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At least 37 records · Page 2Linked to original sources
PubMed1997

A distinct profile of six soluble adhesion molecules (ICAM-1, ICAM-3, VCAM-1, E-selectin, L-selectin and P-selectin) in rheumatoid arthritis.

Soluble forms of ICAM-1, VCAM-1, E-selectin, L-selectin, P-selectin and, more recently, ICAM-3 are known to exist in human serum and have elevated levels in numerous diseases. Previous studies have demonstrated that in rheumatoid arthritis (RA) the levels of circulating sICAM-1 and sE-selectin are elevated relative to healthy controls. We have compared the serum profiles of these six soluble adhesion molecules in patients with RA (n = 22) to those seen in healthy controls (n = 10) using sandwich ELISA. In the patients, there were significant elevations of serum sICAM-1 (P < 0.0001), sICAM-3 (P = 0.0327), sVCAM-1 (P = 0.0025), sL-selectin (P = 0.0194) and sP-selectin (P = 0.0025), but not E-selectin (P = 0.0672). However, only sP-selectin was found to correlate with disease activity in the patients (r = 0.461, P < 0.05). Thus, there is a distinct profile of soluble adhesion molecules in RA of which only sP-selectin correlates with disease activity.

Adult↗
PubMed1999

Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration.

P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To determine its physiological role in cell adhesion as a mediator of leukocyte rolling and migration during inflammation, we prepared mice genetically deficient in PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1-deficient mouse was viable and fertile. The blood neutrophil count was modestly elevated. There was no evidence of spontaneous development of skin ulcerations or infections. Leukocyte infiltration in the chemical peritonitis model was significantly delayed. Leukocyte rolling in vivo, studied by intravital microscopy in postcapillary venules of the cremaster muscle, was markedly decreased 30 min after trauma in the PSGL-1-deficient mouse. In contrast, leukocyte rolling 2 h after tumor necrosis factor alpha stimulation was only modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1-deficient mouse almost completely eliminated leukocyte rolling. These results indicate that PSGL-1 is required for the early inflammatory responses but not for E-selectin-mediated responses. These kinetics are consistent with a model in which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a required counterreceptor for E-selectin under in vivo physiological conditions.

Animals↗
PubMed1994

Intratracheal administration of endotoxin and cytokines: VIII. LPS induces E-selectin expression; anti-E-selectin and soluble E-selectin inhibit acute inflammation.

E-selectin is an inducible endothelial adhesion molecule that binds neutrophils. E-selectin mRNA is not constitutively detectable in the lungs of rats. Intratracheal injection of LPS induces pulmonary E-selectin mRNA expression at 2-4 h. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of mouse F(ab')2 or F(ab') anti-E-selectin monoclonal antibody inhibits the emigration of neutrophils into the bronchoalveolar space at 6 h by 50-70%. TNF and IL-6 bioactivity are not decreased in bronchoalveolar lavage fluid after treatment with anti-E-selectin antibody as compared to controls, suggesting that the anti-E-selectin does not affect the magnitude of the LPS-initiated cytokine cascade. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of soluble E-selectin inhibits neutrophilic emigration at 6 h by 64%, suggesting that endogenous soluble E-selectin shed from activated endothelium may play a role in the endogenous down-regulation of acute inflammation. E-selectin-mediated adhesion of neutrophils to endothelium appears crucial to the full development of the acute inflammation response.

Acute Disease↗
PubMed1996

Soluble L-selectin in peripheral arterial disease: relationship with soluble E-selectin and soluble P-selectin.

Soluble L-selectin, E-selectin and P-selectin were measured in a small case control study of 42 patients with peripheral arterial disease and 42 age and sex matched controls. Levels of soluble L-selectin were 1204 +/- 221 ng/ml (mean +/- S.D.) in the patients compared to 1256 +/- 271 ng/ml in the controls (P = 0.37). There was also no difference in levels of soluble E-selectin (57 +/- 17 ng/ml versus 51 +/- 20 ng/ml, P = 0.15) but levels of soluble P-selectin were increased (249 +/- 101 ng/ml versus 198 +/- 98 ng/ml, P = 0.011). There were no significant correlations between any of the selectins and the risk factors for atherosclerosis or with any leucocyte index. The data point to different mechanisms of release of the soluble selectins in peripheral atherosclerosis and may have important implications for leukocyte/endothelial cell interactions.

Arteriosclerosis↗
PubMed1998

Important contributions of P-selectin glycoprotein ligand-1-mediated secondary capture to human monocyte adhesion to P-selectin, E-selectin, and TNF-alpha-activated endothelium under flow in vitro.

In this study, an in vitro flow model and a blocking mAb to P-selectin glycoprotein ligand-1 (PSGL-1) were used to define the role of PSGL-1 in monocyte attachment and rolling on E- and P-selectin and in attachment and accumulation on 6-h TNF-alpha-activated HUVEC. KPL1, an adhesion-blocking mAb directed against the tyrosine sulfate motif of PSGL-1, abolished monocyte-adhesive interactions with P-selectin, but only partially blocked monocyte interaction with E-selectin. Further analysis showed that on E-selectin, KPL1 blocked only secondary (i.e., monocyte/monocyte) interactions, but did not block primary (i.e., monocyte/E-selectin) interactions, with secondary adhesion accounting for 90% of the total adhesive interactions on either E- or P-selectin. On cytokine-activated HUVEC, monocytes initially attached and formed linear strings of adherent cells, which involved both primary and secondary adhesion. PSGL-1 or L-selectin mAb reduced string formation, and the combination of PSGL-1 and L-selectin mAb prevented monocyte strings and inhibited 86% of accumulation. Monocyte attachment and rolling on purified adherent monocytes were also critically dependent on PSGL-1 on the adherent monocytes. These studies document that secondary interactions between monocytes, mediated by PSGL-1, are crucial for monocyte initial attachment, rolling, and accumulation on activated endothelium under laminar shear flow.

Animals↗
PubMed2001

Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings.

As a part of study of selectin blockers, we have already reported that a non-sugar selectin antagonist (3) was successfully discovered using a computational screening (Hiramatsu, Y.; Tsukida, T.; Nakai, Y.; Inoue, Y.; Kondo, H. J. Med. Chem. 2000, 43, 1476). To investigate the SARs of compound 3 against E-, P-, and L-selectins, we synthesized the derivatives of compound 3 and evaluated their inhibitory activities toward selectin bindings. The structural diversity of compound 3 contained the following: (1) a modification of the spacer unit (4--7), (2) a modification of the tail unit (8--11), (3) a modification of the head unit (12--18). As a result, it was found that a non-sugar based selectin blocker (3) could be a potential lead compound for E-, P-, and L-selectin blockers and some of the derivatives showed broad and/or selective inhibitory activities toward the E-, P-, and L-selectins. In addition, it was found that the experimental evidence well supported that the computational screening using 3D-pharmacophore model could be useful methodology to find out a new lead for the several type of selectin blockers, which included a broad and/or a selective inhibitor.

Benzamides↗
PubMed2005

Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and E-selectin ligand-1, on human metastatic prostate tumor cells.

Prostate tumor cells, which characteristically metastasize to bone, initiate binding interactions with bone marrow endothelium under blood flow conditions through binding interactions with E-selectin. We hypothesized that E-selectin ligands on prostate tumor cells are directly associated with bone-metastatic potential. In this report, we elucidate the identity of E-selectin ligands on human metastatic prostate tumor cells and examine their association with prostate tumor progression and metastasis in vivo. To our surprise, we found that the E-selectin-binding form of P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on the human bone-metastatic prostate tumor MDA PCa 2b cell line. Interestingly, we also found that human prostate tumor cells derived from bone, lymph node, and brain metastases expressed another leukocyte E-selectin ligand, E-selectin ligand-1 (ESL-1). Immunohistochemical analysis of PSGL-1 and ESL-1 in normal prostate tissue and in localized and metastatic prostate tumors revealed that ESL-1 was principally localized to intracellular cell membrane and expressed on all normal and malignant prostate tissue, whereas PSGL-1 was notably detected on the surfaces of bone-metastatic prostate tumor cells. These findings implicate a functional role of PSGL-1 in the bone tropism of prostate tumor cells and establish a new perspective into the molecular mechanism of human prostate tumor metastasis.

Animals↗
PubMed1994

Skin disease-related T cells bind to endothelial selectins: expression of cutaneous lymphocyte antigen (CLA) predicts E-selectin but not P-selectin binding.

Cutaneous lymphocyte antigen (CLA), defined by the HECA-452 antibody, is a cell surface glycoprotein found on a subset of T cells in peripheral blood that binds specifically to E-selectin. This marker is present on the majority of T cells at sites of cutaneous inflammation and immune responses. Based upon such evidence, an association between T cell CLA expression and skin homing has been proposed. To understand better this relationship, we asked whether putative disease-related, antigen-specific T cells expressed CLA. In this study, we employed T helper type 2 (TH2) T cell clones specific for house dust mite (Dermatophagoides pteronyssinus) antigens. These cells were derived from challenged skin of an individual known to react positively to epicutaneous challenge with this agent. In this study, we show that these cloned T cells showed very high homogeneous expression of CLA (nearly 500-fold higher than T cell clones derived from peripheral blood) and bound specifically to recombinant E-selectin. The CLA molecule on these cells was identified not only by HECA-452, but also by CSLEX-1, indicating that it contained sialyl-Le(x) (S-Le(x)) determinants. T cells cloned under similar conditions from peripheral blood were CLA negative or low and bound poorly to E-selectin. Surprisingly, both skin and blood clones bound comparably to P-selectin. This binding was independent of S-Le(x) or CLA expression. We conclude that in sensitized individuals, antigen-specific T cells expressing high levels of CLA localize in skin promptly after epicutaneous challenge. This localization is likely to involve the interaction of S-Le(x) determinants on the CLA molecule with E-selectin on the dermal microvasculature. We further conclude that T cells can interest with P-selectin on endothelium and that S-Le(x) does not appear to be necessary for this interaction.

Animals↗
PubMed2002

[Expression of adhesion molecules LFA-1 and L-selectin on PMN and level of soluble sE-selectin and sL-selectin in the serum of patients with small cell lung cancer].

The aim of this study was to estimate expression of adhesion molecules LFA-1 and L-selectin on PMN of peripheral blood, and level of soluble sE-selectin and sL-selectin in the serum of 16 patients with small cell lung cancer (SCLC) before treatment. We observed significantly higher expression of LFA-1 and L-selectin on PMN in comparison to healthy persons and higher level sE selectin and sL selectin in the serum of SCLC patients. Increasing of adhesion molecules expression on PMN can lead to damage of neoplasmatic cells and may be one of the reasons for create a new cancer sites as well.

Adult↗
PubMed2001

Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G.

In the inflammatory response, leukocyte rolling before adhesion and transmigration through the blood vessel wall is mediated by specific cell surface adhesion receptors. Neutrophil rolling involves the interaction of P-selectin expressed on activated endothelium and its counter-receptor on neutrophils, P-selectin glycoprotein ligand-1 (PSGL-1). Here, it is reported that P-selectin binding to neutrophils is lost under conditions that cause the release of proteinases from neutrophil primary granules. Treatment of neutrophils with the purified neutrophil granule proteinases, cathepsin G and elastase, rapidly abolished their capacity to bind P-selectin. This inactivation corresponded to loss of the N-terminal domain of PSGL-1, as assessed by Western blot analysis. A loss of intact PSGL-1 protein from the surfaces of neutrophils after the induction of degranulation was also detected by Western blot analysis. Cathepsin G initially cleaved near the PSGL-1 N-terminus, whereas neutrophil elastase predominantly cleaved at a more C-terminal site within the protein mucin core. Consistent with this, cathepsin G cleaved a synthetic peptide based on the PSGL-1 N-terminus between Tyr-7/Leu-8. Under conditions producing neutrophil degranulation in incubations containing mixtures of platelets and neutrophils, the loss of PSGL-1, but not P-selectin, from platelet-neutrophil lysates was detected. Cathepsin G- or neutrophil elastase-mediated PSGL-1 proteolysis may constitute a potential autocrine mechanism for down-regulation of neutrophil adhesion to P-selectin.

Amino Acid Sequence↗
PubMed2006

Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial.

BACKGROUND: Inflammatory responses induced by reperfusion of previously ischemic myocardial tissue may lead to further damage of the microvascular structures. A group of cell adhesion molecules, named selectins, initiate those inflammatory changes at the endothelial wall surface. Recombinant P-selectin glycoprotein ligand-immunoglobulin (rPSGL-Ig), a P-selectin antagonist, was shown to have beneficial effects in several animal models of acute myocardial ischemia. We performed a mechanistic study with positron emission tomography to test the potential benefits of rPSGL-Ig in patients with ST-segment elevation acute myocardial infarction. METHODS: Patients with ST-elevation acute myocardial infarction presenting within the first 6 hours of onset of chest pain were enrolled. All patients received alteplase. Patients were randomly assigned in a 1:1:1 ratio to 3 treatment groups: placebo; 75 mg rPSGL-Ig; 150 mg rPSGL-Ig, given intravenously. Coronary angiography was performed 90 minutes after the start of thrombolytic therapy for TIMI flow grading. Myocardial blood flow (MBF) was measured with 13NH3 at rest and after adenosine administration on day 5. Myocardial blood flow at rest was measured again at day 30, followed by measurement of 18FDG uptake. In addition, a multigated acquisition, gated equilibrium blood pool study was performed at day 30. Continuous 12-lead electrocardiogram recording was performed during the first 24 hours. RESULTS: The trial was prematurely stopped by the sponsor for lack of efficacy in an accompanying larger trial after enrolling 88 patients in the current study. Median MBF in the infarct-related territory (expressed as percentage of the normalized blood flow) at day 5 was similar in the 3 treatment groups (9.1% in the placebo group vs 3.8% in the 75-mg dose and 4.3% in the 150-mg rPSGL-Ig treatment group; P = not significant). No significant differences in MBF reserve, myocardial metabolism, ST-segment resolution, left ventricular ejection fraction, or TIMI flow grade were found among the 3 groups. CONCLUSIONS: In this prematurely stopped mechanistic study, there was no evidence of a benefit of rPSGL-Ig given as an adjunct to thrombolysis on epicardial vessel patency, myocardial tissue reperfusion, or recovery of function.

Adolescent↗
PubMed1992

P-selectin and E-selectin. Distinct but overlapping leukocyte ligand specificities.

P-selectin on platelets and endothelial cells and E-selectin on endothelial cells are leukocyte receptors that recognize lineage-specific carbohydrates on neutrophils and monocytes. The proposed ligands for these receptors contain the Le(x) core and sialic acid. Since other investigators have shown that both E-selectin and P-selectin bind to sialylated Le(x), we evaluated whether E-selectin and P-selectin recognize the same counter-receptor on leukocytes. The interaction of HL60 cells with Chinese hamster ovary (CHO) cells expressing P-selectin or E-selectin was studied. To determine whether a protein component is required in addition to sialyl Le(x) for either P-selectin or E-selectin recognition, HL60 cells or neutrophils were digested with proteases, including chymotrypsin, elastase, proteinase Glu-C, ficin, papain, or thermolysin. Cells treated with these proteases bound E-selectin but not P-selectin. Fucosidase or neuraminidase treatment of HL60 cells markedly decreased binding to both E-selectin- and P-selectin-expressing CHO cells. Growth of HL60 cells in tunicamycin inhibited the ability of these cells to support P-selectin-mediated binding and, to a lesser extent, E-selectin-mediated binding. Purified P-selectin inhibited CHO:P-selectin binding to HL60 cells, but incompletely inhibited CHO:E-selectin binding to HL60 cells. However, purified soluble E-selectin inhibited CHO:P-selectin and CHO:E-selectin binding to HL60 cells equivalently and completely. COS cells, unable to bind to E-selectin or P-selectin, bound E-selectin but not P-selectin upon transfection with alpha-1,3-fucosyltransferase or alpha-1,3/1,4-fucosyltransferase. Similarly, LEC 11 cells expressing sialyl Le(x) bound E-selectin- but not P-selectin-expressing CHO cells. Sambucus nigra lectin, specific for the sialyl-2,6 beta Gal/GalNAc linkage, inhibited P-selectin but not E-selectin binding to HL60 cells. Although sialic acid and Le(x) are components of the P-selectin ligand and the E-selectin ligand, these results indicate that the ligands are related, having overlapping specificities, but are structurally distinct. A protein component containing sialyl Le(x) in proximity to sialyl-2,6 beta Gal structures on the P-selectin ligand may contribute to its specificity for P-selectin.

Animals↗
PubMed1997

L-selectin from human, but not from mouse neutrophils binds directly to E-selectin.

L-Selectin on neutrophils as well as inducible E- and P-selectin on endothelium are involved in the recruitment of neutrophils into inflamed tissue. Based on cell attachment assays, L-selectin was suggested to function as a carbohydrate presenting ligand for E- and P-selectin. However, previous affinity isolation experiments with an E-selectin-Ig fusion protein had failed to detect L-selectin among the isolated E-selectin ligands from mouse neutrophils. We show here that L-selectin from human neutrophils, in contrast to mouse neutrophils, can be affinity-isolated as a major ligand from total cell extracts using E-selectin-Ig as affinity probe. Binding of human L-selectin to E-selectin was direct, since purified L-selectin could be reprecipitated with E-selectin-Ig. Recognition of L-selectin was abolished by sialidase-treatment, required Ca2+, and was resistant to treatment with endoglycosidase F. Binding of L-selectin to a P-selectin-Ig fusion protein was not observed. In agreement with the biochemical data, the anti-L-selectin mAb DREG56 inhibited rolling of human neutrophils on immobilized E-selectin-Ig but not on P-selectin-Ig. No such inhibitory effect was seen with the anti-mouse L-selectin mAb MEL14 on mouse neutrophils. Rolling of E-selectin transfectants on purified and immobilized human L-selectin was inhibited by mAb DREG56. We conclude that L-selectin on human neutrophils is a major glycoprotein ligand among very few glycoproteins that can be isolated by an E-selectin affinity matrix. The clear difference between human and mouse L-selectin suggests that E-selectin-binding carbohydrate moieties are attached to different protein scaffolds in different species.

Animals↗
PubMed2002

Differential role of E-selectin and P-selectin in T lymphocyte migration to cutaneous inflammatory reactions induced by cytokines.

E-selectin and P-selectin are thought to be important in the infiltration of T lymphocytes in inflammation, but their role in cytokine-induced cutaneous inflammatory reactions has not been examined. A technique for quantifying labeled T lymphocyte migration to cytokine-induced dermal inflammation in mice was developed. After i.v. injection, (51)Cr-labeled T lymphocytes migrated to lesions induced by IFN-gamma and tumor necrosis factor (TNF)-alpha, and in even greater numbers to the combination of IFN-gamma + TNF-alpha, and to sites injected with concanavalin A (Con A). In E-selectin mAb-treated and in E-selectin-deficient mice, IFN-gamma-, IFN-gamma + TNF-alpha- and Con A-induced T cell accumulation was inhibited by 45-65%, but TNF-alpha-induced infiltration was unaffected. In P-selectin mAb-treated and P-selectin-deficient mice, T cell accumulation remained unchanged in most of the lesions. Combined, E-selectin and P-selectin mAb treatment inhibited T cell accumulation in all four types of reactions, and significantly more than E-selectin blockade alone in migration to Con A. Results in E-selectin- and P-selectin-deficient mice confirmed these observations, and demonstrated strain-dependent differences in the contributions of the two selectins. In conclusion, T cells migrating to dermal inflammatory reactions utilize both E-selectin and P-selectin, but alternate adhesion pathways also contribute, since blocking both endothelial selectins does not abolish T cell migration. P-selectin plays a less important role than E-selectin, since blocking E-selectin, but not P-selectin, alone decreased T cell accumulation. The relative contribution of the selectins varies depending on the initiating inflammatory stimulus and the genetic background.

Animals↗
PubMed1998

Functional characterization of L-selectin ligands on human neutrophils and leukemia cell lines: evidence for mucinlike ligand activity distinct from P-selectin glycoprotein ligand-1.

Recent reports have shown that leukocyte-leukocyte adhesion is dependent on L-selectin and that leukocyte recognition of L-selectin may be mediated by P-selectin glycoprotein ligand-1 (PSGL-1). We show that the specific attachment and rolling of human neutrophils and the leukemia cell lines HL-60 and U937 on immobilized, purified L-selectin under continuous shear stress is only partially inhibited by treatment with the PSGL-1 monoclonal antibody (MoAb), KPL1 (41% to 53% inhibition), suggesting that L-selectin ligand activity in addition to PSGL-1 may mediate myeloid cell rolling on L-selectin. K562 cells cotransfected with cDNAs encoding alpha (1,3)fucosyltransferase-VII (FucT-VII) and PSGL-1 rolled on L-selectin. Adhesion of FucT-VII-PSGL-1 transfectants to L-selectin was completely blocked by MoAb KPL1, indicating that both L-selectin and P-selectin bind similar sites on PSGL-1. In support of existence of a non-PSGL-1 L-selectin ligand activity on leukocytes, an HL-60 membrane preparation immunodepleted of PSGL-1 supported rolling of L-selectin, but not P-selectin transfectants. Treatment of HL-60 cells with O-sialoglycoprotein endopeptidase inhibited attachment and rolling on L-selectin and P-selectin. However, neuraminidase treatment completely blocked HL-60 rolling on L-selectin, but not P-selectin, suggesting L-selectin and P-selectin ligand activities have different contributions of sialic acid. These findings indicate that myeloid cells express sialylated, O-linked glycoprotein ligand activity independent of PSGL-1 that supports L-selectin-mediated rolling.

Antibodies, Monoclonal↗
PubMed1994

Characterization of E-selectin-deficient mice: demonstration of overlapping function of the endothelial selectins.

The initial rolling interaction of leukocytes with the blood vessel wall during leukocyte trafficking has been postulated to rely on members of the selectin family of adhesion molecules. Two selectins, E-selectin and P-selectin, have been identified that are expressed on activated endothelial cells. Mice deficient in E-selectin expression have been produced in order to examine the role of this selectin in leukocyte trafficking. Mice homozygous for an E-selectin null mutation were viable and exhibited no obvious developmental alterations. E-selectin-deficient mice displayed no significant change in the trafficking of neutrophils in several models of inflammation. However, blocking both endothelial selectins by treatment of the E-selectin-deficient animals with an anti-murine P-selectin antibody, 5H1, significantly inhibited neutrophil emigration in two distinct models of inflammation. While neutrophil accumulation at early times during thioglycollate-induced peritonitis was dependent on P-selectin, neutrophil accumulation at later time points was blocked by 5H1 only in E-selectin-deficient mice but not in wild-type mice. Similarly, edema as well as leukocyte accumulation in a model of delayed-type hypersensitivity in the skin was almost completely prevented by blockade of P-selectin function with 5H1 in the E-selectin-deficient mice while the same treatment had no effect in wild-type mice. These data demonstrate that the majority of neutrophil migration in both models requires an endothelial selectin but that E-selectin and P-selectin are functionally redundant. These data have important implications in the use of selectin antagonists in the treatment of inflammatory disease.

Animals↗