The Experts below are selected from a list of 76326 Experts worldwide ranked by ideXlab platform
Eugene C Butcher - One of the best experts on this subject based on the ideXlab platform.
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Comparison of L-Selectin and E-Selectin ligand specificities: The L-Selectin can bind the E-Selectin ligands Sialyl Lex and Sialyl Lea
Biochemical and biophysical research communications, 1992Co-Authors: Ellen L Berg, John L Magnani, R. Aaron Warnock, Robinson Martyn Kim, Eugene C ButcherAbstract:The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le(x) (Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc beta-R), or Sialyl Le(a) (Neu5Ac-alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
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comparison of l Selectin and e Selectin ligand specificities the l Selectin can bind the e Selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
Paul S Frenette - One of the best experts on this subject based on the ideXlab platform.
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a novel Selectin antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting Selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic Selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial Selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-Selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-Selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-Selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.
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A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting Selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic Selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial Selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-Selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p
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complete identification of e Selectin ligands on neutrophils reveals distinct functions of psgl 1 esl 1 and cd44
Immunity, 2007Co-Authors: Andres Hidalgo, Anna Peired, Martin K Wild, Dietmar Vestweber, Paul S FrenetteAbstract:The Selectins and their ligands are required for leukocyte extravasation during inflammation. Several glycoproteins have been suggested to bind to E-Selectin in vitro, but the complete identification of its physiological ligands has remained elusive. Here, we showed that E-Selectin ligand-1 (ESL-1), P-Selectin glycoprotein ligand-1 (PSGL-1), and CD44 encompassed all endothelial-Selectin ligand activity on neutrophils by using gene- and RNA-targeted loss of function. PSGL-1 played a major role in the initial leukocyte capture, whereas ESL-1 was critical for converting initial tethers into steady slow rolling. CD44 controlled rolling velocity and mediated E-Selectin-dependent redistribution of PSGL-1 and L-Selectin to a major pole on slowly rolling leukocytes through p38 signaling. These results suggest distinct and dynamic contributions of these three glycoproteins in Selectin-mediated neutrophil adhesion and signaling.
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Multiple, targeted deficiencies in Selectins reveal a predominant role for P-Selectin in leukocyte recruitment.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Stephen D. Robinson, Denisa D. Wagner, Paul S Frenette, Helen Rayburn, Marge Cummiskey, Mollie Ullman-culleré, Richard O HynesAbstract:We extend our previous analyses of mice deficient in Selectins by describing the generation and comparative phenotype of mice lacking one, two, or three Selectins after sequential ablation of the murine genes encoding P-, E-, and L-Selectins. All mice deficient in Selectins are viable and fertile as homozygotes. However, mice missing both P- and E-Selectins (PE−/−), and mice missing all three Selectins (ELP−/−) develop mucocutaneous infections that eventually lead to death. Mice deficient in multiple Selectins display varying degrees of leukocytosis, resulting in part from alterations in leukocyte rolling and recruitment. PE−/− mice, ELP−/− mice, and mice missing both P- and L-Selectins (PL−/−) show drastic reductions in leukocyte rolling and in extravasation of neutrophils in thioglycollate-induced peritonitis. In a separate inflammatory model (ragweed-induced peritoneal eosinophilia), we demonstrate P-Selectin to be both necessary and sufficient for the recruitment of eosinophils. The phenotype of mice missing both E- and L-Selectins (EL−/−) is less severe than those seen in the other double knockouts. Comparisons among the double knockouts suggest that P-Selectin normally cooperates with both E- and L-Selectins. Our results indicate a preeminent role for P-Selectin in regulating leukocyte behavior in mice. Data from the ELP−/− mice indicate, however, that all three Selectins are important to leukocyte homeostasis and efficient neutrophil recruitment.
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hematopoietic progenitor cell rolling in bone marrow microvessels parallel contributions by endothelial Selectins and vascular cell adhesion molecule 1
Journal of Experimental Medicine, 1998Co-Authors: Irina Mazo, Denisa D. Wagner, Paul S Frenette, Richard O Hynes, Jose C Gutierrezramos, Ulrich H Von AndrianAbstract:We have used intravital microscopy to study physiologically perfused microvessels in murine bone marrow (BM). BM sinusoids and venules, but not adjacent bone vessels, supported rolling interactions of hematopoietic progenitor cells. Rolling did not involve L-Selectin, but was partially reduced in wild-type mice treated with antibodies to P- or E-Selectin and in mice that were deficient in these two Selectins. Selectin-independent rolling was mediated by α4 integrins, which interacted with endothelial vascular cell adhesion molecule (VCAM)-1. Parallel contribution of the endothelial Selectins and VCAM-1 is not known to direct blood cell trafficking to other noninflamed tissues. This combination of constitutively expressed adhesion molecules may thus constitute a BM-specific recruitment pathway for progenitor cells analogous to the vascular addressins that direct selective lymphocyte homing to lymphoid organs.
Ellen L Berg - One of the best experts on this subject based on the ideXlab platform.
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Comparison of L-Selectin and E-Selectin ligand specificities: The L-Selectin can bind the E-Selectin ligands Sialyl Lex and Sialyl Lea
Biochemical and biophysical research communications, 1992Co-Authors: Ellen L Berg, John L Magnani, R. Aaron Warnock, Robinson Martyn Kim, Eugene C ButcherAbstract:The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le(x) (Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc beta-R), or Sialyl Le(a) (Neu5Ac-alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
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comparison of l Selectin and e Selectin ligand specificities the l Selectin can bind the e Selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
John L Magnani - One of the best experts on this subject based on the ideXlab platform.
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A Novel Selectin Antagonist, GMI-1070, Prevents Vaso-Occlusion in Sickle Cell Mice by Inhibiting Leukocyte Adhesion and Activation.
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting Selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic Selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial Selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-Selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p
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a novel Selectin antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
Blood, 2007Co-Authors: Jungshan Chang, Arun K Sarkar, John L Magnani, John T. Patton, Paul S FrenetteAbstract:Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting Selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic Selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial Selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-Selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-Selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-Selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.
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Comparison of L-Selectin and E-Selectin ligand specificities: The L-Selectin can bind the E-Selectin ligands Sialyl Lex and Sialyl Lea
Biochemical and biophysical research communications, 1992Co-Authors: Ellen L Berg, John L Magnani, R. Aaron Warnock, Robinson Martyn Kim, Eugene C ButcherAbstract:The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le(x) (Neu5Ac alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc beta-R), or Sialyl Le(a) (Neu5Ac-alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
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comparison of l Selectin and e Selectin ligand specificities the l Selectin can bind the e Selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
Martyn Kim Robinson - One of the best experts on this subject based on the ideXlab platform.
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comparison of l Selectin and e Selectin ligand specificities the l Selectin can bind the e Selectin ligands sialyl lex and sialyl lea
Biochemical and Biophysical Research Communications, 1992Co-Authors: Aaron R Warnock, Martyn Kim Robinson, John L Magnani, Ellen L Berg, Eugene C ButcherAbstract:Abstract The L- and E-Selectins are leukocyte and endothelial cell surface molecules which mediate leukocyte-endothelial cell adhesion by interacting with carbohydrate ligands. In the present study we find that L-Selectin, like E-Selectin, can interact with synthetic neoglycoproteins containing Sialyl Le x (Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAcβ-R), or Sialyl Le a (Neu5Ac-α2-3Galβ1-3[Fucα1-4]GlcNAcβ-R). Additionally, both the E-Selectin and L-Selectin can bind the peripheral lymph node addressin, a high endothelial venule ligand for L-Selectin. Despite overlapping interactions, the L- and E-Selectins discriminate between their native ligands. The peripheral lymph node addressin is a preferential ligand for L-Selectin; and furthermore, L-Selectin expressing cells do not interact detectably with the cutaneous lymphocyte antigen, a native glycoprotein ligand for E-Selectin found on a subset of lymphocytes associated with the skin.
