contained 2.1 +/- 1.6 and 3.1 +/- 2.1 (mean +/- SD, n = 20) neutrophils within the same grid. Scanning electron microscopy shows activated leukocytes adherent to pulmonary vascular endothelium, but no morphologic evidence of endothelial damage, and no migration of cells into the extravascular space. Margination is associated with an increase in surface expression of CD11b/CD18 on circulating phagocytes, which could contribute to the adhesion to capillary endothelial cells, but CD11b/CD18 levels remain elevated even when demargination is complete. In vitro, monoclonal antibodies (MoAbs) to CD18 and CD11b were able to inhibit neutrophil aggregation and adhesion to endothelium. FMLP-induced neutrophil aggregation was inhibited by 39.8% +/- 11.5% and 44.8% +/- 12.3%, respectively, by MoAbs to CD18 and CD11b (P less than .0005, n = 4 for both); a similar effect was demonstrated on TPA-induced aggregation. MoAb CD18 reduced the adhesion of unstimulated neutrophils to endothelium by 44% (P less than .01, n = 7), and inhibited the amount of GM-CSF-stimulated adhesion by 74% (P less than .001, n = 7), while MoAb to CD11b produced a reduction of unstimulated neutrophil adhesion by 30%, and of GM-CSF-stimulated adhesion by 40% (P less than .01, n = 5, for both). However, when administered in vivo, MoAb CD18 produced only a small, albeit significant, amelioration of GM-CSF-induced margination in vivo, while MoAb CD11b was without effect. These results show that GM-CSF-induced transient leukopenia is associated with enhanced neutrophil adherence to pulmonary vascular endothelium, but suggest that the beta 2 leukocyte integrins CD11/CD18 play only a minor role in this process.
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Guerau-de-Arellano, Mireia, Joseph Alroy, Daniel Bullard, and Brigitte T. Huber. "Aggravated Lyme Carditis in CD11a−/− and CD11c−/− Mice." Infection and Immunity 73, no. 11 (November 2005): 7637–43. http://dx.doi.org/10.1128/iai.73.11.7637-7643.2005.
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ABSTRACT CD18 hypomorph mice expressing reduced levels of the common β2 integrin chain develop aggravated Lyme carditis, compared to that developed by wild-type (WT) mice, upon infection with the spirochete Borrelia burgdorferi. The enhancement of Lyme carditis in these mice is characterized by increased macrophage infiltration, correlating with augmented expression of the monocyte/macrophage chemoattractant protein 1 (MCP-1). The lack of CD18 results in the deficiency of all β2 integrins, i.e., CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1/CR3), CD11c/CD18 (p150,95/CR4), and CD11d/CD18. To determine the roles of the various β2 integrins in controlling the development of aggravated Lyme carditis, disease induction was analyzed in CD11a−/−, CD11b−/−, and CD11c−/− mice. CD11a−/− and CD11c−/− mice, but not CD11b−/− mice, developed aggravated Lyme carditis after exposure to B. burgdorferi. Similarly to CD18 hypomorph mice, CD11c−/− mice expressed higher levels of MCP-1, compared to both WT and CD11a−/− mice, as determined by in vitro analysis of MCP-1 secretion by bone marrow-derived dendritic cells and in vivo analysis of MCP-1 mRNA expression in B. burgdorferi-infected hearts. On the other hand, CD11a deficiency was associated with heightened heart B. burgdorferi burden relative to that of WT mice. Overall, our results suggest that the increased severity of Lyme carditis in CD18 hypomorph mice is caused by deficiency in CD11a or CD11c, possibly via different mechanisms.
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Lynam, EB, SI Simon, YP Rochon, and LA Sklar. "Lipopolysaccharide enhances CD11b/CD18 function but inhibits neutrophil aggregation." Blood 83, no. 11 (June 1, 1994): 3303–11. http://dx.doi.org/10.1182/blood.v83.11.3303.3303.
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Abstract Human neutrophils are primed in the presence of complexes of lipopolysaccharide (LPS) with its serum binding protein (LBP) in a manner dependent on CD14. Cellular consequences of priming include increased responsiveness, the upregulation of surface proteins including the adhesive integrin CD11b/CD18 (Mac-1), the increased binding of certain ligands to CD11b/CD18, and the concurrent shedding of the L-selectin homing receptor. Because expression of both CD11b/CD18 and L-selectin is obligatory for formyl peptide-stimulated neutrophil aggregation in vitro (Simon et al, Blood 82:1097, 1993), we have examined the consequences of bacterial endotoxin on the expression of neutrophil adhesive molecules. We observed that the exposure of neutrophils to LPS/LBP, while enhancing the surface numbers and adhesive function of CD11b/CD18 for latex particles, did not induce aggregation. In contrast, as the LPS/LBP concentration increased (ED50 = 30 ng/mL LPS/LBP), the ability of neutrophils to aggregate decreased in parallel with the shedding of L-selectin. Moreover, when L-selectin adhesive activity was blocked by treatment with Fab fragments of Dreg- 200, aggregation was inhibited to an extent roughly proportional to the available L-selection. Blocking of LPS/LBP with CD14-specific monoclonal antibodies suppressed L-selectin shedding and preserved formyl peptide-stimulated aggregation. Taken together, the data suggest that inhibition of neutrophil aggregation by LPS/LBP is related to the expression of L-selectin via CD14 rather than LPS inhibition of CD11b/CD18 function during cellular stimulation.
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Lynam, EB, SI Simon, YP Rochon, and LA Sklar. "Lipopolysaccharide enhances CD11b/CD18 function but inhibits neutrophil aggregation." Blood 83, no. 11 (June 1, 1994): 3303–11. http://dx.doi.org/10.1182/blood.v83.11.3303.bloodjournal83113303.
Full textAbstract:
Human neutrophils are primed in the presence of complexes of lipopolysaccharide (LPS) with its serum binding protein (LBP) in a manner dependent on CD14. Cellular consequences of priming include increased responsiveness, the upregulation of surface proteins including the adhesive integrin CD11b/CD18 (Mac-1), the increased binding of certain ligands to CD11b/CD18, and the concurrent shedding of the L-selectin homing receptor. Because expression of both CD11b/CD18 and L-selectin is obligatory for formyl peptide-stimulated neutrophil aggregation in vitro (Simon et al, Blood 82:1097, 1993), we have examined the consequences of bacterial endotoxin on the expression of neutrophil adhesive molecules. We observed that the exposure of neutrophils to LPS/LBP, while enhancing the surface numbers and adhesive function of CD11b/CD18 for latex particles, did not induce aggregation. In contrast, as the LPS/LBP concentration increased (ED50 = 30 ng/mL LPS/LBP), the ability of neutrophils to aggregate decreased in parallel with the shedding of L-selectin. Moreover, when L-selectin adhesive activity was blocked by treatment with Fab fragments of Dreg- 200, aggregation was inhibited to an extent roughly proportional to the available L-selection. Blocking of LPS/LBP with CD14-specific monoclonal antibodies suppressed L-selectin shedding and preserved formyl peptide-stimulated aggregation. Taken together, the data suggest that inhibition of neutrophil aggregation by LPS/LBP is related to the expression of L-selectin via CD14 rather than LPS inhibition of CD11b/CD18 function during cellular stimulation.
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Yoshida, N., D. N. Granger, D. C. Anderson, R. Rothlein, C. Lane, and P. R. Kvietys. "Anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 6 (June 1, 1992): H1891—H1898. http://dx.doi.org/10.1152/ajpheart.1992.262.6.h1891.
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Previous studies have shown enhanced neutrophil adhesion to endothelial cells exposed to anoxia and then reoxygenated (A/R). To define the molecular basis for these observations, we evaluated the relative roles of CD11/CD18 determinants (CD11a and CD11b) of neurtrophils and the endothelial adhesion proteins intercellular adhesion molecule 1 (ICAM-1) and endothelial-leukocyte adhesion molecule 1 (ELAM-1). Human umbilical vein endothelial cell (HUVEC) monolayers were exposed to anoxia for 30 min, reoxygenated, and then reacted with 51Cr-labeled neutrophils in adhesion assays. Neutrophil adhesion to HUVEC exposed to A/R was significantly increased (2.7-fold) as compared with that observed with normoxic (control) HUVEC. This A/R-induced hyperadherence was significantly diminished by monoclonal antibodies (MAb) directed at CD11a, CD11b, CD18 or ICAM-1, but not by MAb directed at ELAM-1. The inhibitory effects of anti-CD11a and anti-CD11b were additive and equivalent to that of anti-CD18 MAb. A/R did not elicit increased levels of ICAM-1 or ELAM-1 mRNA or surface protein. However, immunofluorescence flow cytometry indicated that incubation of neutrophils in supernatants of A/R-conditioned HUVEC elicited an increase of surface CD11b and CD18, but not CD11a. Supernatants from A/R-conditioned HUVEC promoted neutrophil adherence to naive HUVEC, and this hyperadhesivity was diminished by a platelet-activating factor (PAF) receptor antagonist and catalase but not by a 5-lipoxygenase inhibitor, a leukotriene B4 receptor antagonist, or superoxide dismutase. These studies indicate that A/R promotes neutrophil adherence via CD11a/CD18- and CD11b/CD18-dependent interactions with ICAM-1 that appear to be mediated by hydrogen peroxide and PAF.
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Varga, Georg, Sandra Balkow, Martin K. Wild, Andrea Stadtbaeumer, Mathias Krummen, Tobias Rothoeft, Tetsuya Higuchi, et al. "Active MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation." Blood 109, no. 2 (September 26, 2006): 661–69. http://dx.doi.org/10.1182/blood-2005-12-023044.
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Abstract The β2 integrins are important for transendothelial migration of leukocytes as well as for T-cell activation during antigen presentation. Despite abundant expression of β2 integrins on antigen-presenting cells (APCs), their functional relevance for antigen presentation is completely unclear. We show here that dendritic cells (DCs) from CD18-deficient mice, which lack all functional β2 integrins, have no defect in antigen presentation. Moreover, DCs from normal mice express inactive β2 integrins that do not become activated on contact with T cells, at least in vitro. Pharmacologic activation of β2 integrins on DCs results in a significant reduction of their T cell–activating capacity. This effect is mediated by Mac-1 (CD11b/CD18) on DCs because it could be reversed via blocking antibodies against CD18 and CD11b. Furthermore, the antigen-presenting capacity of macrophages, which express constitutively active β2 integrins, is significantly enhanced on Mac-1 blockade. We therefore conclude that active CD11b/CD18 (Mac-1) on APCs directly inhibits T-cell activation.
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Skoglund, Göran, Ian Cotgreave, Jorge Rincon, Manuel Patarroyo, and Magnus Ingelman-Sundberg. "H2O2 activates CD11b/CD18-dependent cell adhesion." Biochemical and Biophysical Research Communications 157, no. 2 (December 1988): 443–49. http://dx.doi.org/10.1016/s0006-291x(88)80269-9.
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El-Azami-El-Idrissi, Mohammed, Cécile Bauche, Jirina Loucka, Radim Osicka, Peter Sebo, Daniel Ladant, and Claude Leclerc. "Interaction ofBordetella pertussisAdenylate Cyclase with CD11b/CD18." Journal of Biological Chemistry 278, no. 40 (July 28, 2003): 38514–21. http://dx.doi.org/10.1074/jbc.m304387200.
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Park, Jun Y., M. Amin Arnaout, and Vineet Gupta. "A Simple, No-Wash Cell Adhesion–Based High-Throughput Assay for the Discovery of Small-Molecule Regulators of the Integrin CD11b/CD18." Journal of Biomolecular Screening 12, no. 3 (January 26, 2007): 406–17. http://dx.doi.org/10.1177/1087057106299162.
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The leukocyte-specific integrin CD11b/CD18 plays a key role in the biological function of these cells and represents a validated therapeutic target for inflammatory diseases. Currently, the low affinity interaction between CD11b/CD18 integrin and its respective ligand poses a challenge in the development of cell-based adhesion assays for the high-throughput screening (HTS) environment. Here the authors describe a simple cell-based adhesion assay that can be readily used for HTS for the discovery of functional regulators of CD11b/CD18. The assay consistently produces acceptable Z' values (> 0.5) for HTS. After testing the assay using 2 established blocking antibodies as reference biologicals, the authors performed a proof-of-concept primary screen using a library of 6612 compounds and identified both agonist and antagonist hits. ( Journal of Biomolecular Screening 2007:406-417)
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Barden, A., D. Graham, L. J. Beilin, J. Ritchie, R. Baker, B. N. Walters, and C. A. Michael. "Neutrophil CD11B Expression and Neutrophil Activation in Pre-Eclampsia." Clinical Science 92, no. 1 (January 1, 1997): 37–44. http://dx.doi.org/10.1042/cs0920037.
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1. Neutrophil activation was examined in 22 women with pre-eclampsia and 22 age- and gestation-matched control subjects using whole-blood flow cytometry to assess basal and platelet-activating factor stimulated CD11b and CD18. 2. Basal neutrophil CD11b expression was significantly increased in women with pre-eclampsia compared with normal pregnancy before delivery. A similar non-significant trend for CD18 was also observed. 3. Before delivery, neutrophil CD11b expression increased in a dose-dependent fashion after platelet-activating factor stimulation, with the differences between the groups maintained. A similar dose-dependent increase in CD18 expression was observed after platelet-activating factor. 4. There were no between-group differences in expression of either CD11b or CD18 at either 6 weeks or 6 months post partum, either before or after platelet-activating factor stimulation. 5. Neutrophil CD11b was positively correlated with plasma uric acid (r = 0.44, P = 0.04) in women with pre-eclampsia, suggesting that the extent of neutrophil activation correlates with disease severity. 6. An increase in basal neutrophil CD11b expression in women with pre-eclampsia is likely to be an index of neutrophil activation in vivo. Neutrophil release of free radicals and proteases may then help perpetuate a vicious cycle of endothelial and vascular dysfunction in the placental and systemic circulations. The cause of this activation is not known but could involve platelet activation, increased production of endothelin-1 or release of cytokines. Further studies will be required to elucidate the consequences of neutrophil activation in pre-eclampsia.
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Börgeson, Emma, Johanna Lönn, Ida Bergström, Veronika Patcha Brodin, Sofia Ramström, Fariba Nayeri, Eva Särndahl, and Torbjörn Bengtsson. "Lipoxin A4InhibitsPorphyromonas gingivalis-Induced Aggregation and Reactive Oxygen Species Production by Modulating Neutrophil-Platelet Interaction and CD11b Expression." Infection and Immunity 79, no. 4 (January 24, 2011): 1489–97. http://dx.doi.org/10.1128/iai.00777-10.
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ABSTRACTPorphyromonas gingivalisis an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A4(LXA4) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA4on theP. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathioneS-transferase pulldown assay. The study shows thatP. gingivalisactivates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA4. Furthermore, we found that LXA4significantly inhibitsP. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA4was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA4antagonizesP. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.
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Hartman, KR, and DG Wright. "Identification of autoantibodies specific for the neutrophil adhesion glycoproteins CD11b/CD18 in patients with autoimmune neutropenia." Blood 78, no. 4 (August 15, 1991): 1096–104. http://dx.doi.org/10.1182/blood.v78.4.1096.1096.
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Abstract Anti-neutrophil antibodies have been described in a variety of clinical conditions associated with neutropenia. However, relatively little is known about the antigenic specificities of naturally occurring anti- neutrophil autoantibodies. We investigated the possibility that anti- neutrophil antibodies specific for the neutrophil adhesion glycoprotein (GP) complex CD11b/CD18 might be present in the sera of some patients with autoimmune neutropenia. These membrane GPs have been shown to be highly immunogenic in the production of murine monoclonal antibodies against neutrophil antigens. Moreover, autoantibodies to the platelet membrane GP complex IIb/IIIa, another member of the integrin family of cell adhesion proteins, have been demonstrated in immune thrombocytopenic purpura. Sera from 50 patients known to have anti- neutrophil IgG antibodies were evaluated using an immunobead “antigen capture” assay, modeled after a method used to identify anti-platelet GPIIb/IIIa autoantibodies. This assay detected anti-CD11b/CD18 autoantibodies in seven of the 50 sera. Each of these seven sera demonstrated decreased IgG binding to the neutrophils of a patient with congenital deficiency of CD11b/CD18. The patient with the highest levels of anti-CD11b/CD18 suffered recurrent skin infections and cellulitis, and died of respiratory failure during one of multiple episodes of pneumonia. Purified IgGs from five of these patients demonstrated effects on adhesion and/or opsonin receptor-mediated functions when tested with intact neutrophils in vitro. Our findings indicate that some patients with autoimmune neutropenia have autoantibodies specific for the functionally important neutrophil adhesion proteins CD11b/CD18. Our findings also raise the possibility that these autoantibodies may, in some cases, interfere with neutrophil function, thereby amplifying the risk of infection associated with neutropenia.
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Hartman, KR, and DG Wright. "Identification of autoantibodies specific for the neutrophil adhesion glycoproteins CD11b/CD18 in patients with autoimmune neutropenia." Blood 78, no. 4 (August 15, 1991): 1096–104. http://dx.doi.org/10.1182/blood.v78.4.1096.bloodjournal7841096.
Full textAbstract:
Anti-neutrophil antibodies have been described in a variety of clinical conditions associated with neutropenia. However, relatively little is known about the antigenic specificities of naturally occurring anti- neutrophil autoantibodies. We investigated the possibility that anti- neutrophil antibodies specific for the neutrophil adhesion glycoprotein (GP) complex CD11b/CD18 might be present in the sera of some patients with autoimmune neutropenia. These membrane GPs have been shown to be highly immunogenic in the production of murine monoclonal antibodies against neutrophil antigens. Moreover, autoantibodies to the platelet membrane GP complex IIb/IIIa, another member of the integrin family of cell adhesion proteins, have been demonstrated in immune thrombocytopenic purpura. Sera from 50 patients known to have anti- neutrophil IgG antibodies were evaluated using an immunobead “antigen capture” assay, modeled after a method used to identify anti-platelet GPIIb/IIIa autoantibodies. This assay detected anti-CD11b/CD18 autoantibodies in seven of the 50 sera. Each of these seven sera demonstrated decreased IgG binding to the neutrophils of a patient with congenital deficiency of CD11b/CD18. The patient with the highest levels of anti-CD11b/CD18 suffered recurrent skin infections and cellulitis, and died of respiratory failure during one of multiple episodes of pneumonia. Purified IgGs from five of these patients demonstrated effects on adhesion and/or opsonin receptor-mediated functions when tested with intact neutrophils in vitro. Our findings indicate that some patients with autoimmune neutropenia have autoantibodies specific for the functionally important neutrophil adhesion proteins CD11b/CD18. Our findings also raise the possibility that these autoantibodies may, in some cases, interfere with neutrophil function, thereby amplifying the risk of infection associated with neutropenia.
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Borjesson, Dori L., Scott I. Simon, Emir Hodzic, Hilde E. V. DeCock, Christie M. Ballantyne, and Stephen W. Barthold. "Roles of neutrophil β2 integrins in kinetics of bacteremia, extravasation, and tick acquisition of Anaplasma phagocytophila in mice." Blood 101, no. 8 (April 15, 2003): 3257–64. http://dx.doi.org/10.1182/blood-2002-04-1019.
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AbstractTick saliva contains anti-inflammatory and immunosuppressive substances that facilitate blood feeding and enhance tick-vectored pathogen transmission, including Anaplasma phagocytophila,an etiologic agent of granulocytic ehrlichiosis. As such, inflammation at a tick-feeding site is strikingly different than that typically observed at other sites of inflammation. Up-regulation of CD11b/CD18 occurs in host granulocytes following interaction or infection withA phagocytophila, and the absence of CD11b/CD18 results in early increases in bacteremia. We hypothesized that β2 integrin–dependent infection kinetics and leukocyte extravasation are important determinants of neutrophil trafficking to, and pathogen acquisition at, tick-feeding sites.A phagocytophila infection kinetics were evaluated in CD11a/CD18, CD11b/CD18, and CD18 knock-out mice using quantitative polymerase chain reaction (PCR) of blood, ticks, and skin biopsies in conjunction with histopathology. A marked increase in the rate ofA phagocytophila infection of neutrophils and pathogen burden in blood followed tick feeding. Infection kinetics were modified by β2 integrin expression and systemic neutrophil counts. Significant neutrophil-pathogen trafficking was observed to both suture and tick sites. Despite the prominent role for β2 integrins in neutrophil arrest in flowing blood, successful pathogen acquisition by ticks occurred in the absence of β2 integrins. Establishment of feeding pools that rely less on leukocyte trafficking and more on small hemorrhages may explain the ready amplification of A phagocytophila DNA from ticks infested on CD11/CD18-deficient mouse strains.
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Wang, Shan-Ze, Peter K. Smith, Melanie Lovejoy, Jeffrey J. Bowden, John H. Alpers, and Kevin D. Forsyth. "Shedding of L-selectin and PECAM-1 and upregulation of Mac-1 and ICAM-1 on neutrophils in RSV bronchiolitis." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 5 (November 1, 1998): L983—L989. http://dx.doi.org/10.1152/ajplung.1998.275.5.l983.
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Bronchiolitis is characterized histologically by epithelial necrosis and peribronchial infiltration of leukocytes, with a high percentage of neutrophils in the airways. We investigated the expression of adhesion molecules (CD11a, CD11b, CD18, CD31, CD54, and CD62L) on neutrophils from nasopharyngeal aspirates (NPAs) and peripheral blood (PB) of infants with respiratory syncytial virus (RSV)-induced bronchiolitis. The expression of CD31 and CD62L on neutrophils from NPAs is decreased and the expression of CD11b, CD18, and CD54 on neutrophils from NPAs is increased compared with cells from PB of RSV-infected infants. The expression of CD18 and CD54 on neutrophils from PB of RSV-infected infants is also increased compared with cells from PB of control infants. Shedding of CD31 and CD62L on neutrophils in RSV infection may contribute to the neutrophil emigration from blood to airways; the upregulation of Mac-1 (CD11b/CD18) and CD54 on neutrophils may help explain the high percentage of neutrophils in the airways of RSV bronchiolitis; and the upregulation of Mac-1 may be involved in the increased neutrophil-airway epithelial adhesion in RSV infection.
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Altieri, D. C., S. J. Stamnes, and C. G. Gahmberg. "Regulated Ca2+ signalling through leukocyte CD11b/CD18 integrin." Biochemical Journal 288, no. 2 (December 1, 1992): 465–73. http://dx.doi.org/10.1042/bj2880465.
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General mechanisms of adhesion in the immune response are coordinated by the leukocyte integrins CD11/CD18. The possible participation of these differentiation molecules in early events of transmembrane signalling was investigated. Monoclonal antibody (mAb) cross-linking of CD18, the integrin beta subunit ubiquitously expressed by all leukocytes, increased the cytosolic free Ca2+ concentration ([Ca2+]i) by 2-3-fold in monocyte THP-1 cells. Digitalized imaging in single adherent cells showed that this Ca2+ response is temporally biphasic, involves both release of Ca2+ from the intracellular stores as well as Ca2+ influx from the external compartment, and is dramatically down-modulated by terminal differentiation of THP-1 cells to a mature monocyte phenotype. Similarly, only a minor subset of 20-30% of peripheral blood monocytes heterogeneously maintain the CD18-mediated Ca(2+)-signalling properties. Cross-linking of CD18 also increased cytosolic free [Ca2+]i in a subset of approx. 15-20% of resting T lymphocytes, in a Ca2+ response that was completely abrogated during T-cell mitogenic activation with lectins or alloreactive antigen. While cross-linking of CD11a or CD11c was without effect, occupancy of CD11b increased cytosolic free [Ca2+]i in monocytic cells. This response was functionally coupled with a transient activation state of CD11b/CD18, which was reflected in its increased avidity to bind the complementary ligand fibrinogen. These results suggest that occupancy of CD18 transduces a stimulatory Ca2+ signal that is critically regulated by the state of cell activation/differentiation and by the association with the unique alpha-subunit CD11b. These intrinsic signalling properties may directly participate in regulating the oligospecific ligand recognition of leukocyte integrins.
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Anderson, S. I., N. A. Hotchin, and G. B. Nash. "Role of the cytoskeleton in rapid activation of CD11b/CD18 function and its subsequent downregulation in neutrophils." Journal of Cell Science 113, no. 15 (August 1, 2000): 2737–45. http://dx.doi.org/10.1242/jcs.113.15.2737.
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When rolling adherent neutrophils are stimulated, they rapidly immobilize through activation of integrin CD11b/CD18, and then modulate attachment through this integrin to allow migration. We investigated links between cytoskeletal rearrangement and changes in function of integrin CD11b/CD18 in neutrophils stimulated with formyl peptide (fMLP). Neutrophils treated with the actin-polymerizing agent jasplakinolide became rolling adherent on monolayers of activated platelets, but could not use CD11b/CD18 to become immobilised when fMLP was perfused over them. If treated with jasplakinolide after fMLP, the cells stopped migrating but could not detach when fMLP was removed. Jasplakinolide did not inhibit changes in intracellular Ca(2+) seen after fMLP treatment, or inhibit neutrophil immobilisation induced by externally added Mn(2+). Thus cytoskeletal rearrangement was directly implicated in upregulation and, later, downregulation of CD11b/CD18 binding. Inhibition of RhoA with C3-transferase caused a dose-dependent reduction of initial rolling adhesion of neutrophils, and reduced the rate of migration after stimulation; however, neither the conversion of rolling to stationary adhesion, nor the ability of neutrophils to detach on removal of the stimulus, were inhibited. Thus, Rho may regulate actin polymerisation and motility in neutrophils, but did not appear to control integrin-mediated adhesion itself. Integrin binding may be promoted by disruption of links to the cytoskeleton, effected through depolymerisation of actin or cleavage of linking protein talin by calpain. Disruption of actin filaments with cytochalasin D did not, however, cause integrin-mediated immobilisation of rolling neutrophils. Although the calpain inhibitor calpeptin did inhibit the adhesion response to fMLP, this was only at doses where actin polymerisation was also ablated. We suggest that the cytoskeleton actively regulates binding conformation of CD11b/CD18 as well as its mobility in the membrane.
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Furie, MB, MC Tancinco, and CW Smith. "Monoclonal antibodies to leukocyte integrins CD11a/CD18 and CD11b/CD18 or intercellular adhesion molecule-1 inhibit chemoattractant-stimulated neutrophil transendothelial migration in vitro." Blood 78, no. 8 (October 15, 1991): 2089–97. http://dx.doi.org/10.1182/blood.v78.8.2089.2089.
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Abstract Intercellular adhesion molecule-1 (ICAM-1) is present on the endothelium and binds to one or more members of the CD11/CD18 family of leukocyte surface integrins. To assess the role of these molecules in mediating chemotaxis of neutrophils across the endothelium, an in vitro model consisting of monolayers of human umbilical vein endothelial cells (HUVEC) grown on amniotic connective tissue was used. Neutrophils placed on the apical sides of these cultures migrated across the endothelium in response to chemoattractants added basally. Monoclonal antibodies (MoAbs) to CD11a, CD11b, and CD18 on the neutrophils inhibited this migration by 52% +/- 11%, 29% +/- 19%, and 90% +/- 7%, respectively. An MoAb to ICAM-1 inhibited transendothelial chemotaxis of the leukocytes by 55% +/- 16%. Inhibition was mediated by binding of the MoAb to ICAM-1 on the HUVEC, rather than by any direct effect of the antibody on the neutrophils. When used in combination, MoAbs to CD11a and to CD11b inhibited migration in a nearly additive fashion. A similar additive effect was observed when MoAbs to CD11b and to ICAM-1 were used together. In contrast, MoAbs to CD11a and to ICAM-1 produced no more inhibition when used in combination than when added singly. These results show that ICAM-1, CD11a/CD18, and CD11b/CD18 all participate in controlling migration of neutrophils across endothelial monolayers in response to chemotactic agents.
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Furie, MB, MC Tancinco, and CW Smith. "Monoclonal antibodies to leukocyte integrins CD11a/CD18 and CD11b/CD18 or intercellular adhesion molecule-1 inhibit chemoattractant-stimulated neutrophil transendothelial migration in vitro." Blood 78, no. 8 (October 15, 1991): 2089–97. http://dx.doi.org/10.1182/blood.v78.8.2089.bloodjournal7882089.
Full textAbstract:
Intercellular adhesion molecule-1 (ICAM-1) is present on the endothelium and binds to one or more members of the CD11/CD18 family of leukocyte surface integrins. To assess the role of these molecules in mediating chemotaxis of neutrophils across the endothelium, an in vitro model consisting of monolayers of human umbilical vein endothelial cells (HUVEC) grown on amniotic connective tissue was used. Neutrophils placed on the apical sides of these cultures migrated across the endothelium in response to chemoattractants added basally. Monoclonal antibodies (MoAbs) to CD11a, CD11b, and CD18 on the neutrophils inhibited this migration by 52% +/- 11%, 29% +/- 19%, and 90% +/- 7%, respectively. An MoAb to ICAM-1 inhibited transendothelial chemotaxis of the leukocytes by 55% +/- 16%. Inhibition was mediated by binding of the MoAb to ICAM-1 on the HUVEC, rather than by any direct effect of the antibody on the neutrophils. When used in combination, MoAbs to CD11a and to CD11b inhibited migration in a nearly additive fashion. A similar additive effect was observed when MoAbs to CD11b and to ICAM-1 were used together. In contrast, MoAbs to CD11a and to ICAM-1 produced no more inhibition when used in combination than when added singly. These results show that ICAM-1, CD11a/CD18, and CD11b/CD18 all participate in controlling migration of neutrophils across endothelial monolayers in response to chemotactic agents.
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Guermonprez, Pierre, Nadia Khelef, Eric Blouin, Philippe Rieu, Paola Ricciardi-Castagnoli, Nicole Guiso, Daniel Ladant, and Claude Leclerc. "The Adenylate Cyclase Toxin of Bordetella pertussis Binds to Target Cells via the αMβ2 Integrin (Cd11b/Cd18)." Journal of Experimental Medicine 193, no. 9 (April 30, 2001): 1035–44. http://dx.doi.org/10.1084/jem.193.9.1035.
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The adenylate cyclase toxin (CyaA) of Bordetella pertussis is a major virulence factor required for the early phases of lung colonization. It can invade eukaryotic cells where, upon activation by endogenous calmodulin, it catalyzes the formation of unregulated cAMP levels. CyaA intoxication leads to evident toxic effects on macrophages and neutrophils. Here, we demonstrate that CyaA uses the αMβ2 integrin (CD11b/CD18) as a cell receptor. Indeed, the saturable binding of CyaA to the surface of various hematopoietic cell lines correlated with the presence of the αMβ2 integrin on these cells. Moreover, binding of CyaA to various murine cell lines and human neutrophils was specifically blocked by anti-CD11b monoclonal antibodies. The increase of intracellular cAMP level and cell death triggered by CyaA intoxication was also specifically blocked by anti-CD11b monoclonal antibodies. In addition, CyaA bound efficiently and triggered intracellular cAMP increase and cell death in Chinese hamster ovary cells transfected with αMβ2 (CD11b/CD18) but not in cells transfected with the vector alone or with the αXβ2 (CD11c/CD18) integrin. Thus, the cellular distribution of CD11b, mostly on neutrophils, macrophages, and dendritic and natural killer cells, supports a role for CyaA in disrupting the early, innate antibacterial immune response.
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Deshpande, M. S., T. C. Ambagala, A. P. N. Ambagala, M. E. Kehrli, and S. Srikumaran. "Bovine CD18 Is Necessary and Sufficient To Mediate Mannheimia (Pasteurella) haemolytica Leukotoxin-Induced Cytolysis." Infection and Immunity 70, no. 9 (September 2002): 5058–64. http://dx.doi.org/10.1128/iai.70.9.5058-5068.2002.
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ABSTRACT Leukotoxin (Lkt) secreted by Mannheimia (Pasteurella) haemolytica is an RTX toxin which is specific for ruminant leukocytes. Lkt binds to β2 integrins on the surface of bovine leukocytes. β2 integrins have a common β subunit, CD18, that associates with three distinct α chains, CD11a, CD11b, and CD11c, to give rise to three different β2 integrins, CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), and CD11c/CD18 (CR4), respectively. Our earlier studies revealed that Lkt binds to all three β2 integrins, suggesting that the common β subunit, CD18, may be the receptor for Lkt. In order to unequivocally elucidate the role of bovine CD18 as a receptor for Lkt, a murine cell line nonsusceptible to Lkt (P815) was transfected with cDNA for bovine CD18. One of the transfectants, 2B2, stably expressed bovine CD18 on the cell surface. The 2B2 transfectant was effectively lysed by Lkt in a concentration-dependent manner, whereas the P815 parent cells were not. Immunoprecipitation of cell surface proteins of 2B2 with monoclonal antibodies specific for bovine CD18 or murine CD11a suggested that bovine CD18 was expressed on the cell surface of 2B2 as a heterodimer with murine CD11a. Expression of bovine CD18 and the Lkt-induced cytotoxicity of 2B2 cells were compared with those of bovine polymorphonuclear neutrophils and lymphocytes. There was a strong correlation between cell surface expression of bovine CD18 and percent cytotoxicity induced by Lkt. These results indicate that bovine CD18 is necessary and sufficient to mediate Lkt-induced cytolysis of target cells.
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Zen, Ke, Brian A. Babbin, Yuan Liu, John B. Whelan, Asma Nusrat, and Charles A. Parkos. "JAM-C Is a Component of Desmosomes and a Ligand for CD11b/CD18-mediated Neutrophil Transepithelial Migration." Molecular Biology of the Cell 15, no. 8 (August 2004): 3926–37. http://dx.doi.org/10.1091/mbc.e04-04-0317.
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Neutrophil (PMN) transepithelial migration is dependent on the leukocyte β2integrin CD11b/CD18, yet the identity of epithelial counterreceptors remain elusive. Recently, a JAM protein family member termed JAM-C was implicated in leukocyte adhesive interactions; however, its expression in epithelia and role in PMN-epithelial interactions are unknown. Here, we demonstrate that JAM-C is abundantly expressed basolaterally in intestinal epithelia and localizes to desmosomes but not tight junctions. Desmosomal localization of JAM-C was further confirmed by experiments aimed at selective disruption of tight junctions and desmosomes. In assays of PMN transepithelial migration, both JAM-C mAbs and JAM-C/Fc chimeras significantly inhibited the rate of PMN transmigration. Additional experiments revealed specific binding of JAM-C to CD11b/CD18 and provided evidence of other epithelial ligands for CD11b/CD18. These findings represent the first demonstration of direct adhesive interactions between PMN and epithelial intercellular junctions (desmosomes) that regulate PMN transepithelial migration and also suggest that JAM-C may play a role in desmosomal structure/function.
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Buysmann, S., FJ Bemelman, PT Schellekens, Y. van Kooyk, CG Figdor, and IJ ten Berge. "Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3." Blood 87, no. 1 (January 1, 1996): 404–11. http://dx.doi.org/10.1182/blood.v87.1.404.404.
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Abstract We investigated the mechanism by which antihuman CD3 monoclonal antibodies of the isotypes IgG2a (eg, OKT3) and IgA (eg, IXA) can induce the rapid disappearance of virtually all circulating T lymphocytes. We hypothesize that upregulation of adhesion molecules on the lymphocyte membrane contributes to this effect. However, this hypothesis is difficult to test, because of the inherent lymphocytopenia and/or shifts in lymphocyte populations between intra and extra-vascular compartments. Therefore, studies in vitro were performed, as well. Analysis of peripheral blood lymphocytes isolated at several times after addition of OKT3 or IXA to whole blood of healthy individuals showed an immediate increase in the proportion of T cells expressing NKI-L16, an activation epitope on CD11a/CD18. Likewise, an increase in CD11b/CD18 expression occurred. In parallel experiments, a transiently increased adhesion of T cells to endothelial cell monolayers was observed. This adhesion could be completely blocked by anti-CD18 or anti-CD11a monoclonal antibodies and only partly by an anti-CD11b antibody. Our data indicate that upregulation of activation epitopes of CD11a/CD18, as well as increased expression of CD11b/CD18 on T lymphocytes, may result in increased adhesion of these cells to intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on vascular endothelium. This phenomenon may, at least, partly explain the rapidly occurring peripheral lymphocytopenia observed in vivo.
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Buysmann, S., FJ Bemelman, PT Schellekens, Y. van Kooyk, CG Figdor, and IJ ten Berge. "Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3." Blood 87, no. 1 (January 1, 1996): 404–11. http://dx.doi.org/10.1182/blood.v87.1.404.bloodjournal871404.
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We investigated the mechanism by which antihuman CD3 monoclonal antibodies of the isotypes IgG2a (eg, OKT3) and IgA (eg, IXA) can induce the rapid disappearance of virtually all circulating T lymphocytes. We hypothesize that upregulation of adhesion molecules on the lymphocyte membrane contributes to this effect. However, this hypothesis is difficult to test, because of the inherent lymphocytopenia and/or shifts in lymphocyte populations between intra and extra-vascular compartments. Therefore, studies in vitro were performed, as well. Analysis of peripheral blood lymphocytes isolated at several times after addition of OKT3 or IXA to whole blood of healthy individuals showed an immediate increase in the proportion of T cells expressing NKI-L16, an activation epitope on CD11a/CD18. Likewise, an increase in CD11b/CD18 expression occurred. In parallel experiments, a transiently increased adhesion of T cells to endothelial cell monolayers was observed. This adhesion could be completely blocked by anti-CD18 or anti-CD11a monoclonal antibodies and only partly by an anti-CD11b antibody. Our data indicate that upregulation of activation epitopes of CD11a/CD18, as well as increased expression of CD11b/CD18 on T lymphocytes, may result in increased adhesion of these cells to intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on vascular endothelium. This phenomenon may, at least, partly explain the rapidly occurring peripheral lymphocytopenia observed in vivo.
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Jiang, Y., J. F. Zhu, F. W. Luscinskas, and D. T. Graves. "MCP-1-stimulated monocyte attachment to laminin is mediated by beta 2-integrins." American Journal of Physiology-Cell Physiology 267, no. 4 (October 1, 1994): C1112—C1118. http://dx.doi.org/10.1152/ajpcell.1994.267.4.c1112.
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Migration of monocytes to sites of inflammation involves a series of attachments and detachments to extracellular matrix proteins. We examined the capacity of a chemokine, monocyte chemoattractant protein-1 (MCP-1), to regulate attachment of human monocytes to laminin, collagen I, collagen IV, or fibronectin. MCP-1 increased monocyte attachment to laminin in a dose- and time-dependent manner and stimulated a lesser increase to the other matrix proteins. Function-blocking monoclonal antibodies (MAbs) to the integrin beta 2-subunit (CD18), including Fab' fragments and alpha M (CD11b) blocked > 70% of attachment, whereas MAbs to the beta 1-integrin subunit reduced attachment by < 30%. This suggests that the CD11b/CD18 integrin is the predominant molecule involved in adhesion of MCP-1-stimulated monocytes to laminin. The association of CD11b with F-actin illustrated by confocal microscopy further supports this concept. In contrast, when monocytes were stimulated with the beta 1-stimulatory MAb TS2/16, monocyte adhesion to laminin occurred through beta 1-integrins. Thus MCP-1 can stimulate monocyte attachment to laminin, and this process is mediated through beta 2-integrins, principally CD11b/CD18.
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Sun, X. M., X. W. Qu, W. Huang, D. N. Granger, M. Bree, and W. Hsueh. "Role of leukocyte beta 2-integrin in PAF-induced shock and intestinal injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 1 (January 1, 1996): G184—G190. http://dx.doi.org/10.1152/ajpgi.1996.270.1.g184.
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Leukocyte adhesion and diapedesis, critical steps in the inflammatory process, depend on the expression of integrin CD11b/CD18. In this study, we examined the preventive effect of monoclonal antibodies (MAb) against CD11b (1B6), CD11a, or CD18 (CL26) on platelet-activating factor (PAF)-induced bowel injury. Young male Sprague-Dawley rats were anesthetized and injected with either of two doses of PAF (2.5 or 3 micrograms/kg iv) to induce transient hypotension and irreversible shock. Some rats wee also injected intravenously with 1B6 (anti-CD11b), anti-CD11a, CL26 (anti-CD18), or combined anti-CD11a and 1B6, 30 min before PAF. Animals receiving a low dose of PAF developed mild hypotension, hemoconcentration, increased intestinal myeloperoxidase, and bowel injury after 1 h. These effects were completely prevented by pretreatment with 1B6. A high dose of PAF induced irreversible shock and gross intestinal necrosis. Both CL26 and 1B6 were partially effective in attenuating PAF-induced bowel injury. Addition of anti-CD11a to 1B6 in the treatment further ameliorated the systemic adverse effects of PAF and intestinal injury. However, focal minor injury still developed. Anti-CD11a alone, fucoidin, or anti-P-selectin was ineffective. Rats depleted of neutrophils were also largely protected from the adverse effects of PAF at high doses, although minor intestinal injury often persisted. We conclude that leukocyte beta 2-integrins play an important role in PAF-induced hypotension, leukopenia, hemoconcentration, and intestinal necrosis, and that CD11b/CD18 is the main adhesion molecule involved in the pathogenesis of injury. However, CD11/CD18- and neutrophil-independent pathways exist for mediating PAF-induced bowel injury, although their role is probably a minor one.
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Hamad, Osama A., Ioannis Mitroulis, Karin Fromell, Huda Kozarcanin, Triantafyllos Chavakis, Daniel Ricklin, John D. Lambris, Kristina N. Ekdahl, and Bo Nilsson. "Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18." Thrombosis and Haemostasis 114, no. 12 (2015): 1207–17. http://dx.doi.org/10.1160/th15-02-0162.
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SummaryComplement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16+/CD42a+ PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75–100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.
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Molad, Y., K. A. Haines, D. C. Anderson, J. P. Buyon, and B. N. Cronstein. "Immunocomplexes stimulate different signalling events to chemoattractants in the neutrophil and regulate L-selectin and beta 2-integrin expression differently." Biochemical Journal 299, no. 3 (May 1, 1994): 881–87. http://dx.doi.org/10.1042/bj2990881.
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Neutrophils express receptors for numerous phlogistons which, when occupied, trigger distinct signal-transduction pathways. Previous studies have shown that stimulation of neutrophils with chemoattractants induces shedding of the adhesive molecule L-selectin and increased expression of the beta 2-integrin CD11b/CD18. We determined the effect of ligation of classic, G-protein-linked chemoattractant receptors [C5a, interleukin-8 (IL-8), formylmethionyl-leucylphenylalanine (FMLP) and substance P], receptors for the Fc portion of IgG (Fc gamma receptors) and receptors for transforming growth factor beta (TGF beta) on expression of adhesive molecules by neutrophils and the stimulus-transduction mechanisms thought to mediate these changes. We were surprised to observe that occupancy of Fc gamma receptors by immunocomplexes (BSA-anti-BSA) stimulated increased expression by neutrophils of CD11b/CD18 at concentrations which did not affect L-selectin expression (EC50 9 micrograms/ml versus 350 micrograms/ml respectively, P < 0.00001, n = 5). In contrast, similar to previous studies, recombinant C5a, recombinant IL-8 and FMLP all stimulated increased expression of CD11b/CD18 (170-260% of basal, P < 0.001, n = 5) and shedding of L-selectin (56-75% reduction from basal, P < 0.001, n = 5) at similar concentrations and with similar potencies (EC50 = 2, 5, and 3 nM respectively). In contrast, neither TGF beta 1 nor, surprisingly, substance P affected expression of CD11b/CD18 or L-selectin. The regulation of expression of CD11b/CD18 or L-selectin in response to FMLP or immunocomplexes was unaffected by cytochalasin B (5 micrograms/ml) or the tyrosine kinase inhibitor tyrphostin-25 (25 microM). Although occupancy of both chemoattractant (FMLP) and Fc gamma receptors stimulated increments in the second messenger diacylglycerol, disruption of actin microfilaments by cytochalasin B enhanced diacylglycerol generation in response to FMLP but not in response to ligation of Fc gamma receptors. Moreover, both FMLP and immune aggregates provoked fluxes of intracellular Ca2+ concentration which differed with respect to both magnitude and kinetics and did not correlate well with regulation of adhesive-molecule expression. As upregulation of CD11b/CD18 is tightly linked to exocytosis of specific granules, these results suggest that shedding of L-selectin by activated neutrophils is not linked to exocytosis. These studies provide further evidence that receptors for chemoattractants and immunocomplexes on the neutrophil are linked to multiple signalling pathways.
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Chello, Massimo, Pasquale Mastroroberto, Antonietta R. Marchese, Giovanni Maltese, Ermenegildo Santangelo, and Bruno Amantea. "Nitric Oxide Inhibits Neutrophil Adhesion during Experimental Extracorporeal Circulation." Anesthesiology 89, no. 2 (August 1, 1998): 443–48. http://dx.doi.org/10.1097/00000542-199808000-00021.
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Background Myocardial and pulmonary injuries often occur after cardiopulmonary bypass, mediated in part by neutrophil activation and adhesion to endothelial cells. The effects of nitric oxide (NO) administration on neutrophil adhesion to endothelial cells after simulated extracorporeal circulation were investigated. Methods Two identical extracorporeal circulation circuits were primed with fresh human blood and circulated for 2 h at 37 degrees C. Nitric oxide at a 40-ppm concentration was added to one of the oxygenators in each pair. Neutrophil CD11b/CD18 expression and their adhesion to human umbilical vein endothelial cell monolayers were assayed in leukocytes isolated from samples drawn from the circuit 30, 60, 90, and 120 min after circulation began. In another series of experiments, blocking monoclonal antibodies to both neutrophil CD11b and CD18 were incubated with polymorphonuclear leukocytes after removal from the circuit before the adhesion assay. Results After 60 min of circulation, the neutrophils from NO-treated circuits showed significantly reduced CD11b/CD18 surface expression compared with the control group. There was also a significant reduction in neutrophil-endothelial adhesion in the NO group after 120 min of circulation. Monoclonal antibodies to both CD11b and CD18 significantly inhibited the adhesion of polymorphonuclear leukocytes at endothelial cells after 120 min of circulation. Conclusions These results confirm that neutrophil activation occurs during cardiopulmonary bypass. The addition of NO to the circuits of extracorporeal circulation significantly affects neutrophil adhesion to endothelial cells.
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Rysz, Jacek, Eugeniusz Kocur, Robert Błaszczak, and Robert Stolarek. "Integrin CD11a/CD18, CD11b/CD18 and CD69 expression in patients after renal transplantation." Open Medicine 2, no. 2 (June 1, 2007): 154–58. http://dx.doi.org/10.2478/s11536-007-0015-5.
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AbstractChronic renal failure (CRF) is a complex clinical entity caused by progressive destruction of functional renal parenchyma in the course of various pathological processes resulting in complete failure of renal function and subsequent metabolic, acid base and electrolyte as well as immune disorders. Renal transplantation (RT) is one of the renal replacement therapy options in the terminal stage of chronic renal failure. The replacement of the failing organ with one from a healthy donor may be complicated with immune host response. This study was designed to investigate the changes in serum concentration of integrins CD11a/CD18, CD11b/CD18, CD69 on the surface of human polymorphonuclear leukocytes (PMNL) after the RT within two six-month periods. The study included 25 RT patients (mean 5.4±2.7 yrs after the transplantation, 10 females and 15 males) treated with immune suppressive therapy including cyclosporine A, azathioprine and prednisolone. The expression was assessed with monoclonal antibodies by means of flow cytometry. Also, the expression of CD69 was determined before and after phytohemaglutinine (PHA) stimulation. There was no significant alternation in serum concentration of CD11a/CD18, CD11b/CD18 and CD69 at baseline, six months and twelve months later. The expression of integrins was not altered in renal transplantation patients in the current study setting.
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Forsyth, Christopher B., and Herbert L. Mathews. "Lymphocytes Utilize CD11b/CD18 for Adhesion toCandida albicans." Cellular Immunology 170, no. 1 (May 1996): 91–100. http://dx.doi.org/10.1006/cimm.1996.0138.
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Blouin, Eric, Lise Halbwachs-Mecarelli, and Philippe Rieu. "Redox regulation of β2-integrin CD11b / CD18 activation." European Journal of Immunology 29, no. 11 (November 1999): 3419–31. http://dx.doi.org/10.1002/(sici)1521-4141(199911)29:11<3419::aid-immu3419>3.0.co;2-1.
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Barnett, Carlton C., Ernest E. Moore, Gary W. Mierau, David A. Partrick, Walter L. Biffl, David J. Elzi, and Christopher C. Silliman. "ICAM-1-CD18 interaction mediates neutrophil cytotoxicity through protease release." American Journal of Physiology-Cell Physiology 274, no. 6 (June 1, 1998): C1634—C1644. http://dx.doi.org/10.1152/ajpcell.1998.274.6.c1634.
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Interaction of the β2-integrin complex on the polymorphonuclear neutrophil (PMN) with intercellular adhesion molecule-1 (ICAM-1) has been implicated in PMN-mediated cytotoxicity. This study examined interaction of the CD11a, CD11b, and CD18 subunits of the β2-integrin with ICAM-1, transfected into Chinese hamster ovarian (CHO) cells to avoid effects of other adhesion molecules. Incubation of quiescent PMNs with wild-type and ICAM-1-transfected CHO cells produced nominal cell lysis. Similarly, when phorbol myristate acetate (PMA)-activated PMNs were incubated with wild-type CHO cells, minimal cytotoxicity was produced. However, when ICAM-1-transfected CHO cells were incubated with PMA-activated PMNs, 40% cell lysis occurred. Blockade with a monoclonal antibody (MAb) to ICAM-1 or MAbs to CD11a, CD11b, or CD18 reduced PMN-mediated cytotoxicity to baseline. To examine the role of adhesion in cytotoxicity, we studied β2-integrin-mediated PMN adhesion to ICAM-1-transfected CHO cells and found that MAbs for CD11a, CD11b, and CD18 all abrogated PMN cytotoxicity despite disparate effects on adhesion. To assess the role of CD18, β2-integrin subunits were cross-linked, and CD18 alone mediated protease release. Moreover, ICAM-1 was immunoprecipitated from transfected CHO cells and incubated with PMNs. This soluble ICAM-1 provoked elastase release, similar to PMA, which could be inhibited by MAbs to CD18 but not MAbs to other β2-integrin subunits. In addition, coincubation with protease inhibitors eglin C and AAPVCK reduced PMN-mediated cytotoxicity to control levels. Finally, ICAM-1-transfected CHO cells were exposed to activated PMNs from a patient with chronic granulomatous disease that caused significant cell lysis, equivalent to that of PMNs from normal donors. Collectively, these data suggest that ICAM-1 provokes PMN-mediated cytotoxicity via CD18-mediated protease release.