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Sample records for adhesion molecule vcam-1

  1. Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) as a Biomarker in the Mouse Model of Experimental Autoimmune Myocarditis (EAM)

    PubMed Central

    Grabmaier, U.; Kania, G.; Kreiner, J.; Grabmeier, J.; Uhl, A.; Huber, B. C.; Lackermair, K.; Herbach, N.; Todica, A.; Eriksson, U.; Weckbach, L. T.; Brunner, S.

    2016-01-01

    Vascular cell adhesion molecule-1 (VCAM-1) is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection-triggered dilated cardiomyopathy. Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1) directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM). EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund`s adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1) throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM. PMID:27501319

  2. Synchronous elevation of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) correlates with gastric cancer progression.

    PubMed

    Yoo, N C; Chung, H C; Chung, H C; Park, J O; Rha, S Y; Kim, J H; Roh, J K; Min, J S; Kim, B S; Noh, S H

    1998-02-01

    Soluble forms of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) have been reported from the supernatant of cytokine-activated endothelial cells, cancer cells and from sera of cancer patients. We measured sICAM-1 and sVCAM-1 from the serum of 20 healthy volunteers and 142 gastric cancer patients by ELISA assay. Ninety-five patients were operable and 47 patients were in-operable at the time of this study. Particularly in the 28 operable patients, we sampled both portal and peripheral blood simultaneously and measured the levels of the soluble forms of cell adhesion molecules (sCAMs). The sCAMs level and sero-positivity rate increased with cancer progression in order of the healthy controls, operable patients, and inoperable patients. In in-operable cancer, the sICAM-1 level increased more with liver metastasis. sICAM-1 and sVCAM-1 did not correlate with each other in either portal or peripheral blood. A total of 58.3% of patients with liver metastasis and 22.9% of patients without liver metastasis showed synchronous expression of both sCAMs (p = 0.03). Synchronous sero-positivity of sCAMs and alpha FP was higher with liver metastasis (p = 0.01). The median overall survival duration which co-expressed both sCAMs was 9 months. This showed a significant difference compared with the sICAMs non-expressing group, where the median survival was not reached until 24 months follow-up (p = 0.002). The synchronous expression of sCAMs was an independent risk factor in gastric cancer patients. We raise the possibility that synchronous sICAM-1 and sVCAM-1 elevation may be a useful monitor to determine tumor burden in gastric cancer.

  3. Patterns of myocardial cell adhesion molecule expression in human endomyocardial biopsies after cardiac transplantation. Induced ICAM-1 and VCAM-1 related to implantation and rejection.

    PubMed Central

    Herskowitz, A.; Mayne, A. E.; Willoughby, S. B.; Kanter, K.; Ansari, A. A.

    1994-01-01

    Conflicting patterns of myocardial cell adhesion molecule expression associated with cardiac rejection have emerged from numerous studies of randomly selected cardiac biopsies. We designed a prospective, longitudinal study which reports both qualitative and quantitative levels of myocardial ICAM-1, VCAM-1, E-selectin, and P-selectin expression in sequential human cardiac allograft biopsies. Intense ICAM-1 and VCAM-1 staining was found in all biopsies during the first three weeks after transplant and coincided with elevated serum levels of troponin T, a sensitive marker of ischemic myocyte injury. Baseline ICAM-1 and VCAM-1 expression returned within three to four weeks, as did serum troponin T levels in all patients who did not develop rejection. All 29 rejection episodes encountered were associated with intense ICAM-1 staining, while 24 of the 29 (83%) had intense VCAM-1 staining. Increased ELAM-1 and CD62 staining was only rarely observed. Persistence of increased ICAM-1 and VCAM-1 staining after treated rejection episodes predicted a recurrent rejection episode within two months (75% positive and 100% negative predictive value). Objective quantitative measurements by radioimmunoassay (RIA) confirmed these patterns of induced ICAM-1 and VCAM-1 expression. Thus, longitudinal monitoring of serial biopsies for myocardial ICAM-1 and VCAM-1 expression could be useful in the early detection of rejection episodes and monitoring the efficacy of immunosuppressive therapy. Images Figure 2 PMID:7977640

  4. Tie2 Signaling Enhances Mast Cell Progenitor Adhesion to Vascular Cell Adhesion Molecule-1 (VCAM-1) through α4β1 Integrin

    PubMed Central

    Kanemaru, Kazumasa; Noguchi, Emiko; Tokunaga, Takahiro; Nagai, Kei; Hiroyama, Takashi; Nakamura, Yukio; Tahara-Hanaoka, Satoko; Shibuya, Akira

    2015-01-01

    Mast cell (MC) activation contributes considerably to immune responses, such as host protection and allergy. Cell surface immunoreceptors expressed on MCs play an important role in MC activation. Although various immunoreceptors on MCs have been identified, the regulatory mechanism of MC activation is not fully understood. To understand the regulatory mechanisms of MC activation, we used gene expression analyses of human and mouse MCs to identify a novel immunoreceptor expressed on MCs. We found that Tek, which encodes Tie2, was preferentially expressed in the MCs of both humans and mice. However, Tie2 was not detected on the cell surface of the mouse MCs of the peritoneal cavity, ear skin, or colon lamina propria. In contrast, it was expressed on mouse bone marrow–derived MCs and bone marrow MC progenitors (BM-MCps). Stimulation of Tie2 by its ligand angiopoietin-1 induced tyrosine phosphorylation of Tie2 in MEDMC-BRC6, a mouse embryonic stem cell-derived mast cell line, and enhanced MEDMC-BRC6 and mouse BM-MCp adhesion to vascular cell adhesion molecule-1 (VCAM-1) through α4β1 integrin. These results suggest that Tie2 signaling induces α4β1 integrin activation on BM-MCps for adhesion to VCAM-1. PMID:26659448

  5. The Interaction Affinity between Vascular Cell Adhesion Molecule-1 (VCAM-1) and Very Late Antigen-4 (VLA-4) Analyzed by Quantitative FRET

    PubMed Central

    Wu, Shu-Han; Karmenyan, Artashes; Chiou, Arthur

    2015-01-01

    Very late antigen-4 (VLA-4), a member of integrin superfamily, interacts with its major counter ligand vascular cell adhesion molecule-1 (VCAM-1) and plays an important role in leukocyte adhesion to vascular endothelium and immunological synapse formation. However, irregular expressions of these proteins may also lead to several autoimmune diseases and metastasis cancer. Thus, quantifying the interaction affinity of the VCAM-1/VLA-4 interaction is of fundamental importance in further understanding the nature of this interaction and drug discovery. In this study, we report an ‘in solution’ steady state organic fluorophore based quantitative fluorescence resonance energy transfer (FRET) assay to quantify this interaction in terms of the dissociation constant (Kd). We have used, in our FRET assay, the Alexa Fluor 488-VLA-4 conjugate as the donor, and Alexa Fluor 546-VCAM-1 as the acceptor. From the FRET signal analysis, Kd of this interaction was determined to be 41.82 ± 2.36 nM. To further confirm our estimation, we have employed surface plasmon resonance (SPR) technique to obtain Kd = 39.60 ± 1.78 nM, which is in good agreement with the result obtained by FRET. This is the first reported work which applies organic fluorophore based ‘in solution’ simple quantitative FRET assay to obtain the dissociation constant of the VCAM-1/VLA-4 interaction, and is also the first quantification of this interaction. Moreover, the value of Kd can serve as an indicator of abnormal protein-protein interactions; hence, this assay can potentially be further developed into a drug screening platform of VLA-4/VCAM-1 as well as other protein-ligand interactions. PMID:25793408

  6. Borrelia burgdorferi upregulates the adhesion molecules E-selectin, P-selectin, ICAM-1 and VCAM-1 on mouse endothelioma cells in vitro.

    PubMed

    Böggemeyer, E; Stehle, T; Schaible, U E; Hahne, M; Vestweber, D; Simon, M M

    1994-06-01

    In order to obtain more information on processes leading to Borrelia burgdorferi-induced inflammation in the host, we have developed an in vitro model to study the upregulation of cell surface expression of adhesion molecules on endothelial cells by spirochetes. A mouse endothelioma cell line, derived from brain capillaries, bEnd3, was used as indicator population. bEnd3 cells were incubated with preparations of viable, inactivated or sonicated spirochetes and the expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 was monitored by immunocytochemistry and quantified by cell surface ELISA. We show that all three spirochetal preparations are able to upregulate cell surface expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 on bEnd 3 cells in a dose-dependent manner. The kinetics of cell surface expression of the individual adhesion molecules in the presence of Borrelia burgdorferi showed maxima at about 50 h of incubation or later; this was distinct from results obtained with sonicated-preparations of Escherichia coli bacteria or with enterobacterial LPS where peak expression was observed between 4 h and 16 h. The fact that Borrelia burgdorferi does not contain conventional LPS suggests that the mode of induction of adhesion molecules on endothelial cells is influenced by the phenotype of bacteria. At the peak of spirochete-induced cell surface expression of adhesion molecules (approximately 50 h), bEnd3 cells were found to bind cells of a VLA-4+ B lymphoma line (L1-2) much more efficiently than untreated control cells. The binding of L1-2 cells to presensitized bEnd3 cells was significantly inhibited (more than 75%) in the presence of monoclonal antibodies to both VLA-4 and its endothelial counterreceptor VCAM-1. These findings demonstrate that Borrelia burgdorferi organisms are able to induce functionally active adhesion molecules on endothelial cells in vitro and suggest that E-selectin, P-selectin, ICAM-1 and VCAM-1 play an important role in the

  7. Borrelia burgdorferi upregulates the adhesion molecules E-selectin, P-selectin, ICAM-1 and VCAM-1 on mouse endothelioma cells in vitro.

    PubMed

    Böggemeyer, E; Stehle, T; Schaible, U E; Hahne, M; Vestweber, D; Simon, M M

    1994-06-01

    In order to obtain more information on processes leading to Borrelia burgdorferi-induced inflammation in the host, we have developed an in vitro model to study the upregulation of cell surface expression of adhesion molecules on endothelial cells by spirochetes. A mouse endothelioma cell line, derived from brain capillaries, bEnd3, was used as indicator population. bEnd3 cells were incubated with preparations of viable, inactivated or sonicated spirochetes and the expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 was monitored by immunocytochemistry and quantified by cell surface ELISA. We show that all three spirochetal preparations are able to upregulate cell surface expression of E-selectin, P-selectin, ICAM-1 and VCAM-1 on bEnd 3 cells in a dose-dependent manner. The kinetics of cell surface expression of the individual adhesion molecules in the presence of Borrelia burgdorferi showed maxima at about 50 h of incubation or later; this was distinct from results obtained with sonicated-preparations of Escherichia coli bacteria or with enterobacterial LPS where peak expression was observed between 4 h and 16 h. The fact that Borrelia burgdorferi does not contain conventional LPS suggests that the mode of induction of adhesion molecules on endothelial cells is influenced by the phenotype of bacteria. At the peak of spirochete-induced cell surface expression of adhesion molecules (approximately 50 h), bEnd3 cells were found to bind cells of a VLA-4+ B lymphoma line (L1-2) much more efficiently than untreated control cells. The binding of L1-2 cells to presensitized bEnd3 cells was significantly inhibited (more than 75%) in the presence of monoclonal antibodies to both VLA-4 and its endothelial counterreceptor VCAM-1. These findings demonstrate that Borrelia burgdorferi organisms are able to induce functionally active adhesion molecules on endothelial cells in vitro and suggest that E-selectin, P-selectin, ICAM-1 and VCAM-1 play an important role in the

  8. MIP-1α enhances Jurkat cell transendothelial migration by up-regulating endothelial adhesion molecules VCAM-1 and ICAM-1.

    PubMed

    Ma, Yi-Ran; Ma, Ying-Huan

    2014-11-01

    The aim of this study is to evaluate the expression of macrophage inflammatory protein-1α (MIP-1α) in Jurkat cells and its effect on transendothelial migration. In the present study, human acute lymphoblastic leukemia Jurkat cells (Jurkat cells) were used as a model of T cells in human T-cell acute lymphoblastic leukemia (T-ALL), which demonstrated significantly higher MIP-1α expression compared with that in normal T-cell controls. The ability of Jurkat cells to cross a human brain microvascular endothelial cell (HBMEC) monolayer was almost completely abrogated by MIP-1α siRNA. In addition, the overexpression of MIP-1α resulted in the up-regulated expression of endothelial adhesion molecules, which enhanced the migration of Jurkat cells through a monolayer of HBMEC. MIP-1α levels in Jurkat cells appeared to be an important factor for its transendothelial migration, which may provide the theoretical basis to understand the mechanisms of brain metastases of T-ALL at cellular and molecular levels.

  9. Involvement of VCAM1 in the bovine conceptus adhesion to the uterine endometrium.

    PubMed

    Bai, Rulan; Bai, Hanako; Kuse, Mariko; Ideta, Atsushi; Aoyagi, Yoshito; Fujiwara, Hiroshi; Okuda, Kiyoshi; Imakawa, Kazuhiko; Sakurai, Toshihiro

    2014-08-01

    Following bidirectional communication, the conceptus and the uterine epithelium must establish a proper cell-cell interaction, resulting in the progression of implantation processes. To clarify the mechanism of conceptus attachment to the uterine endometrium, we studied whether vascular cell adhesion molecule (VCAM1) was expressed in bovine conceptuses or endometrium during the peri-attachment period. Uterine VCAM1 expression was minimal in day 17 (day 0=day of estrus) cyclic and pregnant animals, but increased between days 20 and 22 of pregnancy. In the intercaruncular regions, VCAM1 protein was localized to the luminal and glandular epithelia, whereas in the caruncular regions, VCAM1 protein was detected in the stroma and endothelia of the uterine endometrium. In cultured endometrial epithelial cells (EECs), VCAM1 expression was up-regulated when treated with uterine flushings or growth factor and further increased when EECs were cocultured with bovine trophoblast CT1 cells. VCAM1 expression in CT1 cells was also up-regulated with the use of uterine flushings, and further increased when these cells were cocultured with EECs. Expression of VCAM1 receptor, integrin α 4 (ITGA4) mRNA, increased significantly in day 22 conceptuses. In day 22 pregnant uteri, VCAM1 protein was found in both EECs and conceptuses, but ITGA4 was localized only to trophoblasts. These observations indicate that cell-cell interactions between conceptuses and uterine epithelial cells are required for sufficient VCAM1 and ITGA4 expression in the bovine species and suggest that uterine VCAM1 and conceptus ITGA4 play a role in the establishment of conceptus adhesion to the uterine endometrium. PMID:24803492

  10. Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1

    PubMed Central

    1991-01-01

    Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply

  11. Increased erythrocyte adhesion to VCAM-1 during pulsatile flow: Application of a microfluidic flow adhesion bioassay

    PubMed Central

    White, Jennell; Lancelot, Moira; Sarnaik, Sharada; Hines, Patrick

    2015-01-01

    Abstract Sickle cell disease (SCD) is characterized by microvascular occlusion mediated by adhesive interactions of sickle erythrocytes (SSRBCs) to the endothelium. Most in vitro flow adhesion assays measure SSRBC adhesion during continuous flow, although in vivo SSRBC adhesive interactions occur during pulsatile flow. Using a well-plate microfluidic flow adhesion system, we demonstrate that isolated SSRBCs adhere to vascular cell adhesion molecule (VCAM-1) at greater levels during pulsatile versus continuous flow. A significant increase in adhesive interactions was observed between all pulse frequencies 1 Hz to 2 Hz (60–120 beats/min) when compared to non-pulsatile flow. Adhesion of isolated SSRBCs and whole blood during pulsatile flow was unaffected by protein kinase A (PKA) inhibition, and exposure of SSRBCs to pulsatile flow did not affect the intrinsic adhesive properties of SSRBCs. The cell type responsible for increased adhesion of whole blood varied from patient to patient. We conclude that low flow periods of the pulse cycle allow more adhesive interactions between sickle erythrocytes and VCAM-1, and sickle erythrocyte adhesion in the context of whole blood may better reflect physiologic cellular interactions. The microfluidic flow adhesion bioassay used in this study may have applications for clinical assessment of sickle erythrocyte adhesion during pulsatile flow. PMID:24898561

  12. Increased plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell molecule-1 (sVCAM-1) associated with disease severity in a primate model for severe human malaria: Plasmodium coatneyi-Infected Japanese macaques (Macaca fuscata).

    PubMed

    Kawai, Satoru; Matsumoto, Jun; Aikawa, Masamichi; Matsuda, Hajime

    2003-05-01

    In the present study, we investigated plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) in seven Japanese macaques (Macaca fuscata) infected with Plasmodium coatneyi. Concentrations of sICAM-1 and sVCAM-1 were significantly elevated in the severe phase; the levels were maximally increased up to six times and three times those before infection, respectively. We subsequently examined kinetic profiles of sICAM-1 and sVCAM-1 concentration in plasma obtained from two infected monkeys. Both infected monkeys had markedly increased levels of these adhesion molecules when they exhibited severe clinical signs correlated with rapid increase in parasitemia. These results suggest that the elevation of levels of sICAM-1 and sVCAM-1 is a critical step in the pathogenesis of severe malaria in vivo.

  13. Human Peripheral Blood Eosinophils Express a Functional c-kit Receptor for Stem Cell Factor that Stimulates Very Late Antigen 4 (VLA-4)–mediated Cell Adhesion to Fibronectin and Vascular Cell Adhesion Molecule 1 (VCAM-1)

    PubMed Central

    Yuan, Qian; Austen, K. Frank; Friend, Daniel S.; Heidtman, Matthew; Boyce, Joshua A.

    1997-01-01

    We evaluated mature peripheral blood eosinophils for their expression of the surface tyrosine kinase, c-kit, the receptor for the stromal cell–derived cytokine, stem cell factor (SCF). Cytofluorographic analysis revealed that c-kit was expressed on the purified peripheral blood eosinophils from 8 of 8 donors (4 nonatopic and 4 atopic) (mean channel fluorescence intensity 2.0– 3.6-fold, average 2.8 ± 0.6-fold, greater than the negative control). The uniform and selective expression of c-kit by eosinophils was confirmed by immunohistochemical analysis of peripheral blood buffy coats. The functional integrity of c-kit was demonstrated by the capacity of 100 ng/ml (5 nM) of recombinant human (rh) SCF to increase eosinophil adhesion to 3, 10, and 30 μg/ml of immobilized FN40, a 40-kD chymotryptic fragment of plasma fibronectin, in 15 min by 7.7 ± 1.4-, 5.3 ± 3.3-, and 5.4 ± 0.2-fold, respectively, and their adhesion to 0.1, 0.5, and 1.0 μg/ml vascular cell adhesion molecule-1 (VCAM-1), by 12.7 ± 9.2-, 3.8 ± 2.5-, and 1.7 ± 0.6-fold, respectively. The SCF-stimulated adhesion occurred without concomitant changes in surface integrin expression, thereby indicating an avidity-based mechanism. rhSCF (100 ng/ml, 5 nM) was comparable to rh eotaxin (200 ng/ml, 24 nM) in stimulating adhesion. Cell adhesion to FN40 was completely inhibited with antibodies against the α4 and β1 integrin subunits, revealing that the SCF/c-kit adhesion effect was mediated by a single integrin heterodimer, very late antigen 4 (VLA-4). Thus, SCF represents a newly recognized stromal ligand for the activation of eosinophils for VLA-4–mediated adhesion, which could contribute to the exit of these cells from the blood, their tissue localization, and their prominence in inflammatory lesions. PMID:9221761

  14. NADPH Oxidase/ROS-Dependent VCAM-1 Induction on TNF-α-Challenged Human Cardiac Fibroblasts Enhances Monocyte Adhesion

    PubMed Central

    Lin, Chih-Chung; Yang, Chien-Chung; Wang, Chen-Yu; Tseng, Hui-Ching; Pan, Chih-Shuo; Hsiao, Li-Der; Yang, Chuen-Mao

    2016-01-01

    The inflammation-dependent adhesion molecule expressions are characterized in cardiovascular diseases and myocardial tissue infiltrations. Several pro-inflammatory cytokines are elevated in the acute myocardial injury and infarction. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, is raised in the injury tissues and inflammatory regions and involved in the pathogenesis of cardiac injury, inflammation, and apoptosis. In fibroblasts, TNF-α-triggered expression of vascular cell adhesion molecule (VCAM)-1 aggravated the heart inflammation. However, the mechanisms underlying TNF-α-mediated VCAM-1 expression in cardiac fibroblasts remain unclear. Here, the primary cultured human cardiac fibroblasts (HCFs) were used to investigate the effects of TNF-α on VCAM-1 expression. The molecular evidence, including protein, mRNA, and promoter analyses, indicated that TNF-α-induced VCAM-1 gene expression is mediated through the TNFR-dependent manner. Activation of TNF-α/TNFR system triggered PKCα-dependent NADPH oxidase (Nox)/reactive oxygen species (ROS) signal linking to MAPK cascades, and then led to activation of the transcription factor, AP-1. Moreover, the results of mRNA and promoter assay demonstrated that c-Jun/AP-1 phosphorylated by TNF-α turns on VCAM-1 gene expression. Subsequently, up-regulated VCAM-1 on the cell surface of TNF-α-challenged HCFs increased the number of monocytes adhering to these cells. These results indicated that in HCFs, activation of AP-1 by PKCα-dependent Nox/ROS/MAPKs cascades is required for TNF-α-induced VCAM-1 expression. To clarify the mechanisms of TNF-α-induced VCAM-1 expression in HCFs may provide therapeutic strategies for heart injury and inflammatory diseases. PMID:26858641

  15. Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3.

    PubMed Central

    Steinhoff, G.; Behrend, M.; Schrader, B.; Duijvestijn, A. M.; Wonigeit, K.

    1993-01-01

    Vascular expressed adhesion molecules mediate leukocyte reactivity and activation by receptor-ligand binding. A number of different ligand molecules have been identified to mediate the interaction between endothelial cells and leukocyte subpopulations. In this study, the tissue expression of ELAM-1, CD62 (PADGEM, GMP-140), VACM-1 (INCAM-110), ICAM-2, ICAM-1, and LFA-3 was analyzed on various liver endothelial cell types by immunohistology. The results reveal a differential expression of these molecules in normal liver and inflammation or rejection after liver transplantation. The selectins ELAM-1 and CD62 are basally expressed and inducible on portal tract endothelia (arterial and venous) and central vein endothelia with acute and chronic liver inflammation. Sinusoidal endothelia, however, lack this mechanism, even with severe inflammation, as in cases of irreversible rejection and sepsis. Portal and sinusoidal endothelia show a different expression and inducibility of VCAM-1, ICAM-1, ICAM-2, and LFA-3. The differences in expression of adhesion molecules on liver endothelial cell types may reflect their ability to regulate leukocyte trafficking and activation by means of the expression of specific ligand molecules. The inability of sinusoidal endothelia to express selectins may have implications for the pathophysiology of liver graft infiltration. Images Figure 1 PMID:8434643

  16. Lipopolysaccharide induces VCAM-1 expression and neutrophil adhesion to human tracheal smooth muscle cells: Involvement of Src/EGFR/PI3-K/Akt pathway

    SciTech Connect

    Lin, W.-N.; Luo, S.-F.; Wu, C.-B.; Lin, C.-C.; Yang, C.-M.

    2008-04-15

    In our previous study, LPS has been shown to induce vascular cell adhesion molecule-1(VCAM-1) expression through MAPKs and NF-{kappa}B in human tracheal smooth muscle cells (HTSMCs). In addition to these pathways, the non-receptor tyrosine kinases (Src), EGF receptor (EGFR), and phosphatidylinositol 3-kinase (PI3K) have been shown to be implicated in the expression of several inflammatory target proteins. Here, we reported that LPS-induced up-regulation of VCAM-1 enhanced the adhesion of neutrophils onto HTSMC monolayer, which was inhibited by LY294002 and wortmannin. LPS stimulated phosphorylation of protein tyrosine kinases including Src, PYK2, and EGFR, which were further confirmed using specific anti-phospho-Src, PYK2, or EGFR Ab, respectively, revealed by Western blotting. LPS-stimulated Src, PYK2, EGFR, and Akt phosphorylation and VCAM-1 expression were attenuated by the inhibitors of Src (PP1), EGFR (AG1478), PI3-K (LY294002 and wortmannin), and Akt (SH-5), respectively, or transfection with siRNAs of Src or Akt and shRNA of p110. LPS-induced VCAM-1 expression was also blocked by pretreatment with curcumin (a p300 inhibitor) or transfection with p300 siRNA. LPS-stimulated Akt activation translocated into nucleus and associated with p300 and VCAM-1 promoter region was further confirmed by immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation assays. This association of Akt and p300 to VCAM-1 promoter was inhibited by pretreatment with PP1, AG1478, wortmannin, and SH-5. LPS-induced p300 activation enhanced VCAM-1 promoter activity and VCAM-1 mRNA expression. These results suggested that in HTSMCs, Akt phosphorylation mediated through transactivation of Src/PYK2/EGFR promoted the transcriptional p300 activity and eventually led to VCAM-1 expression induced by LPS.

  17. The role of ROS in ionizing radiation-induced VLA-4 mediated adhesion of RAW264.7 cells to VCAM-1 under flow conditions.

    PubMed

    Yuan, Ye; Lee, Shin Hee; Wu, Shiyong

    2013-01-01

    Alteration of adhesion molecule expression on endothelial cells has a direct connection with ionizing radiation-induced atherosclerosis, which is an adverse effect observed after radiotherapy. However, minimal attention has been given to monocytes/macrophages role in atherosclerosis development, which are exposed to the radiation at the same time. Under flow conditions using a parallel plate flow chamber to mimic physiological shear stress, we demonstrate here that the avidity between very late antigen-4 (VLA-4) of RAW264.7 cells and its ligand vascular cell adhesion molecule-1 (VCAM-1), was increased after low dose (0.5 Gy) irradiation, but was reduced after higher dose (5 Gy) treatment of ionizing radiation despite the fact that the surface expression of VLA-4 was up-regulated at 5 Gy of ionizing radiation. Treating the cells with free radical scavenger N-acetylcysteine had no effect on VLA-4 expression, but did reduce the avidity between RAW264.7 cells and VCAM-1 to a similar level, independent of ionizing radiation dose. The effect of H(2)O(2) treatment (from 1-100 μM) on RAW264.7 cell adhesion to VCAM-1 generated a similar bell-shaped graph as ionizing radiation. These results suggest that ionizing radiation regulates adhesive interactions between VLA-4 and VCAM-1, and that reactive oxygen species might function as a regulator, for this increased adhesiveness but with altered expression of integrin not play a major role. PMID:23181590

  18. Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress.

    PubMed

    Toma, Laura; Sanda, Gabriela M; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

    2016-06-01

    Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL). The results showed that 24 h incubation of HEC with gLDL induces (i) stimulation of VCAM-1 expression and secretion, determining increased monocyte adhesion to HEC; (ii) RAGE up-regulation and free cholesterol loading; (iii) ERS activation (increased eIF2α phosphorylation and CHOP mRNA levels, and decreased GRP78 protein expression); and (iv) oxidative stress [increased levels of reactive oxygen species (ROS) and glutamate cysteine ligase catalytic unit gene expression]. Treatment of gLDL-exposed HEC with ERS inhibitors, salubrinal (Sal) and sodium phenylbutyrate (PBA), decreased intracellular ROS. Incubation of gLDL-exposed cells with the anti-oxidant N-acetyl-cysteine (NAC) reduced ERS, revealed by decreased eIF2α phosphorylation and CHOP gene expression and increased GRP78 expression, thus validating the interconnection between ERS and oxidative stress. Sal, PBA, NAC and inhibitors of p38 MAP kinase and NF-kB induced the decrease of VCAM-1 expression and of the ensuing monocyte adhesion induced by gLDL. In conclusion, in HEC, gLDL stimulate the expression of cellular VCAM-1, the secretion of soluble VCAM-1, and the adhesion of monocytes through mechanisms involving p38 MAP kinase and NF-kB signalling pathways activated by RAGE, ERS and oxidative stress, thus contributing to diabetic atherosclerosis. PMID:27206739

  19. The use of the soluble adhesion molecules sE-selectin, sICAM-1, sVCAM-1, sPECAM-1 and their ligands CD11a and CD49d as diagnostic and prognostic biomarkers in septic and critically ill non-septic ICU patients.

    PubMed

    Kjaergaard, Anders G; Dige, Anders; Nielsen, Jeppe S; Tønnesen, Else; Krog, Jan

    2016-10-01

    Endothelial activation is pivotal in the development and escalation of sepsis. Central to endothelial activation is the endothelial up-regulation of cellular adhesion molecules (CAMs) including E-selectin, ICAM-1, VCAM-1, and PECAM-1. Shed CAMs are also found in circulating soluble forms (sCAMs). We investigated whether sCAMs can be used as biomarkers for the differentiation between septic and non-septic patients. Furthermore, we investigated lymphocyte and monocyte expression of LFA-1 (CD11a/CD18) and VLA-4 (CD49d/CD29) ligands for ICAM-1 and VCAM-1, respectively. Twenty-one septic and 15 critically ill non-septic patients were included. All patients had an APACHE II score above 13 at ICU admission. Fifteen healthy volunteers served as controls. Flow cytometry was used to estimate levels of sE-selectin, sICAM-1, sVCAM-1, sPECAM-1, and the cellular expression of CD11a and CD49d. Levels of sE-selectin, sICAM-1 and sPECAM-1 were higher in the septic patients compared with the non-septic patients and controls at admission and during the observation period. Lymphocyte and monocyte expression of CD11a and CD49d was suppressed or unaltered in the septic patients compared with the non-septic patients and controls. Levels of sE-selectin, sICAM-1, and sPECAM-1 were able to discriminate between septic and non-septic patients, indicating that sCAMs may be potential diagnostic biomarkers of sepsis.

  20. The use of the soluble adhesion molecules sE-selectin, sICAM-1, sVCAM-1, sPECAM-1 and their ligands CD11a and CD49d as diagnostic and prognostic biomarkers in septic and critically ill non-septic ICU patients.

    PubMed

    Kjaergaard, Anders G; Dige, Anders; Nielsen, Jeppe S; Tønnesen, Else; Krog, Jan

    2016-10-01

    Endothelial activation is pivotal in the development and escalation of sepsis. Central to endothelial activation is the endothelial up-regulation of cellular adhesion molecules (CAMs) including E-selectin, ICAM-1, VCAM-1, and PECAM-1. Shed CAMs are also found in circulating soluble forms (sCAMs). We investigated whether sCAMs can be used as biomarkers for the differentiation between septic and non-septic patients. Furthermore, we investigated lymphocyte and monocyte expression of LFA-1 (CD11a/CD18) and VLA-4 (CD49d/CD29) ligands for ICAM-1 and VCAM-1, respectively. Twenty-one septic and 15 critically ill non-septic patients were included. All patients had an APACHE II score above 13 at ICU admission. Fifteen healthy volunteers served as controls. Flow cytometry was used to estimate levels of sE-selectin, sICAM-1, sVCAM-1, sPECAM-1, and the cellular expression of CD11a and CD49d. Levels of sE-selectin, sICAM-1 and sPECAM-1 were higher in the septic patients compared with the non-septic patients and controls at admission and during the observation period. Lymphocyte and monocyte expression of CD11a and CD49d was suppressed or unaltered in the septic patients compared with the non-septic patients and controls. Levels of sE-selectin, sICAM-1, and sPECAM-1 were able to discriminate between septic and non-septic patients, indicating that sCAMs may be potential diagnostic biomarkers of sepsis. PMID:27539881

  1. Telmisartan attenuates hyperglycemia-exacerbated VCAM-1 expression and monocytes adhesion in TNFα-stimulated endothelial cells by inhibiting IKKβ expression.

    PubMed

    Song, Kee-Ho; Park, Jung-Hyun; Jo, Inho; Park, Joong-Yeol; Seo, Jungwon; Kim, Soon Ae; Cho, Du-Hyong

    2016-03-01

    Uncontrolled hyperglycemia accelerates endothelial damage and vascular inflammation caused by proinflammatory cytokines including tumor necrosis factor α (TNFα), which leads to arteriosclerotic cardiovascular diseases such as myocardial infarction. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is prescribed for treatment of hypertensive patients with concurrent diabetes mellitus (DM). Although a few clinical trials have suggested that telmisartan decreases cardiovascular complications in diabetic patients, the molecular mechanism for the beneficial effects remains elusive. Here, we investigated a molecular mechanism and effects of telmisartan on the expression of vascular cell adhesion molecule-1 (VCAM-1) and attachment of monocytes onto endothelial cells induced by TNFα in hyperglycemia-treated bovine aortic endothelial cells (BAEC). Telmisartan dose-dependently decreased hyperglycemia-aggravated IκB kinase β (IKKβ) expression and nuclear factor-κB (NF-κB) p65-Ser(536) phosphorylation, which accompanied a decrease in VCAM-1 expression and THP-1 monocytes adhesion. Among ARBs, including losartan and fimasartan, only telmisartan showed the inhibitory effects on expression of VCAM-1 and IKKβ, and phosphorylation of NF-κB p65-Ser(536). The telmisartan's beneficial effects were not changed by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, although GW9662 clearly inhibited rosiglitazone-induced CD36 expression. Finally, ectopic expression of wild type (WT)-IKKβ significantly restored telmisartan-attenuated VCAM-1 expression, NF-κB p65-Ser(536) phosphorylation, and THP-1 monocytes adhesion. Taken together, our findings demonstrate that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by decreasing expression of IKKβ and VCAM-1 independently of PPARγ. Telmisartan may be useful for the treatment of DM-associated vascular

  2. Morin, a Flavonoid from Moraceae, Inhibits Cancer Cell Adhesion to Endothelial Cells and EMT by Downregulating VCAM1 and Ncadherin.

    PubMed

    Lee, JeongHee; Jin, Hana; Lee, Won Sup; Nagappan, Arulkumar; Choi, Yung Hyun; Kim, Gon Sup; Jung, JinMyung; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan; Kim, Hye Jung

    2016-01-01

    Morin, a flavonoid found in figs and other Moraceae species, displays a variety of biological actions, exerting antioxidant, antiinflammatory and anticarcinogenic effects. Here, we investigated the anticancer activity of morin focusing on antiadhesive influence. We performed experiments with MDAMB231 human breast cancer cells. Morin inhibited TNFinduced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. It further inhibited the expression of VCAM1 on MDAMB231 cells as well as HUVECs. Morin also decreased the expression of Ncadherin on MDAMB231 cells. In addition, there was apparent antimetastatic activity in vivo. In conclusion, this study suggested that morin inhibits cancer cell adhesion to HUVECs by reducing VCAM1, and EMT by targeting Ncadherin, and that it features antimetastatic activity in vivo. Further investigation of possible antimetastatic activity of morin against human breast cancer cells is warranted.

  3. Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions

    PubMed Central

    1991-01-01

    T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM- X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1- transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell. PMID:1710227

  4. VCAM-1-targeted core/shell nanoparticles for selective adhesion and delivery to endothelial cells with lipopolysaccharide-induced inflammation under shear flow and cellular magnetic resonance imaging in vitro.

    PubMed

    Yang, Hong; Zhao, Fenglong; Li, Ying; Xu, Mingming; Li, Li; Wu, Chunhui; Miyoshi, Hirokazu; Liu, Yiyao

    2013-01-01

    Multifunctional nanomaterials with unique magnetic and luminescent properties have broad potential in biological applications. Because of the overexpression of vascular cell adhesion molecule-1 (VCAM-1) receptors in inflammatory endothelial cells as compared with normal endothelial cells, an anti-VCAM-1 monoclonal antibody can be used as a targeting ligand. Herein we describe the development of multifunctional core-shell Fe(3)O(4)@SiO2 nanoparticles with the ability to target inflammatory endothelial cells via VCAM-1, magnetism, and fluorescence imaging, with efficient magnetic resonance imaging contrast characteristics. Superparamagnetic iron oxide and fluorescein isothiocyanate (FITC) were loaded successfully inside the nanoparticle core and the silica shell, respectively, creating VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles that were characterized by scanning electron microscopy, transmission electron microscopy, fluorescence spectrometry, zeta potential assay, and fluorescence microscopy. The VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles typically had a diameter of 355 ± 37 nm, showed superparamagnetic behavior at room temperature, and cumulative and targeted adhesion to an inflammatory subline of human umbilical vein endothelial cells (HUVEC-CS) activated by lipopolysaccharide. Further, our data show that adhesion of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles to inflammatory HUVEC-CS depended on both shear stress and duration of exposure to stress. Analysis of internalization into HUVEC-CS showed that the efficiency of delivery of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles was also significantly greater than that of nontargeted Fe(3)O(4)@SiO2(FITC)-NH2 nanoparticles. Magnetic resonance images showed that the superparamagnetic iron oxide cores of the VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles could also act as a contrast agent for magnetic resonance imaging. Taken together, the cumulative adhesion and uptake potential of

  5. VCAM-1-targeted core/shell nanoparticles for selective adhesion and delivery to endothelial cells with lipopolysaccharide-induced inflammation under shear flow and cellular magnetic resonance imaging in vitro.

    PubMed

    Yang, Hong; Zhao, Fenglong; Li, Ying; Xu, Mingming; Li, Li; Wu, Chunhui; Miyoshi, Hirokazu; Liu, Yiyao

    2013-01-01

    Multifunctional nanomaterials with unique magnetic and luminescent properties have broad potential in biological applications. Because of the overexpression of vascular cell adhesion molecule-1 (VCAM-1) receptors in inflammatory endothelial cells as compared with normal endothelial cells, an anti-VCAM-1 monoclonal antibody can be used as a targeting ligand. Herein we describe the development of multifunctional core-shell Fe(3)O(4)@SiO2 nanoparticles with the ability to target inflammatory endothelial cells via VCAM-1, magnetism, and fluorescence imaging, with efficient magnetic resonance imaging contrast characteristics. Superparamagnetic iron oxide and fluorescein isothiocyanate (FITC) were loaded successfully inside the nanoparticle core and the silica shell, respectively, creating VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles that were characterized by scanning electron microscopy, transmission electron microscopy, fluorescence spectrometry, zeta potential assay, and fluorescence microscopy. The VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles typically had a diameter of 355 ± 37 nm, showed superparamagnetic behavior at room temperature, and cumulative and targeted adhesion to an inflammatory subline of human umbilical vein endothelial cells (HUVEC-CS) activated by lipopolysaccharide. Further, our data show that adhesion of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles to inflammatory HUVEC-CS depended on both shear stress and duration of exposure to stress. Analysis of internalization into HUVEC-CS showed that the efficiency of delivery of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles was also significantly greater than that of nontargeted Fe(3)O(4)@SiO2(FITC)-NH2 nanoparticles. Magnetic resonance images showed that the superparamagnetic iron oxide cores of the VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles could also act as a contrast agent for magnetic resonance imaging. Taken together, the cumulative adhesion and uptake potential of

  6. Integrin α4β1–VCAM-1–mediated adhesion between endothelial and mural cells is required for blood vessel maturation

    PubMed Central

    Garmy-Susini, Barbara; Jin, Hui; Zhu, Yuhong; Sung, Rou-Jia; Hwang, Rosa; Varner, Judy

    2005-01-01

    Neovascularization depends on vascular cell proliferation and on the stabilization of vessels by association of vascular smooth muscle–like pericytes with ECs. Here we show that integrin α4β1 (VLA-4) and VCAM-1 promote close intercellular adhesion between ECs and pericytes and that this interaction is required for blood vessel formation. Integrin α4β1 is expressed by proliferating but not quiescent ECs, while its ligand VCAM-1 is expressed by proliferating but not quiescent mural cells. Antagonists of this integrin-ligand pair block the adhesion of mural cells to proliferating endothelia in vitro and in vivo, thereby inducing apoptosis of ECs and pericytes and inhibiting neovascularization. These studies indicate that integrin α4β1 and VCAM-1 facilitate a critical cell-cell adhesion event required for survival of endothelial and mural cells during vascularization. PMID:15902308

  7. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs

    PubMed Central

    Chen, Qing; Zhang, Xiang H.-F.; Massagué, Joan

    2012-01-01

    SUMMARY Aberrant expression of vascular cell adhesion molecule-1 (VCAM-1) in breast cancer cells is associated with lung relapse, but the role of VCAM-1 as a mediator of metastasis has remained unknown. We report that VCAM-1 provides a survival advantage to breast cancer cells that infiltrate leukocyte-rich microenvironments such as the lungs. VCAM-1 tethers metastasis-associated macrophages to cancer cells via counter-receptor α4 integrins. Clustering of cell surface VCAM-1, acting through Ezrin, triggers Akt activation and protects cancer cells from pro-apoptotic cytokines such as TRAIL. This pro-survival function of VCAM-1 can be blocked by antibodies against α4 integrins. Thus, newly disseminated cancer cells expressing VCAM-1 can thrive in leukocyte-rich microenvironments through juxtacrine activation of a VCAM-1–Ezrin-PI3K/Akt survival pathway. PMID:22014578

  8. Chloroform extract of aged black garlic attenuates TNF-α-induced ROS generation, VCAM-1 expression, NF-κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells.

    PubMed

    Lee, Eun Na; Choi, Young Whan; Kim, Hye Kyung; Park, Jin Kyeong; Kim, Hyo Jin; Kim, Myoung June; Lee, Hee Woo; Kim, Ki-Hyung; Bae, Sun Sik; Kim, Bong Seon; Yoon, Sik

    2011-01-01

    Aged black garlic is a type of fermented garlic (Allium sativum) which has been used in Oriental countries for a long time because of various biological properties of garlic derivatives. The current study explored the potential of the chloroform extract of aged black garlic (CEABG) in attenuating the activities of adhesion molecules in tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs). The study was performed on HUVECs that were pretreated with 30 μg/mL of CEABG before TNF-α treatment. Treatment of HUVECs with CEABG significantly inhibited TNF-α-induced reactive oxygen species (ROS) formation. HUVECs treated with CEABG showed markedly suppressed TNF-α-induced mRNA expression of VCAM-1, but little alteration in ICAM-1 and E-selectin mRNA expression. CEABG treatment also significantly decreased the TNF-α-induced cell surface and total protein expression of VCAM-1 without affecting ICAM-1 and E-selectin expression. In addition, treatment of HUVECs with CEABG markedly reduced THP-1 monocyte adhesion to TNF-α-stimulated HUVECs. Furthermore, CEABG significantly inhibited NF-κB transcription factor activation in TNF-α-stimulated HUVECs. The data provide new evidence of the antiinflammatory properties of CEABG that may have a potential therapeutic use for the prevention and treatment of vascular diseases such as atherosclerosis through mechanisms involving the inhibition of VCAM-1 expression and NF-κB activation in vascular endothelial cells.

  9. Expression and cell distribution of the intercellular adhesion molecule, vascular cell adhesion molecule, endothelial leukocyte adhesion molecule, and endothelial cell adhesion molecule (CD31) in reactive human lymph nodes and in Hodgkin's disease.

    PubMed Central

    Ruco, L. P.; Pomponi, D.; Pigott, R.; Gearing, A. J.; Baiocchini, A.; Baroni, C. D.

    1992-01-01

    The immunocytochemical expression of intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelial leukocyte adhesion molecule (ELAM-1), endothelial cell adhesion molecule (EndoCAM CD31), and HLA-DR antigens was investigated in sections of 24 reactive lymph nodes and in 15 cases of Hodgkin's disease. ICAM-1 was detected in sinus macrophages, follicular dendritic reticulum cells (FDRCs), interdigitating reticulum cells (IDRCs), epithelioid macrophages, Hodgkin's cells (HCs), and vascular endothelium. ICAM-1 expression was often associated with that of HLA-DR antigens. VCAM-1 was detected in FDRCs, in fibroblast reticulum cells (FRCs), in macrophages, and in rare blood vessels. EndoCAM (CD31) was constitutively expressed in all types of endothelial cells, sinus macrophages, and in epithelioid granulomas. ELAM-1 was selectively expressed by activated endothelial cells of high endothelium venules (HEVs). When expression of the inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 was comparatively evaluated in HEVs, it was found that ICAM-1 + HEVs were present in all reactive and HD nodes, whereas ELAM-1 and/or VCAM-1 were expressed only in those pathologic conditions characterized by high levels of interleukin-1/tumor necrosis factor (IL-1/TNF) production, such as granulomatosis and Hodgkin's disease. In Hodgkin's disease, the expression of ELAM-1/VCAM-1 was more pronounced in cases of nodular sclerosis and was associated with a significantly higher content of perivascular neutrophils. Images Figure 1 Figure 2 PMID:1605306

  10. Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment

    PubMed Central

    Terpos, E; Migkou, M; Christoulas, D; Gavriatopoulou, M; Eleutherakis-Papaiakovou, E; Kanellias, N; Iakovaki, M; Panagiotidis, I; Ziogas, D C; Fotiou, D; Kastritis, E; Dimopoulos, M A

    2016-01-01

    Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly-diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM-1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells. PMID:27232930

  11. Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment.

    PubMed

    Terpos, E; Migkou, M; Christoulas, D; Gavriatopoulou, M; Eleutherakis-Papaiakovou, E; Kanellias, N; Iakovaki, M; Panagiotidis, I; Ziogas, D C; Fotiou, D; Kastritis, E; Dimopoulos, M A

    2016-01-01

    Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly-diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM-1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells. PMID:27232930

  12. Canonical Wnt Pathway Signaling Suppresses VCAM-1 Expression by Marrow Stromal and Hematopoietic Cells

    PubMed Central

    Malhotra, Sachin; Kincade, Paul W.

    2009-01-01

    Objective The Wnt family may contribute to hematopoietic stem cell (HSC) maintenance in bone marrow, but many questions remain concerning mechanisms. Vascular cell adhesion molecule-1 (VCAM-1) is expressed in cellular compartments of the bone marrow and might contribute to the HSC niche, but mechanisms concerning its constitutive expression are largely unknown. We now explore the influence of Wnt signaling on cellular adhesion molecule (CAM) expression by bone marrow stromal and hematopoietic cells. Methods Recombinant Wnt ligands, retroviral Wnt transductions and co-cultures with Wnt secreting cells were used to analyze the effect of Wnt on adhesion molecule expression by stromal and hematopoietic cells. In vivo experiments were also done to assess the ability of Wnt3a induced, VCAM-1 deficient hematopoietic cells to engraft bone marrow. Results We now report that the beta-catenin dependent canonical Wnt signaling pathway negatively regulates VCAM-1 expression on two types of bone marrow cells. Wnt pathway inhibitors, Axin (intracellular) or Dkk1 (extracellular) blocked the regulation of VCAM-1 by diffusible Wnt3a. Interestingly, lipopolysaccharide (LPS) restored a substantial degree of VCAM-1 expression, suggesting functional cross-talk between Wnt and TLR4 signaling pathways. Decreasing VCAM-1 on HSC enriched Lin- Sca-1+ c-KitHi Thy1.1Lo cells by exposure to Wnt3a did not prevent their successful transplantation. Conclusions Our results suggest that cells comprising and residing in the HSC niche can respond to Wnt ligands and extinguish VCAM-1. This response may be important for export of hematopoietic cells. Given the known contribution of VCAM-1 to inflammation, this may represent a new avenue for therapeutic intervention. PMID:18951693

  13. The roles of Akt and NOSs in regulation of VLA-4-mediated melanoma cell adhesion to endothelial VCAM-1 after UVB-irradiation.

    PubMed

    Liu, Wei; Wu, Shiyong

    2011-04-15

    UVB-reduced avidity between M624 melanoma and HUVEC cells is dependent on the interaction of VLA-4 with its endothelial ligand VCAM-1. Our previous studies suggested that a spatial organization of α4 integrin, one of the two subunits of VLA-4, on the melanoma cell surface contributed to the changes in avidity for VCAM-1 upon UVB-irradiation. In this study, we demonstrate that Akt plays an important role in regulation of the expression and surface level of α4 integrin on melanoma cells upon UVB-irradiation. While the cell surface level of α4 integrin is not significantly affected by UVB-irradiation or Akt inhibitor alone, it is dynamically altered after UVB-irradiation when Akt is inhibited. Inhibition of Akt also reverses the reduction of avidity of cells after the irradiation. Our data also shows that UVB reduces the level of Akt. The inhibition of Akt activity correlates with a reduced amount of coupled cNOS and reduced amount of iNOS after UVB-irradiation. However, the effect of NOSs on melanoma cell adhesion appears due to their roles in regulation of apoptosis after UVB-irradiation. Base on these results, we propose that the UVB-induced reduction of avidity of melanoma cells is coordinatively regulated by NOSs and Akt through two differential mechanisms. PMID:21129359

  14. CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion.

    PubMed

    Liu, Ju-Fang; Hou, Sheng-Mou; Tsai, Chun-Hao; Huang, Chun-Yin; Hsu, Chin-Jung; Tang, Chih-Hsin

    2013-05-01

    CCN4 is a cysteine-rich protein that belongs to the Cyr61, CTGF, Nov family of matricellular proteins. Here, we investigated the intracellular signaling pathways involved in CCN4-induced vascular cell adhesion molecule-1 expression in human osteoarthritis synovial fibroblasts. Stimulation of OASFs with CCN4 induced VCAM-1 expression. CCN4-induced VCAM-1 expression was attenuated by αvβ5 or α6β1 integrin antibody, Syk inhibitor, PKCδ inhibitor (rottlerin), JNK inhibitor (SP600125), and AP-1 inhibitors (curcumin and tanshinone). Stimulation of cells with CCN4 increased Syk, PKCδ, and JNK activation. Treatment of OASFs with CCN4 also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element in the VCAM-1 promoter. Moreover, up-regulation of VCAM-1 increased the adhesion of monocytes to OASF monolayers, and this adhesion was attenuated by transfection with a VCAM-1 siRNA. Our results suggest that CCN4 increases VCAM-1 expression in human OASFs via the Syk, PKCδ, JNK, c-Jun, and AP-1 signaling pathways. The CCN4-induced VCAM-1 expression promoted monocyte adhesion to human OASFs. PMID:23313051

  15. High-density lipoprotein of patients with breast cancer complicated with type 2 diabetes mellitus promotes cancer cells adhesion to vascular endothelium via ICAM-1 and VCAM-1 upregulation.

    PubMed

    Huang, Xiaoqin; He, Dan; Ming, Jia; He, Yubin; Zhou, Champion; Ren, Hui; He, Xin; Wang, Chenguang; Jin, Jingru; Ji, Liang; Willard, Belinda; Pan, Bing; Zheng, Lemin

    2016-02-01

    Adhesion of disseminating tumor cells to vascular endothelium is a pivotal starting point in the metastasis cascade. We have shown previously that diabetic high-density lipoprotein (HDL) has the capability of promoting breast cancer metastasis, and this report summarizes our more recent work studying the role of abnormal HDL in facilitating the adhesion of the circulating tumor cells to the endothelium. This is an initiating step in breast cancer metastasis, and this work assesses the role of ICAM-1 and VCAM-1 in this process. MDA-MB-231, MCF 7, and human umbilical vein endothelial cells (HUVECs) were treated with normal HDL from healthy controls (N-HDL), HDL from breast cancer patients (B-HDL), or HDL from breast cancer patients complicated with type 2 diabetes mellitus (BD-HDL), and the cell adhesion abilities were determined. ICAM-1 and VCAM-1 expression as well as the protein kinase C (PKC) activity were evaluated. The effect of PKC inhibitor and PKC siRNA on adhesion was also studied. The immunohistochemical staining of ICAM-1, VCAM-1, and E-selectin from breast cancer patients and breast cancer patients complicated with type 2 diabetes mellitus (T2DM) were examined. Our results indicate that BD-HDL promoted an increase in breast cancer cell adhesion to HUVECs and stimulated higher ICAM-1 and VCAM-1 expression on the cells surface of both breast cancer and HUVEC cells, along with the activation of PKC. Increased tumor cell (TC)-HUVEC adhesion, as well as ICAM-1 and VCAM-1 expression induced by BD-HDL, could be inhibited by staurosporine and PKC siRNA. In addition, a Db/db type 2 diabetes mouse model has more TC-Vascular Endothelium adhesion compared to a normal model. However, BD patients have a lower expression of ICAM-1, VCAM-1, and E-selectin in their tumor tissues. BD-HDL facilitates the adhesion of tumor cells to vascular endothelium by upregulating the expression of ICAM-1 and VCAM-1, thereby promoting the initial progression of breast cancer metastasis

  16. Plasma concentrations of sVCAM-1 and severity of dengue infections.

    PubMed

    Murgue, B; Cassar, O; Deparis, X

    2001-09-01

    Adhesion molecules are essential for the immune response. They are involved in the regulation of cell-to-cell contact, thereby enabling leukocytes to communicate. Circulating forms of adhesion molecules are found in the serum of healthy individuals. Raised levels have been associated with disease severity in HCV and other infections and thus appear to be good markers of endothelial damage. The levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and of sP and sL-selectin in the plasma of children hospitalised for dengue in French Polynesia were monitored. Studies from the 1996/1997 dengue-2 outbreak, showed that levels of sVCAM-1 increase steadily during the febrile period, peak on day 7, and then decline relatively rapidly. Disregarding the time frame within the febrile period, sVCAM-1 levels were always higher compared to controls. There was a significant association between sVCAM-1 levels and dengue haemorrhagic fever, a severe manifestation of dengue virus infection characterised by plasma leakage. No association was apparent between sVCAM-1 levels and primary vs. secondary dengue virus infections. Levels of sP-selectin and sL-selectin were significantly higher in primary compared with secondary infection but were not different in patients presenting with plasma leakage. Lastly, sVCAM-1 levels were significantly higher in an outbreak of severe disease in 1989/1990 (dengue-3) when compared to a non-severe outbreak in 1988/1989 (dengue-1) and a mild outbreak in 1996/1997 (dengue-2). The results suggested that levels of sVCAM-1 production might prove to be a useful marker in the management of severe dengue.

  17. Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells.

    PubMed Central

    Iademarco, M F; Barks, J L; Dean, D C

    1995-01-01

    Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and alpha 4 integrins on leukocytes is thought to mediate the selective recruitment of eosinophils and lymphocytes that occurs in allergic diseases. IL-4 is associated with allergic conditions, and it has been shown to selectively increase expression of VCAM-1 on endothelial cells in vivo, suggesting that it could be responsible for VCAM-1 expression in allergic disease. Using a combination of immunofluorescence, flow cytometry, and Northern analysis, we compared the effect of TNF-alpha and IL-4 on VCAM-1 expression. TNF-alpha is also associated with allergic diseases, and it rapidly increases transcription of the VCAM-1 gene. The effect of IL-4 was relatively modest with prolonged kinetics: VCAM-1 was not detected until 72 h after treatment with IL-4. However, when TNF-alpha and IL-4 were combined, there was a synergistic increase in VCAM-1 expression and a dramatic prolongation of the appearance of VCAM-1 on the cell surface. This synergy results from a combination of transcriptional activation by TNF-alpha and the stabilization of resulting transcripts by IL-4. We propose that IL-4 allows subthreshold concentrations of TNF-alpha (concentrations that would not normally activate expression of adhesion molecules on the endothelium) to selectively increase VCAM-1 expression and to prolong its appearance on the surface of cells in allergic disease. Images PMID:7529260

  18. VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice.

    PubMed

    Ferjančič, Špela; Gil-Bernabé, Ana M; Hill, Sally A; Allen, Philip D; Richardson, Peter; Sparey, Tim; Savory, Edward; McGuffog, Jane; Muschel, Ruth J

    2013-04-18

    Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis.

  19. Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene

    SciTech Connect

    Cybulsky, M.I.; Fries, J.W.U.; Williams, A.J.; Sultan, P.; Gimbrone, M.A. Jr.; Collins, T. ); Eddy, R.; Byers, M.; Shows, T. )

    1991-09-01

    Vascular cell adhesion molecule 1 (VCAM-1) is a cell surface glycoprotein adhesive for certain blood leukocytes and tumor cells, which is expressed by activated endothelium in a variety of pathologic conditions including atherosclerosis. Genomic clones encoding the VCAM1 gene were isolated and the organization of the gene was determined. The gene, which is present in a single copy in the human genome, contains 9 exons spanning {approx}25 kilobases of DNA. Exons 2-8 contain C2 or H-type immunoglobulin domains. At least two different VCAM-1 precursors can be generated from the human gene as a result of alternative mRNA splicing events, which include or exclude exon 5. A consensus TATAA element is located upstream of the transcriptional start site. The VCAM1 promoter contains consensus binding sites for NF-{kappa}B, the GATA family of transcription factors, as well as an AP1 site. The VCAM1 gene was assigned to the 1p31-32 region of chromosome 1 based on the analysis of human-mouse hybrid cell lines and in situ hybridization. Structural analysis of the human VCAM1 gene provides the basis for alternative mRNA splicing and an initial approach to elucidating the regulation of VCAM-1 expression.

  20. Serum levels of thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the acute phase of Plasmodium vivax malaria.

    PubMed

    Ohnishi, K

    1999-02-01

    Elevated plasma or serum levels of thrombomodulin (TM), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin have been reported in several diseases. However, plasma or serum levels of TM, ICAM-1, VCAM-1, and E-selectin have not been investigated in the acute phase of Plasmodium vivax malaria. Serum TM, ICAM-1, VCAM-1, E-selectin, and creatinine levels were determined in six Japanese patients in the acute phase of vivax malaria and in seven healthy Japanese controls. Parasitemias of the peripheral blood were < 0.1% in five patients and 0.8% in one patient. The patients' mean +/- SD serum levels of TM, ICAM-1, VCAM-1, and E-selectin were 5.7 +/- 1.3 Fujirebio units/ml, 709 +/- 397 ng/ml, 2,112 +/- 782 ng/ml, and 99 +/- 28 ng/ml, respectively, and all were significantly greater than those in the controls (TM; P < 0.005, ICAM-1; P < 0.025, VCAM-1; P < 0.005, E-selectin; P < 0.025). However, no significant difference was identified between patients and controls for serum creatinine values. The serum levels of TM and VCAM-1 were not related to parasitemia. The elevation of serum TM levels suggests that endothelial cell damage occurs in the acute phase of vivax malaria.

  1. Evaluation of soluble cell adhesion molecules in atopic dermatitis.

    PubMed

    Koide, M; Furukawa, F; Tokura, Y; Shirahama, S; Takigawa, M

    1997-02-01

    Recent studies have indicated the importance of cell adhesion molecules (CAMs) between the vascular endothelium and activated leukocytes in various inflammatory skin diseases. Soluble forms of CAMs (sCAMs) have also been detected in sera from such diseases. In order to elucidate the role of the soluble forms in skin inflammation, we determined the serum levels of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in patients with atopic dermatitis (AD). Using an enzyme-linked immunosorbent assay, we quantified sCAMs levels in 21 patients with atopic dermatitis and in 16 healthy controls. In severe AD patients, levels of these three types of sCAMs were markedly elevated. sE-selectin was significantly elevated in severe AD over the levels in mild AD. A positive correlation with individual clinical activity was found for changes in the sE-selectin and sVCAM-1 levels. sE-selectin levels were correlated with the serum IgE levels and the number of eosinophils. The sVCAM-1 level was also significantly correlated with the number of monocytes. Among these three molecules, sE-selectin appeared to be the most sensitive clinical parameter in monitoring the clinical course of AD patients.

  2. siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells.

    PubMed

    Ho, Theodore T; You, Jin-Oh; Auguste, Debra T

    2016-04-01

    Leukocyte recruitment plays a key role in chronic inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, and cancer. Leukocyte rolling and arrest are mediated in part by the temporally-regulated surface expression of vascular cell adhesion molecule-1 (VCAM1) on endothelial cells (ECs). In this paper, we engineered a pH-responsive vehicle comprised of 30 mol% dimethylaminoethyl methacrylate (30D) and 70 mol% hydroxyethyl methacrylate (70H) to encapsulate, protect, and deliver VCAM1 small interfering RNA (siRNA). The ability of siRNA to reduce VCAM1 gene expression is in direct opposition to its activation by cytokines. At 12 h post-activation, VCAM1 gene knockdown was 90.1 ± 7.5% when delivered via 30D/70H nanoparticles, which was on par with a leading commercial transfection agent. This translated into a 68.8 ± 6.7% reduction in the surface density of VCAM1 on cytokine-activated ECs. The pH-responsive delivery of VCAM1 siRNA efficiently reduced temporal surface protein expression, which may be used to avert leukocyte recruitment.

  3. Polychlorinated biphenyl-induced VCAM-1 expression is attenuated in aortic endothelial cells isolated from caveolin-1 deficient mice

    SciTech Connect

    Han, Sung Gu; Eum, Sung Yong; Toborek, Michal; Smart, Eric; Hennig, Bernhard

    2010-07-15

    Exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of cardiovascular diseases such as atherosclerosis. Vascular cell adhesion molecule-1 (VCAM-1) is a critical mediator for adhesion and uptake of monocytes across the endothelium in the early stages of atherosclerosis development. The upregulation of VCAM-1 by PCBs may be dependent on functional membrane domains called caveolae. Caveolae are particularly abundant in endothelial cell membranes and involved in trafficking and signal transduction. The objective of this study was to investigate the role of caveolae in PCB-induced endothelial cell dysfunction. Primary mouse aortic endothelial cells (MAECs) isolated from caveolin-1-deficient mice and background C57BL/6 mice were treated with coplanar PCBs, such as PCB77 and PCB126. In addition, siRNA gene silencing technique was used to knockdown caveolin-1 in porcine vascular endothelial cells. In MAECs with functional caveolae, VCAM-1 protein levels were increased after exposure to both coplanar PCBs, whereas expression levels of VCAM-1 were not significantly altered in cells deficient of caveolin-1. Furthermore, PCB-induced monocyte adhesion was attenuated in caveolin-1-deficient MAECs. Similarly, siRNA silencing of caveolin-1 in porcine endothelial cells confirmed the caveolin-1-dependent VCAM-1 expression. Treatment of cells with PCB77 and PCB126 resulted in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), and pharmacological inhibition of ERK1/2 diminished the observed PCB-induced increase in monocyte adhesion. These findings suggest that coplanar PCBs induce adhesion molecule expression, such as VCAM-1, in endothelial cells, and that this response is regulated by caveolin-1 and functional caveolae. Our data demonstrate a critical role of functional caveolae in the activation and dysfunction of endothelial cells by coplanar PCBs.

  4. A benzothiophene-carboxamide is a potent inhibitor of IL-1beta induced VCAM-1 gene expression in human endothelial cells.

    PubMed

    Cobb, R R; Felts, K A; McKenzie, T C; Parry, G C; Mackman, N

    1996-03-18

    Vascular endothelial cells respond to cytokines such as IL-1 beta or TNF-alpha by undergoing a number of functional alterations. Among these alterations is the induction of cell surface adhesion molecules, including VCAM-1. In this report, we investigated the effects of a 3-alkoxybenzo[beta]thiophene-2-carboxamide (BZT) on the cytokine induction of VCAM-1 expression and activation of the transcription factor NF-kappa B in human endothelial cells. BZT blocked the IL-1 beta induced cell surface expression of VCAM-1 in human endothelial cells but did not prevent nuclear translocation of NF-kappa B. This study demonstrates that BZT is a potent inhibitor of VCAM-1 expression in human endothelial cells.

  5. Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors

    PubMed Central

    2011-01-01

    Background VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB) that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs) in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA) in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV) infection of brain endothelial cells using in vitro and in vivo approaches. Methods i) in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii) in vivo: CB1 receptor deficient mice (Cnr1-/-) infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. Results Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-), the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor exacerbated

  6. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease.

    PubMed

    Taylor, James G; Tang, Delia C; Savage, Sharon A; Leitman, Susan F; Heller, Seth I; Serjeant, Graham R; Rodgers, Griffin P; Chanock, Stephen J

    2002-12-15

    Stroke is a major cause of morbidity and mortality in sickle cell (SS) disease. Genetic risk factors have been postulated to contribute to this clinical outcome. The human genome project has substantially increased the catalog of variations in genes, many of which could modify the risk for manifestations of disease outcome in a monogenic disease, namely SS. VCAM1 is a cell adhesion molecule postulated to play a critical role in the pathogenesis of SS disease. We identified a total of 33 single nucleotide polymorphisms (SNPs) by sequencing the entire coding region, 2134 bp upstream of the 5' end of the published cDNA, 217 bp downstream of the 3' end of the cDNA, and selected intronic regions of the VCAM1 locus. Allelic frequencies for selected SNPs were determined in a healthy population. We subsequently analyzed 4 nonsynonymous coding, 2 synonymous coding, and 4 common promoter SNPs in a genetic association study of clinically apparent stroke in SS disease conducted in a cohort derived from a single institution in Jamaica (51 symptomatic cases and 51 matched controls). Of the 10 candidate SNPs analyzed in this pilot study, the variant allele of the nonsynonymous SNP, VCAM1 G1238C, may be associated with protection from stroke (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.83, P =.04). Further study is required to confirm the importance of this variant in VCAM1 as a clinically useful modifier of outcome in SS disease. PMID:12393616

  7. VCAM-1 directed target-sensitive liposomes carrying CCR2 antagonists bind to activated endothelium and reduce adhesion and transmigration of monocytes.

    PubMed

    Calin, Manuela; Stan, Daniela; Schlesinger, Martin; Simion, Viorel; Deleanu, Mariana; Constantinescu, Cristina Ana; Gan, Ana-Maria; Pirvulescu, Monica Madalina; Butoi, Elena; Manduteanu, Ileana; Bota, Marian; Enachescu, Marius; Borsig, Lubor; Bendas, Gerd; Simionescu, Maya

    2015-01-01

    Chemokines are critically involved in the development of chronic inflammatory-associated diseases such as atherosclerosis. We hypothesized that targeted delivery of compounds to the surface of activated endothelial cells (EC) interferes with chemokine/receptor interaction and thereby efficiently blocks inflammation. We developed PEGylated target-sensitive liposomes (TSL) encapsulating a CCR2 antagonist (Teijin compound 1) coupled with a specific peptide recognized by endothelial VCAM-1 (Vp-TSL-Tj). TSL were characterized for size (by dynamic light scattering), the amount of peptide coupled at the liposomal surface and Teijin release (by HPLC). We report that Vp-TSL-Tj binds specifically to activated EC in vitro and in situ, release the entrapped Teijin and prevent the transmigration of monocytes through activated EC. This is the first evidence that nanocarriers which transport and release chemokine inhibitors at specific pathological sites can reduce chemokine-dependent inflammatory processes.

  8. Elevated vascular cell adhesion molecule-1 in AIDS encephalitis induced by simian immunodeficiency virus.

    PubMed Central

    Sasseville, V. G.; Newman, W. A.; Lackner, A. A.; Smith, M. O.; Lausen, N. C.; Beall, D.; Ringler, D. J.

    1992-01-01

    AIDS encephalitis is a common sequela to HIV-1 infection in humans and simian immunodeficiency virus (SIVmac) infection in macaques. Although lentiviral-infected macrophages comprise parenchymal inflammatory infiltrates in affected brain tissue, the mechanisms responsible for leukocyte trafficking to the central nervous system in AIDS are unknown. In this study, we investigated the expression of various endothelial-derived leukocyte adhesion proteins in SIVmac-induced AIDS encephalitis. Encephalitic brains from SIVmac-infected macaques, but not uninflamed brains from other SIVmac-infected animals, were found to express abundant vascular cell adhesion molecule-1 (VCAM-1) protein on the majority of arteriolar, venular, and capillary endothelial cells. Soluble VCAM-1 concentrations in cerebrospinal fluid (CSF) from encephalitic animals were increased approximately 20-fold above those from animals without AIDS encephalitis. Expression of other endothelial-related adhesion molecules, including E-selectin, P-selectin, and intercellular adhesion molecule-1 (ICAM-1), was not uniformly associated with AIDS encephalitis. Thus, the presence of VCAM-1 in both brain and CSF was uniformly associated with SIVmac-induced disease of the central nervous system, and this expression may, at least in part, influence monocyte and lymphocyte recruitment to the central nervous system during the development of AIDS encephalitis. Moreover, measurement of soluble VCAM-1 in CSF may assist in the clinical assessment of animals or people with AIDS. Images Figure 1 PMID:1279978

  9. Cytokine and adhesion molecule expression evolves between the neutrophilic and lymphocytic phases of viral meningitis.

    PubMed

    Makis, Alexandros; Shipway, David; Hatzimichael, Eleftheria; Galanakis, Emmanouil; Pshezhetskiy, Dmitry; Chaliasos, Nikolaos; Stebbing, Justin; Siamopoulou, Antigone

    2010-09-01

    Viral meningitis is characterized by cerebrospinal fluid (CSF) lymphocyte pleocytosis, although neutrophils may predominate in the early phase. The T helper 1 (Th1)/Th2 cytokine balance and expression of adhesion molecules seem to be involved in the CSF chemotaxis. We aimed to determine expression of cytokines and adhesion molecules in enteroviral meningitis. We investigated the serum and CSF levels of adhesion molecules (E-selectin, L-selectin, vascular cell adhesion molecule-1 [VCAM-1], and intracellular adhesion molecule-1 [ICAM-1]) and cytokines (interleukin-12 [IL-12] and IL-4) in 105 children during an outbreak of enteroviral meningitis. Diagnosis was confirmed with positive polymerase chain reaction (PCR) and/or serology for echovirus or Coxsackie virus, and matched with control subjects for clinical features but with negative PCR and/or serology. Apart from VCAM-1, the CSF levels of all investigated inflammatory molecules were significantly increased. In serum, sL-selectin and ICAM-1 levels were significantly higher than control subjects. Serum and CSF L-selectin, serum VCAM-1, and CSF IL-12 were all observed to be expressed in significantly higher levels in the neutrophil-dominant subgroup (72% had duration of symptoms <24 h) than in the lymphocyte-dominant group (87.5% had duration of symptoms >24 h). Serum and CSF ICAM-1 was found at significantly higher levels in the latter group. Evolving expression of adhesion molecules and cytokines indicates a shift from Th1 to Th2 immune responses as infection progresses.

  10. Enhanced Biosensor Platforms for Detecting the Atherosclerotic Biomarker VCAM1 Based on Bioconjugation with Uniformly Oriented VCAM1-Targeting Nanobodies

    PubMed Central

    Ta, Duy Tien; Guedens, Wanda; Vranken, Tom; Vanschoenbeek, Katrijn; Steen Redeker, Erik; Michiels, Luc; Adriaensens, Peter

    2016-01-01

    Surface bioconjugation of biomolecules has gained enormous attention for developing advanced biomaterials including biosensors. While conventional immobilization (by physisorption or covalent couplings using the functional groups of the endogenous amino acids) usually results in surfaces with low activity, reproducibility and reusability, the application of methods that allow for a covalent and uniformly oriented coupling can circumvent these limitations. In this study, the nanobody targeting Vascular Cell Adhesion Molecule-1 (NbVCAM1), an atherosclerotic biomarker, is engineered with a C-terminal alkyne function via Expressed Protein Ligation (EPL). Conjugation of this nanobody to azidified silicon wafers and Biacore™ C1 sensor chips is achieved via Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” chemistry to detect VCAM1 binding via ellipsometry and surface plasmon resonance (SPR), respectively. The resulting surfaces, covered with uniformly oriented nanobodies, clearly show an increased antigen binding affinity, sensitivity, detection limit, quantitation limit and reusability as compared to surfaces prepared by random conjugation. These findings demonstrate the added value of a combined EPL and CuAAC approach as it results in strong control over the surface orientation of the nanobodies and an improved detecting power of their targets—a must for the development of advanced miniaturized, multi-biomarker biosensor platforms. PMID:27399790

  11. Concentration of soluble adhesion molecules in cerebrospinal fluid and serum of epilepsy patients.

    PubMed

    Luo, Jing; Wang, Wei; Xi, Zhiqin; Dan, Chen; Wang, Liang; Xiao, Zheng; Wang, Xuefeng

    2014-12-01

    Mounting evidence supports the involvement of brain inflammation and the associated blood-brain barrier damage from which spontaneous and recurrent seizures originate. Detection of the soluble form of adhesion molecules (AM) has also been proven to predict outcomes in central nervous system (CNS) disorders. A recent study has shown that expression of AM in brain vessels was upregulated 24 h after kainic acid (KA) induced seizures. The aim of the present study was to investigate soluble AM levels in the cerebrospinal fluid (CSF) and serum of epilepsy patients. Paired CSF and serum samples were analyzed by sandwich enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Increased serum concentrations of sICAM-1 were present in epileptic patients (41 localization-related of unknown etiology, 19 idiopathic generalized). Serum sICAM-1 level in drug-refractory epilepsy was elevated as compared to new diagnosis epilepsy and drug-responsive epilepsy. CSF sVCAM-1 and serum sVCAM-1 concentrations in the epilepsy group were higher as compared to the neurosis group. Moreover, CSF sVCAM-1 and serum sVCAM-1 concentrations in drug-refractory epilepsy were raised as compared to drug-responsive epilepsy and new diagnosis epilepsy. However, there were no significant differences in concentrations of CSF sICAM-1 between the epilepsy and neurosis groups. Our results suggest that sVCAM-1 and sICAM-1 could play an important role in the drug-refractory epilepsy. PMID:25001004

  12. Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion.

    PubMed

    Abe, Y; El-Masri, B; Kimball, K T; Pownall, H; Reilly, C F; Osmundsen, K; Smith, C W; Ballantyne, C M

    1998-05-01

    Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316+/-28.8 versus 225+/-16.6 ng/mL), sVCAM-1 (743+/-52.2 versus 522+/-43.6 ng/mL), and soluble E-selectin (83+/-5.9 versus 49+/-3.6 ng/mL). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for > or =7 months, triglyceride level was reduced by 47+/-4.6%, sICAM-1 level was reduced by 9+/-3.4% (P=.02), and soluble E-selectin level was reduced by 16+/-3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5+/-7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.

  13. [Endothelial cell adhesion molecules].

    PubMed

    Ivanov, A N; Norkin, I A; Puchin'ian, D M; Shirokov, V Iu; Zhdanova, O Iu

    2014-01-01

    The review presents current data concerning the functional role of endothelial cell adhesion molecules belonging to different structural families: integrins, selectins, cadherins, and the immunoglobulin super-family. In this manuscript the regulatory mechanisms and factors of adhesion molecules expression and distribution on the surface of endothelial cells are discussed. The data presented reveal the importance of adhesion molecules in the regulation of structural and functional state of endothelial cells in normal conditions and in pathology. Particular attention is paid to the importance of these molecules in the processes of physiological and pathological angiogenesis, regulation of permeability of the endothelial barrier and cell transmigration.

  14. Lobaric Acid Inhibits VCAM-1 Expression in TNF-α-Stimulated Vascular Smooth Muscle Cells via Modulation of NF-κB and MAPK Signaling Pathways

    PubMed Central

    Kwon, Ii-Seul; Yim, Joung-Han; Lee, Hong-Kum; Pyo, Suhkneung

    2016-01-01

    Lichens have been known to possess multiple biological activities, including anti-proliferative and anti-inflammatory activities. Vascular cell adhesion molecule-1 (VCAM-1) may play a role in the development of atherosclerosis. Hence, VCAM-1 is a possible therapeutic target in the treatment of the inflammatory disease. However, the effect of lobaric acid on VCAM-1 has not yet been investigated and characterized. For this study, we examined the effect of lobaric acid on the inhibition of VCAM-1 in tumor necrosis factor-alpha (TNF-α)-stimulated mouse vascular smooth muscle cells. Western blot and ELISA showed that the increased expression of VCAM-1 by TNF-α was significantly suppressed by the pre-treatment of lobaric acid (0.1–10 μg/ml) for 2 h. Lobaric acid abrogated TNF-α-induced NF-κB activity through preventing the degradation of IκB and phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 mitogen activated protein (MAP) kinase. Lobaric acid also inhibited the expression of TNF-α receptor 1 (TNF-R1). Overall, our results suggest that lobaric acid inhibited VCAM-1 expression through the inhibition of p38, ERK, JNK and NF-κB signaling pathways, and downregulation of TNF-R1 expression. Therefore, it is implicated that lobaric acid may suppress inflammation by altering the physiology of the atherosclerotic lesion. PMID:26759698

  15. Aortic VCAM-1: an early marker of vascular inflammation in collagen-induced arthritis.

    PubMed

    Denys, Anne; Clavel, Gaëlle; Lemeiter, Delphine; Schischmanoff, Olivier; Boissier, Marie-Christophe; Semerano, Luca

    2016-05-01

    Cardiovascular disease (CVD) is a major cause of morbidity and mortality in rheumatoid arthritis (RA). There are limited experimental data on vascular involvement in arthritis models. To study the link between CVD and inflammation in RA, we developed a model of vascular dysfunction and articular inflammation by collagen-induced arthritis (CIA) in C57Bl/6 (B6) mice. We studied the expression of vascular inflammatory markers in CIA with and without concomitant hyperlipidic diet (HD). Collagen-induced arthritis was induced with intradermal injection of chicken type-II collagen followed by a boost 21 days later. Mice with and without CIA were fed a standard diet or an HD for 12 weeks starting from the day of the boost. Arthritis severity was evaluated with a validated clinical score. Aortic mRNA levels of vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS) and interleukin-17 were analysed by quantitative RT-PCR. Vascular cell adhesion molecule-1 localization in the aortic sinus was determined by immunohistochemistry. Atherosclerotic plaque presence was assessed in aortas. Collagen-induced arthritis was associated with increased expression of VCAM-1, independent of diet. VCAM-1 overexpression was detectable as early as 4 weeks after collagen immunization and persisted after 15 weeks. The HD induced atheroma plaque formation and aortic iNOS expression regardless of CIA. Concomitant CIA and HD had no additive effect on atheroma or VCAM-1 or iNOS expression. CIA and an HD diet induced a distinct and independent expression of large-vessel inflammation markers in B6 mice. This model may be relevant for the study of CVD in RA. PMID:26859834

  16. Soluble Adhesion Molecules in Patients Coinfected with HIV and HCV: A Predictor of Outcome

    PubMed Central

    Aldámiz-Echevarría, Teresa; Berenguer, Juan; Miralles, Pilar; Jiménez-Sousa, María A.; Carrero, Ana; Pineda-Tenor, Daniel; Díez, Cristina; Tejerina, Francisco; Pérez-Latorre, Leire; Bellón, José M.; Resino, Salvador

    2016-01-01

    Background Higher serum levels of adhesion molecules (sICAM-1 and sVCAM-1) are associated with advanced liver fibrosis in patients coinfected with human immunodeficiency virus and hepatitis C virus. We assessed the relationship between serum levels of adhesion molecules and liver-related events (LRE) or death, in coinfected patients. Methods We studied clinical characteristics and outcomes of 182 coinfected patients with a baseline liver biopsy (58 with advanced fibrosis) and simultaneous plasma samples who were followed for median of 9 years. We used receiver-operating characteristic (ROC) curves to calculate optimized cutoff values (OCV) of sICAM-1 and sVCAM-1, defined as the values with the highest combination of sensitivity and specificity for LRE. We used multivariate regression analysis to test the association between OCVs of sICAM-1 and sVCAM-1 and outcomes. The variables for adjustment were age, HIV transmission category, liver fibrosis, baseline CD4+ T-cell counts, antiretroviral therapy, and sustained virologic response (SVR). Results During the study period 51 patients had SVR, 19 had LRE, and 16 died. The OCVs for LRE were 5.68 Log pg/mL for sICAM-1 and 6.25 Log pg/mL for sVCAM-1, respectively. The adjusted subhazard ratio (aSHR) (95% confidence interval [CI]) of death or LRE, whichever occurred first, for sICAM-1 and sVCAM-1 > OCV were 3.98 ([1.14; 13.89], P = 0.030) and 2.81 ([1.10; 7.19], respectively (P = 0.030). Conclusions Serum levels of sICAM-1 and sVCAM-1 can serve as markers of outcome in HIV/HCV-coinfected patients. Therapies targeting necroinflammatory damage and fibrogenesis may have a role in the management chronic hepatitis C. PMID:26849641

  17. Air Pollution, Obesity, Genes, and Cellular Adhesion Molecules

    PubMed Central

    Madrigano, Jaime; Baccarelli, Andrea; Wright, Robert O.; Suh, Helen; Sparrow, David; Vokonas, Pantel S.; Schwartz, Joel

    2011-01-01

    Objectives Particulate matter (PM) has been associated with acute cardiovascular outcomes, but our understanding of the mechanism is incomplete. We examined the association between PM and cell adhesion molecules. We also investigated the modifying effect of genotype and phenotype variation to gain insight into the relevant biological pathways for this association. Methods We used mixed regression models to examine the association of PM2.5 and black carbon (BC) with serum concentrations of soluble Intercellular Adhesion Molecule (sICAM-1) and soluble Vascular Cell Adhesion Molecule (sVCAM-1), markers of endothelial function and inflammation, in a longitudinal study of 809 participants in the Normative Aging Study (1819 total observations). We also examined whether this association was modified by genotype, obesity, or diabetes status. Genes selected for analyses were either related to oxidative stress, endothelial function, lipid metabolism or metal processing. Results BC during the 2 days prior to blood draw was significantly associated with increased sVCAM-1 (4.5% increase per 1μg/m3 95% CI 1.1, 8.0). Neither pollutant was associated with sICAM-1. Larger effects of BCon sVCAM were seen in subjects with obesity (p=0.007) and who were GSTM1 null (p=0.02). Conclusions BC is associated with markers of endothelial function and inflammation. Genes related to oxidative defense may modify this association. PMID:19884647

  18. Adhesion molecule expression in Graves' thyroid glands; potential relevance of granule membrane protein (GMP-140) and intercellular adhesion molecule-1 (ICAM-1) in the homing and antigen presentation processes.

    PubMed Central

    Miyazaki, A; Mirakian, R; Bottazzo, G F

    1992-01-01

    To assess the potential role of adhesion molecules in the pathogenesis of Graves' disease, we examined the expression of several of these adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1) and granule membrane protein-140 (GMP-140), in sections of Graves' thyroid glands and control thyroids, using immunohistochemical techniques. Up-regulated expression of GMP-140 was frequently observed on endothelial cells (EC) of post-capilliary venules in all Graves' thyroids examined, compared with an occasional weak staining on EC control glands. Some capillary EC around thyroid follicles (perifollicular EC) were strongly positive for GMP-140 in the Graves' thyroids in contrast to a negative staining on the same structures in the control glands. In addition, there was a correlation between the reactivity and frequency of GMP-140 expression on EC and the severity of mononuclear cell (MNC) infiltration in the Graves' thyroids. The expression of ICAM-1 was up-regulated on perifollicular EC and EC of small venules in some thyroids of both Graves' and control groups. Conversely, no significant expression was observed on any type of EC for both endothelial-leucocyte adhesion molecule-1 (ELAM-1) and VCAM-1. However, dendritic-like cells, present within lymphocytic infiltrates, were positive for VCAM-1 in most of the Graves' thyroids examined, especially in those with a severe lymphocytic infiltration. Thyrocytes were constantly negative for the expression of all four adhesion molecules investigated. These data suggest that GMP-140, as well as ICAM-1, could play an important role in the initiation of MNC infiltration in Graves' disease. ELAM-1 and VCAM-1 appear not to be relevant for the migration of MNC from the blood vessels into the target gland, although VCAM-1 expression on dendritic-like cells might play an additively tissue-selective role in autoantigen presentation and subsequent elicitation of autoimmune

  19. Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β.

    PubMed

    Verginelli, Federica; Adesso, Laura; Limon, Isabelle; Alisi, Anna; Gueguen, Marie; Panera, Nadia; Giorda, Ezio; Raimondi, Lavinia; Ciarapica, Roberta; Campese, Antonio F; Screpanti, Isabella; Stifani, Stefano; Kitajewski, Jan; Miele, Lucio; Rota, Rossella; Locatelli, Franco

    2015-12-22

    The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.

  20. Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β.

    PubMed

    Verginelli, Federica; Adesso, Laura; Limon, Isabelle; Alisi, Anna; Gueguen, Marie; Panera, Nadia; Giorda, Ezio; Raimondi, Lavinia; Ciarapica, Roberta; Campese, Antonio F; Screpanti, Isabella; Stifani, Stefano; Kitajewski, Jan; Miele, Lucio; Rota, Rossella; Locatelli, Franco

    2015-12-22

    The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium. PMID:26646450

  1. Osteoblast-derived WNT-induced secreted protein 1 increases VCAM-1 expression and enhances prostate cancer metastasis by down-regulating miR-126.

    PubMed

    Tai, Huai-Ching; Chang, An-Chen; Yu, Hong-Jeng; Huang, Chao-Yuan; Tsai, Yu-Chieh; Lai, Yu-Wei; Sun, Hui-Lung; Tang, Chih-Hsin; Wang, Shih-Wei

    2014-09-15

    Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-1-induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular adhesion molecule-1 (VCAM)-1 expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP-1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast-derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1-enhanced migration and VCAM-1 expression. This study suggests that osteoblast-derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via αvβ1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis.

  2. Osteoblast-derived WISP-1 increases VCAM-1 expression and enhances prostate cancer metastasis by down-regulating miR-126

    PubMed Central

    Tai, Huai-Ching; Chang, An-Chen; Yu, Hong-Jeng; Huang, Chao-Yuan; Tsai, Yu-Chieh; Lai, Yu-Wei; Sun, Hui-Lung; Tang, Chih-Hsin; Wang, Shih-Wei

    2014-01-01

    Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-induced secreted protein-1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular cell adhesion molecule-1 (VCAM-1) expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP-1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast-derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1-enhanced migration and VCAM-1 expression. This study suggests that osteoblast-derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via αvβ1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis. PMID:25277191

  3. Glycosylated VCAM-1 isoforms revealed in 2D western blots of HUVECs treated with tumoral soluble factors of breast cancer cells

    PubMed Central

    2009-01-01

    Background Several common aspects of endothelial phenotype, such as the expression of cell adhesion molecules, are shared between metastasis and inflammation. Here, we analyzed VCAM-1 variants as biological markers of these two types of endothelial cell activation. With the combination of 2-DE and western blot techniques and the aid of tunicamycin, we analyzed N-glycosylation variants of VCAM-1 in primary human endothelial cells stimulated with either TNF or tumoral soluble factors (TSF's) derived from the human breast cancer cell line ZR75.30. Results Treatments induced a pro-adhesive endothelial phenotype. 2D western blots analysis of cells subjected to both treatments revealed the expression of the two known VCAM-1 isoforms and of previously unknown isoforms. In particular TSFZR75.30 induced an isoform with a relative molecular mass (Mr) and isoelectric point (pI) of 75-77 kDa and 5.0, respectively. Conclusion The unknown isoforms of VCAM-1 that were found to be overexpressed after treatment with TSF's compared with TNF, could serve as biomarkers to discriminate between inflammation and metastasis. 2D western blots revealed three new VCAM-1 isoforms expressed in primary human endothelial cells in response to TSF stimulation. Each of these isoforms varies in Mr and pI and could be the result of differential glycosylation states. PMID:19930605

  4. Soluble form of ICAM-1, VCAM-1, E- and L-selectin in human milk.

    PubMed Central

    Xyni, K; Rizos, D; Giannaki, G; Sarandakou, A; Phocas, I; Creatsas, G

    2000-01-01

    In breast milk and paired serum from 70 lactating women and 40 of their term, infection-free neonates, on the 2nd and 5th day postpartum slCAM-1, sVCAM-1, sE- and sL-selectin were measured by ELISA and compared with those in 26 healthy adults (controls). Seven infant formulas and fresh milk from five cows were also analyzed. Human colostrum values of slCAM-1, sVCAM-1 (similar to those in maternal and control serum), sE-selectin and sL-selectin (-10 and -100 times lower than in maternal and control serum) were significantly higher than those in milk, while they varied widely. None of the adhesion molecules was detected in fresh cow's milk or infant formulas. Exclusively breast-fed infants showed significantly higher values of slCAM-1 and sL-selectin on the 2nd day of life than those supplemented also with formula. Only slCAM-1 values correlated positively between colostrum and time-matched maternal serum. These findings show in human milk important amounts of slCAM-1 and sVCAM-1 but minimal amounts of sE- and sL-selectin, which could affect the immune system of the neonate. PMID:11132769

  5. Artemether Combined with shRNA Interference of Vascular Cell Adhesion Molecule-1 Significantly Inhibited the Malignant Biological Behavior of Human Glioma Cells

    PubMed Central

    Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

    2013-01-01

    Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

  6. Correlation between the levels of circulating adhesion molecules and atherosclerosis in type-2 diabetic normotensive patients

    PubMed Central

    Vargas-Robles, Hilda; Serrano, Alberto Maceda; Lozano-Nuevo, Jose Juan; Escalante-Acosta, Bruno Alfonso

    2009-01-01

    Endothelial dysfunction is a common feature in type-2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules and atherosclerosis. The aim of this study was to evaluate the relationship between the levels of circulating soluble adhesion molecules and the degree of atherosclerosis in normotensive type-2 diabetic patients. Results: We found significant correlations between ICAM-1 (r = 0.69, p < 0.001 95% IC 0.65 to 0.82) and VCAM-1 (r = 0.4, p < 0.03, 95% IC 0.65 to 0.82) levels and maximal carotid artery intimal-medial thickness, whereas no correlation was observed with E-selectin. Methods: We studied 30 normotensive type-2 diabetic patients in whom VCAM-1, ICAM-1 and E-selectin were measured by ELISA. Additionally, the intimal-medial thickness of both the common and internal carotid arteries was measured (B-mode ultrasound). The levels of circulating adhesion molecules and maximal carotid artery intimal-medial thicknesses were correlated using the Spearman correlation coefficient test. Statistical analysis was performed with ANOVA. Conclusion: Our results suggest that ICAM-1 and VCAM-1 are markers associated, and correlated with the degree of atherosclerosis in normotensive type-2 diabetic patients. PMID:19717975

  7. Omentin inhibits TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via ERK/NF-{kappa}B pathway

    SciTech Connect

    Zhong, Xia; Li, Xiaonan; Liu, Fuli; Tan, Hui; Shang, Deya

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Omentin inhibited TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Black-Right-Pointing-Pointer Omentin reduces expression of ICAM-1 and VCAM-1 induced by TNF-{alpha} in HUVECs. Black-Right-Pointing-Pointer Omentin inhibits TNF-{alpha}-induced ERK and NF-{kappa}B activation in HUVECs. Black-Right-Pointing-Pointer Omentin supreeses TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 via ERK/NF-{kappa}B pathway. -- Abstract: In the present study, we investigated whether omentin affected the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-{alpha} (TNF-{alpha}) induced human umbilical vein endothelial cells (HUVECs). Our data showed that omentin decreased TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 in HUVECs. In addition, omentin inhibited TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Further, we found that omentin inhibited TNF-{alpha}-activated signal pathway of nuclear factor-{kappa}B (NF-{kappa}B) by preventing NF-{kappa}B inhibitory protein (I{kappa}B{alpha}) degradation and NF-{kappa}B/DNA binding activity. Omentin pretreatment significantly inhibited TNF-{alpha}-induced ERK activity and ERK phosphorylation in HUVECs. Pretreatment with PD98059 suppressed TNF-{alpha}-induced NF-{kappa}B activity. Omentin, NF-kB inhibitor (BAY11-7082) and ERK inhibitor (PD98059) reduced the up-regulation of ICAM-1 and VCAM-1 induced by TNF-{alpha}. These results suggest that omentin may inhibit TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via blocking ERK/NF-{kappa}B pathway.

  8. Role of TLR4/NADPH oxidase/ROS-activated p38 MAPK in VCAM-1 expression induced by lipopolysaccharide in human renal mesangial cells

    PubMed Central

    2012-01-01

    Background In bacteria-induced glomerulonephritis, Toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS, a key component of the outer membranes of Gram-negative bacteria) can increase oxidative stress and the expression of vascular cell adhesion molecule-1 (VCAM-1), which recruits leukocytes to the glomerular mesangium. However, the mechanisms underlying VCAM-1 expression induced by LPS are still unclear in human renal mesangial cells (HRMCs). Results We demonstrated that LPS induced VCAM-1 mRNA and protein levels associated with an increase in the promoter activity of VCAM-1, determined by Western blot, RT-PCR, and promoter assay. LPS-induced responses were inhibited by transfection with siRNAs of TLR4, myeloid differentiation factor 88 (MyD88), Nox2, Nox4, p47phox, c-Src, p38 MAPK, activating transcription factor 2 (ATF2), and p300 or pretreatment with the inhibitors of reactive oxygen species (ROS, edaravone), NADPH oxidase [apocynin (APO) or diphenyleneiodonium chloride (DPI)], c-Src (PP1), p38 MAPK (SB202190), and p300 (GR343). LPS induced NADPH oxidase activation, ROS production, and p47phox translocation from the cytosol to the membrane, which were reduced by PP1 or c-Src siRNA. We observed that LPS induced TLR4, MyD88, c-Src, and p47phox complex formation determined by co-immunoprecipitation and Western blot. We further demonstrated that LPS stimulated ATF2 and p300 phosphorylation and complex formation via a c-Src/NADPH oxidase/ROS/p38 MAPK pathway. Up-regulation of VCAM-1 led to enhancing monocyte adhesion to HRMCs challenged with LPS, which was inhibited by siRNAs of c-Src, p47phox, p38 MAPK, ATF2, and p300 or pretreatment with an anti-VCAM-1 neutralizing antibody. Conclusions In HRMCs, LPS-induced VCAM-1 expression was, at least in part, mediated through a TLR4/MyD88/ c-Src/NADPH oxidase/ROS/p38 MAPK-dependent p300 and ATF2 pathway associated with recruitment of monocyte adhesion to kidney. Blockade of these pathways may reduce monocyte

  9. Homocysteine, circulating vascular cell adhesion molecule and carotid atherosclerosis in postmenopausal vegetarian women and omnivores.

    PubMed

    Su, Ta-Chen; Jeng, Jiann-Shing; Wang, Jung-Der; Torng, Pao-Ling; Chang, Sue-Joan; Chen, Chen-Fang; Liau, Chiau-Suong

    2006-02-01

    Since the adoption of vegetarian diets as a healthy lifestyle has become popular, the cardiovascular effects of long-term vegetarianism need to be explored. The present study aimed to compare the presence and severity of carotid atherosclerosis (CA), and the blood levels of Vitamin B12, homocysteine (Hcy) and soluble vascular cell adhesion molecule-1 (sVCAM-1) between 57 healthy postmenopausal vegetarians and 61 age-matched omnivores. Carotid atherosclerosis, as measured by ultrasound, was found to be of no significant difference between the two groups. Yet, fasting blood glucose, low-density lipoprotein cholesterol, and Vitamin B12 were significantly lower, while Hcy and sVCAM-1 were higher in the vegetarians as comparing with the omnivores. Multivariate regression analysis showed that the level of Vitamin B12 was negatively associated with the level of Hcy. Vegetarianism itself and Hcy level were significantly associated with sVCAM-1 level in univariate analysis; however, after adjustment for covariates, we identified age but not vegetarianism as the determinant of sVCAM-1 level. Multiple linear regression analysis identified age and systolic blood pressure, but not vegetarianism, as determinants of common carotid artery IMT. In conclusion, there was no significant difference in CA between apparently healthy postmenopausal vegetarians and omnivores. The findings of elevated Hcy in vegetarians indicate the importance of prevention of Vitamin B12 deficiency.

  10. Bilirubin acts as an endogenous regulator of inflammation by disrupting adhesion molecule-mediated leukocyte migration

    PubMed Central

    Vogel, Megan E.; Zucker, Stephen D.

    2016-01-01

    There is a growing body of evidence that bilirubin, which is generated during the physiological breakdown of heme, exerts potent anti-inflammatory effects. Previous work by our group suggests that bilirubin is able to suppress inflammatory responses by preventing the migration of leukocytes into target tissues through disruption of vascular cell adhesion molecule-1 (VCAM-1)-dependent cell signaling. As VCAM-1 is an important mediator of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. As anticipated, bilirubin-treated animals manifested significantly less colonic injury and reduced infiltration of inflammatory cells into colon tissues. We further observed that bilirubin administration was associated with a reduced number of eosinophils and monocytes in the small intestine, with a corresponding increase in peripheral blood eosinophilia, regardless of whether mice received DSS. These findings suggest that bilirubin impairs the normal migration of eosinophils into intestinal tissues, as supported by in vitro experiments showing that bilirubin blocks the VCAM-1-dependent movement of Jurkat cells across human endothelial cell monolayers. Taken together, our findings support that bilirubin ameliorates DSS-induced colitis and disrupts the physiological trafficking of leukocytes to the intestine by preventing transmigration across the vascular endothelium, potentially through the inhibition VCAM-1-mediated signaling. Our findings raise the possibility that bilirubin functions as an endogenous regulator of inflammatory responses. PMID:26925435

  11. Effect of palmitic acid and linoleic acid on expression of ICAM-1 and VCAM-1 in human bone marrow endothelial cells (HBMECs)

    PubMed Central

    Sanadgol, Nima; Mansouri, Kamran; Bahrami, Gholamreza

    2012-01-01

    Introduction The amount and type of fatty acids (FAs) in the diet influence the risk of atherosclerosis. Palmitic acid and linoleic acid exist at high levels in Iranian edible oils. In this study, we investigated the effect of palmitic acid and linoleic acid on expression of soluble and cell-associated forms of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human bone marrow endothelial cells (HBMECs). Material and methods The endothelial cells were induced with bacterial lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α), and thereafter incubated with palmitic or linoleic acid. The level of soluble and cell-associated VCAM-1 and ICAM-1 were analyzed using ELISA and western blot. Results Our findings indicated that palmitic acid up-regulates the expression of ICAM-1 and VCAM-1 in HBMECs when these cells are induced with TNF-α or LPS. In addition, the results suggest that linoleic acid could sustain up-regulated ICAM-1 and VCAM-1 in activated endothelial cells. Conclusions Chronic activation of endothelial cells in the presence of palmitic and linoleic may account for pathogenesis of cardiovascular events. These findings provide further support for the detrimental effects of these fatty acids, especially palmitic acid, in promotion and induction of cardiovascular diseases which are prevalent in the Iranian population. PMID:22661989

  12. Quantitative genetic analysis of cellular adhesion molecules: the Fels Longitudinal Study.

    PubMed

    Lee, Miryoung; Czerwinski, Stefan A; Choh, Audrey C; Demerath, Ellen W; Sun, Shumei S; Chumlea, Wm C; Towne, Bradford; Siervogel, Roger M

    2006-03-01

    Circulating concentrations of inflammatory markers predict cardiovascular disease (CVD) risk and are closely associated with obesity. However, little is known concerning genetic influences on serum levels of inflammatory markers. In this study, we estimated the heritability (h2) of soluble cellular adhesion molecule (sCAM) concentrations and examined the correlational architecture between different sCAMs. The study population included 234 men and 270 women aged 18-76 years, belonging to 121 families participating in the Fels Longitudinal Study. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sESEL-1) and P-selectin (sPSEL-1) were assayed using commercially available kits. A variance components-based maximum likelihood method was used to estimate the h2 of the different serum inflammatory markers while simultaneously adjusting for the effects of known CVD risk factors, such as age and smoking. Additionally, we used bivariate extensions of these methods to estimate genetic and random environmental correlations among sCAMs. Levels of sCAMs were significantly heritable: h2=0.24+/-0.10 for sICAM-1, h2=0.22+/-0.10 for sVCAM-1, h2=0.50+/-0.11 for sESEL-1, and h2=0.46+/-0.10 for sPSEL-1. In addition, a significant genetic correlation (rho(G)=0.63) was found between sICAM-1 and sVCAM-1 indicating some degree of shared genetic control. In the Fels Longitudinal Study, the levels of four sCAMs are significantly influenced by genetic effects, and sICAM-1 shares a common genetic background with sVCAM-1.

  13. Circulating levels of soluble E-selectin, ICAM-1 and VCAM-1 in bullous pemphigoid during low-dose methotrexate therapy. A prospective study.

    PubMed

    Dahlman-Ghozlan, K; Heilborn, J D; Stephansson, E

    2000-10-01

    Soluble iso-forms of cellular adhesion molecules (sCAMs) have been described and reported to be elevated in various inflammatory diseases. Elevated levels of sE-selectin have recently been detected and found to correlate with the number of blisters in bullous pemphigoid (BP) during oral corticosteroid therapy. In this prospective study we analysed levels of sCAMs in 10 elderly BP patients during low-dose oral pulse methotrexate monotherapy. We used standardised ELISA kits for soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin on 65 sera from 10 patients and 19 controls. Results were correlated with clinical parameters. Before therapy, we found significant elevation of sE-selectin (P=0.004) and sVCAM-1 (P=0.002) but not of sICAM-1. sE-selectin levels decreased during the efficient therapy and correlated with the number of blisters. Our results further support the proposition that sE-selectin might be a future clinical and predictive tool; but whether the elevation of sVCAM-1 also might reflect the disease activity in BP needs more investigation. The findings also indicate that BP might be more a cellularly mediated disease where interactions of different adhesion molecules play a crucial role.

  14. Simple modifications to Methimazole that enhance its inhibitory effect on Tumor Necrosis Factor-α-induced Vascular Cell Adhesion Molecule-1 expression by human endothelial cells

    PubMed Central

    Alapati, Anuja; Deosarkar, Sudhir P.; Lanier, Olivia L.; Qi, Chunyan; Carlson, Grady E.; Burdick, Monica M.; Schwartz, Frank L.; McCall, Kelly D.; Bergmeier, Stephen C.; Goetz, Douglas J.

    2015-01-01

    The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor – α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves’ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24 h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24 h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds. PMID:25641748

  15. Interleukin-12-induced adhesion molecule expression in murine liver.

    PubMed Central

    Myers, K. J.; Eppihimer, M. J.; Hall, L.; Wolitzky, B.

    1998-01-01

    Systemically administered interleukin (IL)-12 causes liver inflammation in mice characterized by Kupffer cell proliferation and hypertrophy, hepatocyte necrosis, and multifocal accumulations of leukocytes in the hepatic parenchyma and around portal tracts and central veins. We have used both immunohistochemical staining and radiolabeled antibody quantitation to examine adhesion molecule expression in the livers of mice dosed daily with murine IL-12. Cells infiltrating livers of IL-12-treated mice were primarily mononuclear leukocytes expressing LFA-1, VLA-4, MAC-1, and CD18 adhesion molecules but little L-selectin. Kupffer cells constitutively expressed LFA-1 and smaller amounts of MAC-1, and high levels of ICAM-1 were constitutively expressed by liver sinusoidal lining cells, portal tract, and central vein endothelia. With IL-12 treatment, existing ICAM-1 expression was up-regulated and de novo expression occurred along bile duct epithelia. VCAM-1 levels were dramatically increased, with induced expression occurring along portal tract and central vein endothelia and scattered bile duct epithelial cells and in aggregations of cells in perivascular areas and the liver parenchyma. Although constitutive expression of E- and P-selectin was negligible, Il-12 induced a moderate rise in E-selectin levels. These increases in adhesion molecule expression may have implications for the therapeutic use of IL-12, especially in patients with liver disease or autoimmune conditions where augmented adhesion molecule expression may be critical to disease pathogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9466572

  16. The P2Y2 nucleotide receptor mediates UTP-induced vascular cell adhesion molecule-1 expression in coronary artery endothelial cells.

    PubMed

    Seye, Cheikh I; Yu, Ningpu; Jain, Renu; Kong, Qiongman; Minor, Tess; Newton, Jessica; Erb, Laurie; González, Fernando A; Weisman, Gary A

    2003-07-01

    P2Y2 receptor up-regulation and activation induces intimal hyperplasia and monocyte/macrophage infiltration in the collared rabbit carotid artery model of vascular injury, suggesting a potential role for P2Y2 receptors in monocyte recruitment by vascular endothelium. In this study, we addressed the hypothesis that activation of P2Y2 receptors by extracellular nucleotides modulates the expression of adhesion molecules on vascular endothelial cells that are important for monocyte recruitment. Results indicated that the equipotent P2Y2 receptor agonists UTP or ATP (1-100 microm) stimulated the expression of vascular cell adhesion molecule-1 (VCAM-1) in human coronary artery endothelial cells (HCAEC) in a time- and dose-dependent manner. P2Y2 antisense oligonucleotides inhibited VCAM-1 expression induced by UTP but not by tumor necrosis factor-alpha. Furthermore, UTP induced VCAM-1 expression in human 1321N1 astrocytoma cell transfectants expressing the recombinant P2Y2 receptor, whereas vector-transfected control cells did not respond to UTP. The effect of UTP on VCAM-1 expression in HCAEC was prevented by depletion of intracellular calcium stores with thapsigargin or by inhibition of p38 mitogen-activated protein kinase or Rho kinase, but was not affected by inhibitors of the mitogen-activated protein/extracellular signal-regulated kinase pathway (i.e. MEK1/2). Consistent with a role for VCAM-1 in the recruitment of monocytes, UTP or ATP increased the adherence of monocytic U937 cells to HCAEC, an effect that was inhibited by anti-VCAM-1 antibodies. These findings suggest a novel role for the P2Y2 receptor in the p38- and Rho kinase-dependent expression of VCAM-1 that mediates the recruitment of monocytes by vascular endothelium associated with the development of atherosclerosis.

  17. ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro.

    PubMed

    Steffen, B J; Breier, G; Butcher, E C; Schulz, M; Engelhardt, B

    1996-06-01

    The expression of cell adhesion molecules (CAMs) in the choroid plexus was studied in normal brain and during experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse during inflammation induced by intracerebral injection of killed Corynebacterium parvum in the C3H/He mouse. Both ICAM-1 and VCAM-1, but not MAdCAM-1, were constitutively expressed on choroid plexus epithelium but not on the fenestrated capillary endothelial cells within the choroid plexus. During EAE, we observed an up-regulation of ICAM-1 and VCAM-1 and de novo expression of MAdCAM-1 on choroid plexus epithelial cells. In contrast, endothelial cells in the choroid plexus were not induced to express any of the investigated CAMs. In in situ hybridization analysis we demonstrated that ICAM-1, VCAM-1, and MAdCAM-1 were locally synthesized and that the amount of their mRNAs increased in the inflamed choroid plexus. In vitro, primary choroid plexus epithelial cells could be induced to express ICAM-1, VCAM-1, and MAdCAM-1 on their surface after treatment with proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, interferon-gamma, and lipopolysaccharide. To investigate the functional status of the expressed CAMs we performed Stamper-Woodruff binding assays on frozen sections of inflamed and naive brains. ICAM-1, VCAM-1, and MAdCAM-1 expressed in choroid plexus epithelial cells mediated binding of lymphocytes via their known ligands LFA-1 and alpha4-integrin, respectively. The expression of ICAM-1, VCAM-1, and MAdCAM-1 on choroid plexus epithelial cells together with the lack of their expression on the fenestrated choroid plexus endothelium raises the possibility that the epithelial blood-cerebrospinal-fluid barrier plays an important role in the immunosurveillance of the central nervous system. PMID:8669469

  18. Plasma zinc levels inversely correlate with vascular cell adhesion molecule-1 concentration in children with sickle cell disease.

    PubMed Central

    Kuvibidila, Solo R.; Sandoval, Manuel; Lao, Juan; Velez, Maria; Yu, Lolie; Ode, David; Gardner, Renée; Lane, Gerald; Warrier, Raj P.

    2006-01-01

    Zinc deficiency has been implicated in impaired cell-mediated immunity of children with sickle cell disease (SCD). However, its influence on the expression of vascular cell-adhesion molecule-1 (VCAM-1) on endothelial cells, a protein involved in vasoocclusion, has not been previously investigated. We therefore measured (soluble) sVCAM-1 and zinc in 76 SCD children and 96 non-SCD children, mean age 7.73 years and 11.24 years, respectively. Although mean zinc levels of both groups were within the normal range (approximately 14.5 micromol/l), 14.5 % of SCD and 11% of non-SCD children (without inflammation) had levels below normal (10.7 micromol/L). Mean sVCAM-1 concentrations of SCD children (837 microg/l) were significantly higher than those of controls (627 microg/l) (p < 0.001). Differences persisted after taking into account age, hemoglobin phenotype, and inflammation (alpha-l acid glycoprotein >l g/l and C-reactive protein >10 mg/I). sVCAM-1 negatively correlated with serum (r = -0.444) and red blood cells zinc (r = -0.242, p < 0.05) but not with acute-phase proteins. Mean sVCAM-1 tended to be higher in SCD children with than in those without a history of a health problem (infection, pain crisis or were transfused; not significant). Data suggest that zinc may modulate the clinical status of SCD children through VCAM-1 expression, and zinc supplementation may be beneficial in these patients. PMID:16916123

  19. Could both vitamin D and geomagnetic activity impact serum levels of soluble cell adhesion molecules in young men?

    NASA Astrophysics Data System (ADS)

    Bleizgys, Andrius; Šapoka, Virginijus

    2016-07-01

    Vitamin D might have a role in diminishing endothelial dysfunction (ED). The initial aim was to test the hypothesis of reciprocity between levels of 25-hydroxyvitamin D (25(OH)D) and levels of soluble endothelial cell adhesion molecules (CAMs) that could serve as biomarkers of ED. Randomly selected men of age 20-39 were examined at February or March (cold season) and reexamined at August or September (warm season). Some lifestyle and anthropometrical data were recorded. Laboratory measurements, including those for serum levels of soluble CAMs—sICAM-1, sVCAM-1, sE-selectin and sP-selectin—were also performed. As some of the results were rather unexpected, indices of geomagnetic activity (GMA), obtained from the online database, were included in further analysis as a confounder. In 2012-2013, 130 men were examined in cold season, and 125 of them were reexamined in warm season. 25(OH)D levels were found to be significantly negatively associated with sVCAM-1 levels ( β = -0.15, p = 0.043 in warm season; β = -0.19, p = 0.007 for changes). Levels of sVCAM-1 and sICAM-1 from the same seasons were notably different between years and have changed in an opposite manner. Soluble P-selectin levels were higher at warm season in both years. GMA was positively associated with sVCAM-1 ( β = 0.17, p = 0.039 in cold season; β = 0.22, p = 0.002 for changes) and negatively with sICAM-1 ( β = -0.30. p < 0.001 in cold season) levels. Vitamin D might play a role in diminishing sVCAM-1 levels. Levels of sVCAM-1 and sICAM-1 were associated with the GMA; this implies a need for further research.

  20. Expression of Adhesion Molecules in Synovia of Patients with Treatment-Resistant Lyme Arthritis

    PubMed Central

    Akin, Evren; Aversa, John; Steere, Allen C.

    2001-01-01

    The expression of adhesion molecules in synovium in patients with Lyme arthritis is surely critical in the control of Borrelia burgdorferi infection but may also have pathologic consequences. For example, molecular mimicry between a dominant T-cell epitope of B. burgdorferi outer surface protein A and an adhesion molecule, human lymphocyte function-associated antigen 1 (LFA-1), has been implicated in the pathogenesis of treatment-resistant Lyme arthritis. Using immunohistochemical methods, we examined synovial samples for expression of adhesion molecules in 29 patients with treatment-resistant Lyme arthritis and in 15 patients with rheumatoid arthritis or chronic inflammatory monoarthritis. In Lyme arthritis synovia, endothelial cells showed intense expression of P-selectin and vascular adhesion protein-1 (VAP-1). Expression of LFA-1 was also intense on infiltrating cells, particularly in lymphoid aggregates, and intercellular adhesion molecule-1 (ICAM-1) was markedly expressed on synovial lining and endothelial and infiltrating cells. Moderate expression of vascular cell adhesion molecule-1 (VCAM-1) was seen on synovial lining and endothelial cells, and mild expression of its ligand, very late antigen-4, was apparent in perivascular lymphoid infiltrates. Except for lesser expression of VCAM-1 in Lyme synovia, the levels of expression of these adhesion molecules were similar in the three patient groups. We conclude that certain adhesion molecules, including ICAM-1 and LFA-1, are expressed intensely in the synovia of patients with Lyme arthritis. Upregulation of LFA-1 on lymphocytes in this lesion may be critical in the pathogenesis of treatment-resistant Lyme arthritis. PMID:11179355

  1. Release of VCAM-1 associated endothelial microparticles following simulated SCUBA dives.

    PubMed

    Vince, R V; McNaughton, L R; Taylor, L; Midgley, A W; Laden, G; Madden, L A

    2009-03-01

    Microparticles (MP) are shed into the circulation from endothelium following activation or apoptosis. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on endothelial cells following activation and here we report quantification of VCAM-1 positive microparticles (VCAM + MP) following simulated SCUBA dives, breathing either air or oxygen. VCAM + MP were quantified pre-dive (09:00 and 13:00) and post-dive (+1, +3 and +15 h) on both air and oxygen dives and compared with control samples taken from the same subjects. VCAM + MP followed a similar trend in all experiments, however both dives caused a change in endothelial state, as measured by VCAM + MP. A significant increase in VCAM + MP was observed 1 h post-air dive relative to the control (p = 0.013), which was not observed after the oxygen dive (p = 0.095). Oxidative stress (TBARS) was correlated with VCAM + MP. Data presented highlights the potential of MP as a biological marker of both endothelial state and decompression illness.

  2. VCAM-1 expression on dystrophic muscle vessels has a critical role in the recruitment of human blood-derived CD133+ stem cells after intra-arterial transplantation.

    PubMed

    Gavina, Manuela; Belicchi, Marzia; Rossi, Barbara; Ottoboni, Linda; Colombo, Fabio; Meregalli, Mirella; Battistelli, Maurizio; Forzenigo, Laura; Biondetti, Piero; Pisati, Federica; Parolini, Daniele; Farini, Andrea; Issekutz, Andrew C; Bresolin, Nereo; Rustichelli, Franco; Constantin, Gabriela; Torrente, Yvan

    2006-10-15

    Recently our group demonstrated the myogenic capacity of human CD133(+) cells isolated from peripheral blood when delivered in vivo through the arterial circulation into the muscle of dystrophic scid/mdx mice. CD133(+) stem cells express the adhesion molecules CD44, LFA-1, PSGL-1, alpha4-integrins, L-selectin, and chemokine receptor CCR7. Moreover these cells adhere in vitro to VCAM-1 spontaneously and after stimulation with CCL19. Importantly, after muscle exercise, we found that the expression of VCAM-1 is strongly up-regulated in dystrophic muscle vessels, whereas the number of rolling and firmly adhered CD133(+) stem cells significantly increased. Moreover, human dystrophin expression was significantly increased when muscle exercise was performed 24 hours before the intra-arterial injection of human CD133(+) cells. Finally, treatment of exercised dystrophic mice with anti-VCAM-1 antibodies led to a dramatic blockade of CD133(+) stem cell migration into the dystrophic muscle. Our results show for the first time that the expression of VCAM-1 on dystrophic muscle vessels induced by exercise controls muscle homing of human CD133(+) stem cells, opening new perspectives for a potential therapy of muscular dystrophy based on the intra-arterial delivery of CD133(+) stem cells.

  3. Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells123

    PubMed Central

    Warner, Emily F; Zhang, Qingzhi; Raheem, K Saki; O’Hagan, David; O’Connell, Maria A; Kay, Colin D

    2016-01-01

    Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites. Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1). Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM. Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no

  4. Activation of ROS/NF-{kappa}B and Ca{sup 2+}/CaM kinase II are necessary for VCAM-1 induction in IL-1{beta}-treated human tracheal smooth muscle cells

    SciTech Connect

    Luo, S.-F.; Chang, C.-C.; Lee, I-T.; Lee, C.-W.; Lin, W.-N.; Lin, C.-C.; Yang, C.-M.

    2009-05-15

    Histone acetylation regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a critical role in the expression of inflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1). Oxidative processes have been shown to induce VCAM-1 expression. Here, we investigated the mechanisms underlying IL-1{beta}-induced VCAM-1 expression in human tracheal smooth muscle cells (HTSMCs). Our results showed that IL-1{beta} enhanced HTSMCs-monocyte adhesion through up-regulation of VCAM-1, which was inhibited by pretreatment with selective inhibitors of PKC{alpha} (Goe6976), c-Src (PP1), NADPH oxidase [diphenylene iodonium (DPI) and apocynin (APO)], intracellular calcium chelator (BAPTA/AM), PI-PLC (U73122), CaM (calmidazolium chloride), CaM kinase II (KN62), p300 (garcinol), NF-{kappa}B (Bay11-7082), HDAC (trichostatin A), and ROS scavenger [N-acetyl-L-cysteine (NAC)] or transfection with siRNAs of MyD88, PKC{alpha}, Src, p47{sup phox}, p300, and HDAC4. Moreover, IL-1{beta} stimulated NF-{kappa}B and CaMKII phosphorylation through MyD88-dependent PI-PLC/PKC{alpha}/c-Src/ROS and PI-PLC/Ca{sup 2+}/CaM pathways, respectively. Activation of NF-{kappa}B and CaMKII may eventually lead to the acetylation of histone residues and phosphorylation of histone deacetylases. These findings suggested that IL-1{beta} induced VCAM-1 expression via these multiple signaling pathways in HTSMCs. Blockade of these pathways may reduce monocyte adhesion via VCAM-1 suppression and attenuation of the inflammatory responses in airway diseases.

  5. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.

    PubMed

    Meng, Charles Q; Somers, Patricia K; Hoong, Lee K; Zheng, X Sharon; Ye, Zhihong; Worsencroft, Kimberly J; Simpson, Jacob E; Hotema, Martha R; Weingarten, M David; MacDOnald, Mathew L; Hill, Russell R; Marino, Elaine M; Suen, Ki-Ling; Luchoomun, Jayraz; Kunsch, Charles; Landers, Laura K; Stefanopoulos, Dimitria; Howard, Randy B; Sundell, Cynthia L; Saxena, Uday; Wasserman, Martin A; Sikorski, James A

    2004-12-01

    Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively. PMID:15566311

  6. EOLA1 Inhibits Lipopolysaccharide-Induced Vascular Cell Adhesion Molecule-1 Expression by Association with MT2A in ECV304 Cells

    PubMed Central

    Leng, Weiling; Lei, Xiaotian; Meng, Hao; Ouyang, Xinshou; Liang, Ziwen

    2015-01-01

    Our research group firstly discovered endothelial-overexpressed lipopolysaccharide-associated factor 1 (EOLA1, GenBank number AY074889) as a lipopolysaccharide (LPS) responsive gene in ECV304 cells. The previous studies have further demonstrated the association of EOLA1 with metallothionein 2A (MT2A), while the role of EOLA1 during LPS-induced inflammatory response in ECV304 cells is unknown. In this report, we determined the subcellular localization of EOLA1 and the regulatory capacity of EOLA1 on vascular cell adhesion molecule-1 (VCAM-1) in response to LPS in ECV304 cells. Our results show that EOLA1 is broadly diffuse in the cells, and EOLA1 expression is dramatically induced by LPS. EOLA1 knockdown results in significant enhancement of LPS-induced VCAM-1 production. Consistent with this, overexpression of EOLA1 leads to the reduction of LPS-induced VCAM-1 production. Furthermore, MT2A knockdown reduces LPS-induced VCAM-1 production. Collectively, our results demonstrate a negative regulatory role of EOLA1 on LPS-induced VCAM-1 expression involving its association with MT2A in ECV304 cells. PMID:26881174

  7. Sequential expression of adhesion and costimulatory molecules in graft-versus-host disease target organs after murine bone marrow transplantation across minor histocompatibility antigen barriers.

    PubMed

    Eyrich, Matthias; Burger, Gudrun; Marquardt, Katja; Budach, Wilfried; Schilbach, Karin; Niethammer, Dietrich; Schlegel, Paul G

    2005-05-01

    Graft-versus-host disease (GVHD) is a potentially fatal complication after allogeneic bone marrow transplantation. However, few data exist thus far on the molecular signals governing leukocyte trafficking during the disease. We therefore investigated the sequential pattern of distinct adhesion, costimulatory, and apoptosis-related molecules in GVHD organs (ileum, colon, skin, and liver) after transplantation across minor histocompatibility barriers (B10.D2 --> BALB/c, both H-2d). To distinguish changes induced by the conditioning regimen from effects achieved by allogeneic cell transfer, syngeneic transplant recipients (BALB/c --> BALB/c) and irradiated nontransplanted mice were added as controls. Irradiation upregulated the expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-l, and B7-2 in ileum, as well as VCAM-1 and B7-2 in colon, on day 3 in all animals. Whereas in syngeneic mice these effects were reversed from day 9 on, allogeneic recipients showed further upregulation of VCAM-1, ICAM-1, B7-1, and B7-2 in these organs on day 22, when GVHD became clinically evident. Infiltration of CD4+ and CD8+ donor T cells was noted on day 9 in skin and liver and on day 22 in ileum and colon. Surprisingly, the expression of several other adhesion molecules, such as ICAM-2, platelet-endothelial cell adhesion molecule 1, E-selectin, and mucosal addressin cell adhesion molecule 1, did not change. Proapoptotic and antiapoptotic markers were balanced in GVHD organs with the exception of spleen, in which a preferential expression of the proapoptotic Bax could be noted. Our results indicate that irradiation-induced upregulation of VCAM-1, ICAM-1, and B7-2 provides early costimulatory signals to incoming donor T cells in the intestine, followed by a cascade of proinflammatory signals in other organs once the alloresponse is established.

  8. The role of soluble cell adhesion molecules in patients with suspected deep vein thrombosis.

    PubMed

    Bucek, Robert A; Reiter, Markus; Quehenberger, Peter; Minar, Erich; Baghestanian, Mehrdad

    2003-10-01

    Activation of the endothelium, platelets and leukocytes has been shown to play an important role in the aetiology of deep venous thrombosis (DVT) in in-vitro experiments, resulting in the release of soluble cell adhesion molecules (sCAMs). We therefore assessed the value of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin and soluble P-selectin for the diagnostic process in 69 consecutive patients with suspected DVT. Final diagnosis was based on the results of Duplex sonography or ascending venography. Thirty-seven patients (53.6%) finally suffered from DVT. Mean levels of sVCAM-1 were 589 +/- 530 ng/ml for controls and 587 +/- 328 ng/ml for patients. Corresponding levels concerning sICAM-1 were 316 +/- 161 and 342 +/- 186 ng/ml, those concerning soluble E-selectin were 54 +/- 38 and 42 +/- 18 ng/ml, and those concerning soluble P-selectin were 94 +/- 37 and 99 +/- 36 ng/ml (all P > 0.05). There was no significant correlation of the thrombus extension (all P > 0.05) or the duration of symptoms with sCAMs (all P > 0.05). In conclusion, we detected no significant differences concerning the concentration of four major sCAMs between patients with DVT and controls, so their assessment does not add any useful information for the diagnostic process of DVT.

  9. Differential Associations between CDH13 Genotypes, Adiponectin Levels, and Circulating Levels of Cellular Adhesive Molecules

    PubMed Central

    Teng, Ming-Sheng; Wu, Semon; Hsu, Lung-An; Chou, Hsin-Hua; Ko, Yu-Lin

    2015-01-01

    CDH13 gene variants with lower adiponectin levels are paradoxically associated with a more favorable metabolic profile. We investigated the statistical association between CDH13 locus variants and adiponectin levels by examining 12 circulating inflammation marker levels and adiposity status in 530 Han Chinese people in Taiwan. After adjustments for clinical covariates, adiponectin levels were positively associated with soluble vascular cell adhesion molecule-1 (sVCAM1) levels and negatively associated with adiposity status and levels of C-reactive protein (CRP), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 (sICAM1). In addition, minor alleles of the CDH13 rs12051272 polymorphism were found to have lower adiponectin levels and higher CRP, sE-selectin, sICAM1, and sVCAM1 levels as well as higher body mass indices and waist circumferences in participants (all P < 0.05). In a subgroup analysis stratified by sex, significant associations between CDH13 genotypes and sE-selectin levels occurred only in men (P = 3.9 × 10−4 and interaction P = 0.005). CDH13 locus variants and adiponectin levels are associated with circulating levels of cellular adhesion molecules and adiposity status in a differential manner that interacts with sex. These results provide further evidence for the crucial role of adiponectin levels and CDH13 gene variants in immune-mediated and inflammatory diseases. PMID:26600672

  10. The coffee diterpene kahweol inhibits tumor necrosis factor-{alpha}-induced expression of cell adhesion molecules in human endothelial cells

    SciTech Connect

    Kim, Hyung Gyun; Kim, Ji Young; Hwang, Yong Pil; Lee, Kyung Jin; Lee, Kwang Youl; Kim, Dong Hee; Kim, Dong Hyun; Jeong, Hye Gwang . E-mail: hgjeong@chosun.ac.kr

    2006-12-15

    Endothelial cells produce adhesion molecules after being stimulated with various inflammatory cytokines. These adhesion molecules play an important role in the development of atherogenesis. Recent studies have highlighted the chemoprotective and anti-inflammatory effects of kahweol, a coffee-specific diterpene. This study examined the effects of kahweol on the cytokine-induced monocyte/human endothelial cell interaction, which is a crucial early event in atherogenesis. Kahweol inhibited the adhesion of TNF{alpha}-induced monocytes to endothelial cells and suppressed the TNF{alpha}-induced protein and mRNA expression of the cell adhesion molecules, VCAM-1 and ICAM-1. Furthermore, kahweol inhibited the TNF{alpha}-induced JAK2-PI3K/Akt-NF-{kappa}B activation pathway in these cells. Overall, kahweol has anti-inflammatory and anti-atherosclerotic activities, which occurs partly by down-regulating the pathway that affects the expression and interaction of the cell adhesion molecules on endothelial cells.

  11. Monocyte Adhesion Molecules Expression in Patients with Chronic Hepatitis C Liver Disease

    PubMed Central

    El-Bassiouni, Nora E.I.; Mahmoud, Ola M.; El Ahwani, Eman G; Ibrahim, Raafat A.; El Bassiouny, Azza E.I.

    2013-01-01

    Background Chronic viral hepatitis is histologically characterized by predominantly periportal infiltration of mononuclear cells, including lymphocytes and monocytes/macrophages. Intralobular infiltration of these inflammatory cells is an ominous sign of deterioration and a criterion for disease activity. Objective To assess the monocyte inflammatory milieu, monocytes adhesion molecules, their endothelial receptors, cytokines and chemokines in patients with HCV induced chronic liver disease, in an attempt to clarify the role of blood monocytes in induction of inflammation and fibrogenesis in chronic hepatitis C liver disease. Subjects and Methods The current study included 60 patients with chronic liver disease categorized into 2groups: Patients chronic hepatitis C (CHC) and patients with liver cirrhosis (LC), 15 patients each; 15 healthy subjects were included as normal controls. Immunophenotype characterization was carried out by flowcytometric analysis for identification of CD11a, CD11b and CD49d monocyte surface antigen expression in different groups studied. The circulating levels of the soluble adhesion molecules (sE-selectin, sICAM-1 and sVCAM-1), cytokines (TNF-α and IL-1) and chemokines (MCP-1) were also assessed by immunoassays. Results Data demonstrated a significant increase (p<0.01) in the surface expression of CD11a on peripheral blood monocytes and in the circulating levels sE-selectins, sICAM-1, sVCAM-1 and TNF-α in both groups of patients compared to healthy subjects. Data also revealed a significant increase (p<0.01) in the surface expression of each of CD11b and CD49d on peripheral blood monocytes and in the circulating levels sICAM-1, sVCAM-1 and TNF-α in patients with LC compared to those with CHC. Moreover, data demonstrated that the increase in surface antigen expression of each CD11a (p<0.01), CD11b (p<0.05) and CD49d (p<0.01) on circulating peripheral blood monocytes is positively correlated with the increase in the circulating levels of

  12. Association between Arsenic Exposure from Drinking Water and Plasma Levels of Soluble Cell Adhesion Molecules

    PubMed Central

    Chen, Yu; Santella, Regina M.; Kibriya, Muhammad G.; Wang, Qiao; Kappil, Maya; Verret, Wendy J.; Graziano, Joseph H.; Ahsan, Habibul

    2007-01-01

    Background Epidemiologic studies of cardiovascular disease risk factors and appropriate biomarkers in populations exposed to a wide range of arsenic levels are a public health research priority. Objective We investigated the relationship between inorganic arsenic exposure from drinking water and plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), both markers of endothelial dysfunction and vascular inflammation, in an arsenic-exposed population in Araihazar, Bangladesh. Methods The study participants included 115 individuals with arsenic-related skin lesions participating in a 2 × 2 randomized, placebo-controlled, double-blind trial of vitamin E and selenium supplementation. Arsenic exposure status and plasma levels of sICAM-1 and sVCAM-1 were assessed at baseline and after 6 months of follow-up. Results Baseline well arsenic, a long-term measure of arsenic exposure, was positively associated with baseline levels of both sICAM-1 and sVCAM-1 and with changes in the two markers over time. At baseline, for every 1-μg/L increase in well arsenic there was an increase of 0.10 ng/mL [95% confidence interval (CI), 0.00–0.20] and 0.33 ng/mL (95% CI, 0.15–0.51) in plasma sICAM-1 and sVCAM-1, respectively. Every 1-μg/L increase in well arsenic was associated with a rise of 0.11 ng/mL (95% CI, 0.01–0.22) and 0.17 ng/mL (95% CI, 0.00–0.35) in sICAM-1 and sVCAM-1 from baseline to follow-up, respectively, in spite of recent changes in urinary arsenic as well as vitamin E and selenium supplementation during the study period. Conclusions The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation that persists over time and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease. PMID:17938729

  13. Soluble adhesion molecules correlate with surface expression in an in vitro model of endothelial activation.

    PubMed

    Kjaergaard, Anders G; Dige, Anders; Krog, Jan; Tønnesen, Else; Wogensen, Lise

    2013-10-01

    Endothelial activation is a pivotal event in the development and progression of inflammation. Central to endothelial activation is the up-regulation of cellular adhesion molecules (CAMs) including E-selectin (CD62E), ICAM-1 (CD54), VCAM-1 (CD106) and PECAM-1 (CD31). These CAMs are also found in soluble forms (sCAMs). In this in vitro study of endothelial activation, we examined whether the levels of sCAMs correlate with the endothelial surface expression of CAMs in a dose-dependent and time-dependent manner. Such a correlation would support the use of sCAMs as surrogate markers for endothelial activation in inflammatory conditions. Human umbilical vein endothelial cells (HUVEC) were cultured with various concentrations of TNF-α for 8 hr and at a fixed concentration of TNF-α for various durations. The levels of soluble and surface-bound E-selectin, ICAM-1, VCAM-1 and PECAM-1 were quantified by flow cytometry. TNF-α stimulation increased CAM and sCAM expression in a dose-dependent and time-dependent manner. There was a significant positive correlation between the levels of ICAM-1 and sICAM-1 and between the levels of VCAM and sVCAM-1 in both the dose-response and time-response experiments. A positive correlation between the levels of E-selectin and sE-selectin was observed in the time-response experiment. This study supports the use of sCAMs as potential biomarkers of endothelial activation. In particular, the use of sICAM-1, sVCAM-1 and sE-selectin seems promising.

  14. Hydrogen peroxide mediates vascular cell adhesion molecule-1 expression from interleukin-18-activated hepatic sinusoidal endothelium: implications for circulating cancer cell arrest in the murine liver.

    PubMed

    Mendoza, L; Carrascal, T; De Luca, M; Fuentes, A M; Salado, C; Blanco, J; Vidal-Vanaclocha, F

    2001-08-01

    The mechanism of intrasinusoidal arrest of circulating cancer cells, which is a critical step in liver metastasis, appears to be facilitated by tumor-derived proinflammatory factors that increase sinusoidal cell adhesion receptors for cancer cells. However, how this prometastatic microenvironment is up-regulated remains unknown. Using intrasplenically injected B16 melanoma (B16M) cells, we show that the expression of vascular cell adhesion molecule-1 (VCAM-1) significantly increased in hepatic sinusoidal endothelium (HSE) cells over physiologic baseline within the first 24 hours of metastatic cancer cell infiltration in the liver. This correlated with increased in vitro adhesion of B16M cells to HSE cells isolated from B16M cell-injected mice. In vivo VCAM-1 blockade with specific antibodies before B16M cell injection decreased sinusoidal retention of luciferase-transfected B16M cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated HSE cells had a prometastatic contribution. Because VCAM-1 expression is oxidative stress-inducible, recombinant catalase was in vivo administered, resulting in a complete abrogation of both VCAM-1 expression and B16M cell adhesion increases in HSE cells isolated from B16M cell-injected mice. Catalase also abrogated the proadhesive response of HSE cells to B16M-conditioned medium (B16M-CM) in vitro, although this did not affect the concomitant release of major proinflammatory cytokines by HSE cells. HSE cells treated with B16M-CM released interleukin (IL)-18 via tumor necrosis factor-alpha (TNF-alpha)-dependent IL-1beta in vitro. In turn, H(2)O(2) production from B16M-CM-treated HSE cells was regulated by IL-18. Thus, liver-infiltrating B16M cells activated their adhesion to HSE through a sequential process involving TNF-alpha-dependent IL-1beta, which induced IL-18 to up-regulate VCAM-1 via H(2)O(2). The pivotal position of H(2)O(2) was further supported by the fact that incubation of HSE

  15. Soluble Forms of Intercellular and Vascular Cell Adhesion Molecules Independently Predict Progression to Type 2 Diabetes in Mexican American Families

    PubMed Central

    Kulkarni, Hemant; Mamtani, Manju; Peralta, Juan; Almeida, Marcio; Dyer, Thomas D.; Goring, Harald H.; Johnson, Matthew P.; Duggirala, Ravindranath; Mahaney, Michael C.; Olvera, Rene L.; Almasy, Laura; Glahn, David C.; Williams-Blangero, Sarah; Curran, Joanne E.; Blangero, John

    2016-01-01

    Objective While the role of type 2 diabetes (T2D) in inducing endothelial dysfunction is fairly well-established the etiological role of endothelial dysfunction in the onset of T2D is still a matter of debate. In the light of conflicting evidence in this regard, we conducted a prospective study to determine the association of circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) with incident T2D. Methods Data from this study came from 1,269 Mexican Americans of whom 821 initially T2D-free individuals were longitudinally followed up in the San Antonio Family Heart Study. These individuals were followed for 9752.95 person-years for development of T2D. Prospective association of sICAM-1 and sVCAM-1 with incident T2D was studied using Kaplan-Meier survival plots and mixed effects Cox proportional hazards modeling to account for relatedness among study participants. Incremental value of adhesion molecule biomarkers was studied using integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indexes. Results Decreasing median values for serum concentrations of sICAM-1 and sVCAM-1 were observed in the following groups in this order: individuals with T2D at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal glucose tolerant (NGT) individuals who remained T2D-free during follow-up. Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment—insulin resistance (HOMA-IR). Mixed effects Cox proportional hazards modeling revealed that after correcting for important clinical confounders, high sICAM-1 and sVCAM-1 concentrations were associated with 2.52 and 1.99 times faster progression to T2D as compared to low concentrations, respectively. Individuals with high concentrations for both sICAM-1 and sVCAM-1 progressed to T2D 3.42 times faster than those with low

  16. Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts.

    PubMed

    Ahmed, Salahuddin; Riegsecker, Sharayah; Beamer, Maria; Rahman, Ayesha; Bellini, Joseph V; Bhansali, Pravin; Tillekeratne, L M Viranga

    2013-07-15

    In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1-5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5-5 μM) inhibited the constitutive expression of HDAC1 (0-30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~220% with a concomitant decrease in HDAC5 [30-58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α+LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA.

  17. Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice.

    PubMed

    Ramos, C L; Huo, Y; Jung, U; Ghosh, S; Manka, D R; Sarembock, I J; Ley, K

    1999-06-11

    Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerotic lesions throughout the arterial tree, including the carotid bifurcation. Although the expression of adhesion molecules such as ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and P-selectin on endothelium that overlie atherosclerotic plaques has been implicated in monocyte recruitment to developing lesions, monocyte adhesion in atherosclerotic vessels has not been observed directly. To investigate which adhesion molecules may be important in monocyte adhesion to atherosclerotic lesions, an isolated mouse carotid artery preparation was developed and perfused with mononuclear cells. We show rolling and attachment of the human monocytic cell line U937 and the mouse monocyte-macrophage cell line P388D1 in carotid arteries from 10- to 12-week-old ApoE-/- and C57BL/6 wild-type mice fed a Western-type diet (21% fat wt/wt) for 4 to 5 weeks. No rolling was observed in carotid arteries from C57BL/6 or BALB/c wild-type mice fed a chow diet and little was observed in BALB/c mice fed a Western-type diet. This model represents early lesion development as shown by minimal macrophage infiltration in the intima of carotid arteries from ApoE-/- mice fed a Western-type diet. Rolling was observed at shear stresses that were characteristic of the low-shear recirculation zone near the carotid bifurcation. Mononuclear cell attachment and rolling were significantly inhibited by monoclonal antibody blockade of P-selectin or its leukocyte ligand P-selectin glycoprotein ligand-1. Rolling velocities increased after monoclonal antibody blockade of mononuclear cell alpha4-integrin or VCAM-1, which indicates that alpha4-integrin interacting with VCAM-1 stabilizes rolling interactions and prolongs monocyte transit times.

  18. Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules

    PubMed Central

    Mulvihill, N; Foley, J; Murphy, R; Curtin, R; Crean, P; Walsh, M

    2001-01-01

    OBJECTIVE—To assess prospectively the prognostic value of soluble cellular adhesion molecules (CAMs) in patients with unstable angina and non-Q wave myocardial infarction and to compare their prognostic accuracy with that of C reactive protein (CRP).
DESIGN AND SETTING—Prospective observational study of patients presenting acutely with unstable angina and non-Q wave myocardial infarction to a single south Dublin hospital.
METHODS—Patients with Braunwald IIIA unstable angina and non-Q wave myocardial infarction had serum samples taken at presentation before initiation of antithrombotic treatment and were followed for six months. The primary end point was the occurrence of major adverse cardiovascular events (recurrent unstable angina, non-fatal myocardial infarction, and cardiovascular death) at six months. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin, and soluble platelet selectin were measured using an enzyme linked immunosorbent assay technique. CRP was measured with an immunophelometric assay.
RESULTS—91 patients (73 men and 18 women, mean (SD) age 61 (11) years) were studied; 27 patients (30%) had major adverse cardiac events during the six months of follow up. Concentration of CRP were significantly raised in patients who had an ischaemic event (mean (SEM) 11.5 (6.4) mg/l v 5.4 (2.5) mg/l, p < 0.001). Concentrations of sVCAM-1 were also significantly raised in the ischaemic event group (979 (30) ng/ml v 729 (22) ng/ml, p < 0.001). Both sVCAM-1 and CRP concentrations correlated strongly with the occurrence of an adverse event. The sensitivity of CRP > 3 mg/l and sVCAM-1 > 780 ng/ml for predicting future events was > 90%. There was no difference in concentrations of sICAM-1, soluble endothelin selectin, or soluble platelet selectin between event and non-event groups.
CONCLUSION—Raised concentrations of sVCAM-1 and CRP

  19. Carboxylated, heteroaryl-substituted chalcones as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.

    PubMed

    Meng, Charles Q; Ni, Liming; Worsencroft, Kimberly J; Ye, Zhihong; Weingarten, M David; Simpson, Jacob E; Skudlarek, Jason W; Marino, Elaine M; Suen, Ki-Ling; Kunsch, Charles; Souder, Amy; Howard, Randy B; Sundell, Cynthia L; Wasserman, Martin A; Sikorski, James A

    2007-03-22

    Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders. PMID:17323940

  20. P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line.

    PubMed

    Baker, Olga J; Camden, Jean M; Rome, Danny E; Seye, Cheikh I; Weisman, Gary A

    2008-01-01

    Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease that causes salivary and lacrimal gland tissue destruction resulting in impaired secretory function. Although lymphocytic infiltration of salivary epithelium is associated with SS, the mechanisms involved have not been adequately elucidated. Our previous studies have shown that the G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is up-regulated in response to damage or stress of salivary gland epithelium, and in salivary glands of the NOD.B10 mouse model of SS-like autoimmune exocrinopathy. Additionally, we have shown that P2Y2R activation up-regulates vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells leading to the binding of monocytes. The present study demonstrates that activation of the P2Y2R in dispersed cell aggregates from rat submandibular gland (SMG) and in human submandibular gland ductal cells (HSG) up-regulates the expression of VCAM-1. Furthermore, P2Y2R activation mediated the up-regulation of VCAM-1 expression in HSG cells leading to increased adherence of lymphocytic cells. Inhibitors of EGFR phosphorylation and metalloprotease activity abolished P2Y2R-mediated VCAM-1 expression and decreased lymphocyte binding to HSG cells. Moreover, silencing of EGFR expression abolished UTP-induced VCAM-1 up-regulation in HSG cells. These results suggest that P2Y2R activation in salivary gland cells increases the EGFR-dependent expression of VCAM-1 and the binding of lymphocytes, a pathway relevant to inflammation associated with SS.

  1. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

    SciTech Connect

    Zhang, Haimou; Qin, Gangjian; Liang, Gang; Li, Jinan; Chiu, Isaac; Barrington, Robert A.; Liu, Dongxu . E-mail: dxliu001@yahoo.com

    2007-07-13

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.

  2. Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice

    PubMed Central

    Huang, Jin; Filipe, Anne; Rahuel, Cécile; Bonnin, Philippe; Mesnard, Laurent; Guérin, Coralie; Wang, Yu; Le Van Kim, Caroline; Colin, Yves; Tharaux, Pierre-Louis

    2014-01-01

    Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury. PMID:24429403

  3. Nicorandil attenuates endothelial VCAM-1 expression via thioredoxin production in diabetic rats induced by streptozotocin.

    PubMed

    Liu, Lihua; Liu, Yun; Qi, Benling; Wu, Qinqin; Li, Yuanyuan; Wang, Zhaohui

    2014-06-01

    The anti-angina agent nicorandil has been reported to be beneficial even in patients who have angina with diabetes. However, the mechanism underlying the effect of nicorandil in patients with diabetes remains to be elucidated. In this study, the protective effect of nicorandil on thioredoxin (TRX) protein was investigated, as TRX is a multifunctional endogenous redox regulator that protects cells against various types of cellular and tissue stress. This study was conducted to examine whether nicorandil induces the expression of TRX for the protection against diabetic damage in the vascular tissue of rats. Diabetes was induced in rats by intraperitoneal injection of streptozotocin (STZ) (fasting glucose levels in STZ-induced rats were >14 mmol/l). Diabetic rats were divided into a diabetic control and a nicorandil-treated group. Nicorandil was administered at a dosage of 15 mg/kg/day by gavage feeding. After five weeks of nicorandil administration, blood samples were obtained from the angular vein to measure levels of stress markers, serum superoxide dismutase and malondialdehyde, using the ELISA. The expression of TRX in STZ-induced rat vascular tissue was analyzed by immunohistochemistry, quantitative polymerase chain reaction (qPCR) and western blot analysis. The oral administration of nicorandil induced TRX protein and mRNA expression in the vascular tissue of STZ-induced diabetic rats. In the diabetic control group, the levels of stress were markedly higher than those in the nicorandil-treated group, indicating that nicorandil reduces oxidative stress in serum. In addition to inducing TRX expression, nicorandil attenuated the expression of the vascular cell adhesion molecule-1 (VCAM-1) in diabetic rat vascular endothelial cells. In conclusion, nicorandil attenuates the formation of reactive oxygen species and induces TRX protein expression, consequently resulting in the suppression of VCAM-1 secretion in the vascular endothelial cells of STZ-induced diabetic

  4. TNF-α enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-κB, ERK and JNK signaling pathways

    PubMed Central

    LU, ZI-YUAN; CHEN, WAN-CHENG; LI, YONG-HUA; LI, LI; ZHANG, HANG; PANG, YAN; XIAO, ZHI-FANG; XIAO, HAO-WEN; XIAO, YANG

    2016-01-01

    The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor-α (TNF-α) increased the level of vascular cell adhesion molecule-1 (VCAM-1) expression in a dose-dependent manner. The nuclear factor-κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM-1 expression induced by TNF-α at the mRNA and protein levels (P<0.05). TNF-α augmented the activation of NF-κB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF-κB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NF-κB, ERK and JNK signaling pathways. PMID:27221006

  5. Cytokines and Adhesion Molecules Expression in the Brain in Human Cerebral Malaria

    PubMed Central

    Armah, Henry; Wiredu, Edwin Kwame; Dodoo, Alfred Kofi; Adjei, Andrew Anthony; Tettey, Yao; Gyasi, Richard

    2005-01-01

    Although the role of systemic proinflammatory cytokines, IL-1β and TNF-α, and their up-regulation of adhesion molecules, ICAM-1, VCAM-1 and E-Selectin, in the pathogenesis of cerebral malaria (CM) is well established, the role of local cytokine release remain unclear. Immunohistochemistry (IHC) was used to compare the expression of ICAM-1, VCAM-1, E-Selectin, IL-1β, TNF-α and TGF- β at light microscopic level in cerebral, cerebellar and brainstem postmortem cryostat sections from 10 CM, 5 severe malarial anemia (SMA), 1 purulent bacterial meningitis (PBM), 2 non-central nervous system infections (NCNSI) and 3 non-infections (NI) deaths in Ghanaian children. Fatal malaria and Salmonella sepsis showed significantly higher vascular expression of all 3 adhesion molecules, with highly significant co-localization with sequestration in the malaria cases. However, there was negligible difference between CM and SMA. TGF-β showed intravascular and perivascular distribution in all cases, but expression was most intense in the PBM case and CM group. TNF-α and IL-1β showed prominent brain parenchymal staining, in addition to intravascular and perivascular staining, in only the PBM case and CM group. The maximal expression of all 6 antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation is a feature of fatal malaria and Salmonella sepsis, with adhesion molecule expression being highly correlated with sequestration. IL-1β and TNF-α are upregulated in only cases with neurodegenerative lesions, whilst TGF-β is present in all cases. Both cytokines and adhesion molecules were maximally upregulated in the cerebellar sections of the malaria cases. PMID:16705810

  6. Circulating adhesion molecules after short-term exposure to particulate matter among welders

    PubMed Central

    Fang, S C; Eisen, E A; Cavallari, J M; Mittleman, M A; Christiani, D C

    2011-01-01

    Background Studies from several countries indicate that welders experience increased risk of mortality and morbidity from ischaemic heart disease. Although the underlying mechanisms are unclear, vascular responses to particulate matter contained in welding fumes may play a role. To investigate this, we studied the acute effects of welding fume exposure on the endothelial component of vascular function, as measured by circulating adhesion molecules involved in leukocyte adhesion (sICAM-1 and sVCAM-1) and coagulation (vWF). Methods A panel of 26 male welders was studied repeatedly across a 6 h work-shift on a high exposure welding day and/or a low exposure non-welding day. Personal PM2.5 exposure was measured throughout the work-shift. Blood samples were collected in the morning (baseline) prior to the exposure period, immediately after the exposure period, and the following morning. To account for the repeated measurements, we used linear mixed models to evaluate the effects of welding (binary) and PM2.5 (continuous) exposure on each blood marker, adjusting for baseline blood marker concentration, smoking, age and time of day. Results Welding and PM2.5 exposure were significantly associated with a decrease in sVCAM-1 in the afternoon and the following morning and an increase in vWF in the afternoon. Conclusions The data suggest that welding and short-term occupational exposure to PM2.5 may acutely affect the endothelial component of vascular function. PMID:19736177

  7. Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts

    SciTech Connect

    Ahmed, Salahuddin; Riegsecker, Sharayah; Beamer, Maria; Rahman, Ayesha; Bellini, Joseph V.; Bhansali, Pravin; Tillekeratne, L.M. Viranga

    2013-07-15

    In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1–5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5–5 μM) inhibited the constitutive expression of HDAC1 (0–30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ∼ 220% with a concomitant decrease in HDAC5 [30–58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α + LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA. - Highlights: • Largazole enhances TNF-α-induced ICAM-1 and VCAM-1. • Largazole upregulates class II HDAC (HDAC6) in RA synovial fibroblasts. • Largazole also induces the expression of phospho-p38

  8. An ethanol root extract of Cynanchum wilfordii containing acetophenones suppresses the expression of VCAM-1 and ICAM-1 in TNF-α-stimulated human aortic smooth muscle cells through the NF-κB pathway.

    PubMed

    Koo, Hyun Jung; Sohn, Eun-Hwa; Pyo, Suhkneung; Woo, Han Goo; Park, Dae Won; Ham, Young-Min; Jang, Seon-A; Park, Soo-Yeong; Kang, Se Chan

    2015-04-01

    The root of Cynanchum wilfordii (C. wilfordii) contains several biologically active compounds which have been used as traditional medicines in Asia. In the present study, we evaluated the anti-inflammatory effects of an ethanol root extract of C. wilfordii (CWE) on tumor necrosis factor (TNF)-α-stimulated human aortic smooth muscle cells (HASMCs). The inhibitory effects of CWE on vascular cell adhesion molecule (VCAM)-1 expression under an optimum extraction condition were examined. CWE suppressed the expression of VCAM-1 and ICAM-1 and the adhesion of THP-1 monocytes to the TNF-α-stimulated HASMCs. Consistent with the in vitro observations, CWE inhibited the aortic expression of ICAM-1 and VCAM-1 in atherogenic diet-fed mice. CWE also downregulated the expression of nuclear factor-κB (NF-κB p65) and its uclear translocation in the stimulated HASMCs. In order to identify the active components in CWE, we re-extracted CWE using several solvents, and found that the ethyl acetate fraction was the most effective in suppressing the expression of VCAM-1 and ICAM-1. Four major acetophenones were purified from the ethyl acetate fraction, and two components, p-hydroxyacetophenone and cynandione A, potently inhibited the expression of ICAM-1 and VCAM-1 in the stimulated HASMCs. We assessed and determined the amounts of these two active components from CWE, and our results suggested that the root of C. wilfordii and its two bioactive acetophenones may be used for the prevention and treatment of atherosclerosis and vascular inflammatory diseases. PMID:25716870

  9. Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity.

    PubMed

    Michigami, T; Shimizu, N; Williams, P J; Niewolna, M; Dallas, S L; Mundy, G R; Yoneda, T

    2000-09-01

    Myeloma is a unique hematologic malignancy that exclusively homes in the bone marrow and induces massive osteoclastic bone destruction presumably by producing cytokines that promote the differentiation of the hematopoietic progenitors to osteoclasts (osteoclastogenesis). It is recognized that neighboring bone marrow stromal cells influence the expression of the malignant phenotype in myeloma cells. This study examined the role of the interactions between myeloma cells and neighboring stromal cells in the production of osteoclastogenic factors to elucidate the mechanism underlying extensive osteoclastic bone destruction. A murine myeloma cell line 5TGM1, which causes severe osteolysis, expresses alpha(4)beta(1)-integrin and tightly adheres to the mouse marrow stromal cell line ST2, which expresses the vascular cell adhesion molecule-1 (VCAM-1), a ligand for alpha(4)beta(1)-integrin. Co-cultures of 5TGM1 with primary bone marrow cells generated tartrate-resistant acid phosphatase-positive multinucleated bone-resorbing osteoclasts. Co-cultures of 5TGM1 with ST2 showed increased production of bone-resorbing activity and neutralizing antibodies against VCAM-1 or alpha(4)beta(1)-integrin inhibited this. The 5TGM1 cells contacting recombinant VCAM-1 produced increased osteoclastogenic and bone-resorbing activity. The activity was not blocked by the neutralizing antibody to known osteoclastogenic cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor, or parathyroid hormone-related peptide. These data suggest that myeloma cells are responsible for producing osteoclastogenic activity and that establishment of direct contact with marrow stromal cells via alpha(4)beta(1)-integrin/VCAM-1 increases the production of this activity by myeloma cells. They also suggest that the presence of stromal cells may provide a microenvironment that allows exclusive colonization of myeloma cells in the bone marrow. (Blood. 2000;96:1953-1960) PMID:10961900

  10. Could both vitamin D and geomagnetic activity impact serum levels of soluble cell adhesion molecules in young men?

    PubMed

    Bleizgys, Andrius; Šapoka, Virginijus

    2016-07-01

    Vitamin D might have a role in diminishing endothelial dysfunction (ED). The initial aim was to test the hypothesis of reciprocity between levels of 25-hydroxyvitamin D (25(OH)D) and levels of soluble endothelial cell adhesion molecules (CAMs) that could serve as biomarkers of ED. Randomly selected men of age 20-39 were examined at February or March (cold season) and reexamined at August or September (warm season). Some lifestyle and anthropometrical data were recorded. Laboratory measurements, including those for serum levels of soluble CAMs-sICAM-1, sVCAM-1, sE-selectin and sP-selectin-were also performed. As some of the results were rather unexpected, indices of geomagnetic activity (GMA), obtained from the online database, were included in further analysis as a confounder. In 2012-2013, 130 men were examined in cold season, and 125 of them were reexamined in warm season. 25(OH)D levels were found to be significantly negatively associated with sVCAM-1 levels (β = -0.15, p = 0.043 in warm season; β = -0.19, p = 0.007 for changes). Levels of sVCAM-1 and sICAM-1 from the same seasons were notably different between years and have changed in an opposite manner. Soluble P-selectin levels were higher at warm season in both years. GMA was positively associated with sVCAM-1 (β = 0.17, p = 0.039 in cold season; β = 0.22, p = 0.002 for changes) and negatively with sICAM-1 (β = -0.30. p < 0.001 in cold season) levels. Vitamin D might play a role in diminishing sVCAM-1 levels. Levels of sVCAM-1 and sICAM-1 were associated with the GMA; this implies a need for further research. PMID:26546313

  11. Cell adhesion molecules as a marker reflecting the reduction of endothelial activation induced by glucocorticoids.

    PubMed

    Leone, Marc; Boutière-Albanèse, Brigitte; Valette, Sarah; Camoin-Jau, Laurence; Barrau, Karine; Albanèse, Jacques; Martin, Claude; Dignat-George, Françoise

    2004-04-01

    In vitro, steroids down-regulate the expression of cell adhesion molecules (CAMs) in endothelial cells stimulated by lipopolysaccharide. Low-dose hydrocortisone is a new treatment of patients with septic shock, a state that is characterized by an endothelial injury. The aim of the present study was to investigate whether the plasma levels of soluble CAMs, reflecting in vivo endothelial activation, could be modulated in patients with septic shock treated by hydrocortisone. This was a prospective and observational study conducted in the intensive care unit at a university hospital. The subjects included 40 patients with septic shock (American College of Chest Physicians Consensus Conference/Society of Critical Care Medicine definition); 45 healthy blood donors served as controls. The patients receiving the standard care ("reference group") during the first 6 months were compared with the patients receiving the hydrocortisone therapy ("hydrocortisone group") for the next 6 months. Measurements of sCAMs were performed on days 1 and 3 of the disease. On day 1, sE-selectin, sP-selectin, sVCAM-1, and sICAM-1 were significantly elevated in patients with septic shock compared with healthy donors. sE-selectin levels significantly decreased between days 1 and 3 in the "hydrocortisone group," whereas there was no significant change in the "reference group". Surprisingly, sICAM-1 levels significantly increased between days 1 and 3 only in patients treated by hydrocortisone. No significant changes were observed for sP-selectin and sVCAM-1 levels in the two groups. In patients with septic shock, glucocorticoids differently affected the pattern of evolution of sCAMs, with sE-selectin being decreased and sICAM-1 being increased. Expression of sP-selectin and sVCAM-1 was not affected.

  12. Different patterns of soluble adhesion molecules in systemic and cutaneous lupus erythematosus.

    PubMed

    Nyberg, F; Acevedo, F; Stephansson, E

    1997-10-01

    Circulating isoforms of cellular adhesion molecules (CAMs) have been described recently, and elevated levels of certain sCAMs have been reported in various inflammatory diseases such as systemic lupus erythematosus (SLE). There are previously no reports on sCAMs in cutaneous LE. Sera from 61 patients with LE: systemic (SLE: n=24), chronic cutaneous (discoid LE, DLE: n= 19) or subacute cutaneous (SCLE: n=8), chronic biologically false positive (CBFP) reactors for syphilis (n= 10) and 32 controls were examined for sICAM-1, sVCAM-1 and sE-Selectin with specific ELISA kits. Protocol forms were reviewed. We found significantly elevated levels of sE-Selectin in patients with DLE and widespread cutaneous symptoms, and a correlation between active cutaneous disease as well as polymorphous light eruption (PLE) and elevated levels of sE-Selectin. In contrast, patients with systemic LE did not have elevated levels of sE-Selectin, but in concordance with earlier reports, sICAM-1 and sVCAM-1 levels were elevated compared to controls in SLE, as well as in SCLE patients, which has not been reported previously. Since activated endothelial cells are the only source for E-Selectin, the elevated sE-Selectin level in patients with widespread and active cutaneous disease suggests a more important role for endothelial cells in the pathogenesis of cutaneous LE than previously assumed.

  13. Evaluation of Endothelial Cell Adhesion Molecules and Anti-C1q Antibody in Discriminating between Active and Non-Active Systemic Lupus Erythematosus

    PubMed Central

    Mahayidin, Hasni; Yahya, Nurul Khaiza; Wan Ghazali, Wan Syamimee; Mohd Ismail, Asmahan; Wan Ab Hamid, Wan Zuraida

    2016-01-01

    Background Detecting the active state of systemic lupus erythematosus (SLE) is important but challenging. This study aimed to determine the diagnostic accuracy of serum endothelial cell adhesion molecules (ICAM-1 and VCAM-1) and anti-C1q antibody in discriminating between active and non-active SLE. Methods Using SELENA-SLE disease activity index (SLEDAI), 95 SLE patients (45 active and 50 non-active) were assessed. A score above five was considered indicative of active SLE. The blood samples were tested for serum ICAM-1, VCAM-1 and anti-C1q antibody using enzyme-linked immunosorbent assay (ELISA). Results The levels of serum VCAM-1 and anti-C1q antibody were significantly higher in active SLE patients. Both VCAM-1 and anti-C1q were able to discriminate between active and non-active SLE (p-value < 0.001 and 0.005, respectively). From the receiver operating characteristic curves (ROCs) constructed, the optimal cut-off values for VCAM-1 and anti-C1q antibody in discriminating between active and non-active SLE were 30.5 ng/mL (69.0% sensitivity, 60.0% specificity, PPV 58.5%, NPV 66.7%) and 7.86 U/mL (75.6% sensitivity, 80% specificity, PPV 77.3%, NPV 78.4%), respectively. However, serum ICAM-1 level was unable to discriminate between the two groups (p-value = 0.193). Conclusion Anti-C1q antibody demonstrated the best diagnostic accuracy in discriminating between active and non-active SLE patients. PMID:27418866

  14. Circulating soluble adhesion molecules in patients with giant cell arteritis. Correlation between soluble intercellular adhesion molecule-1 (sICAM-1) concentrations and disease activity

    PubMed Central

    Coll-Vinent, B.; Vilardell, C.; Font, C.; Oristrell, J.; Hernandez-Rodrigu..., J.; Yague, J.; Urbano-Marquez, A.; Grau, J.; Cid, M.

    1999-01-01

    OBJECTIVE—To evaluate whether changes in concentrations of circulating adhesion molecules are related to disease activity in patients with giant cell arteritis (GCA).
METHODS—A sandwich ELISA was used to measure soluble intercellular adhesion molecule-1 (sICAM-1), sICAM-3, vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and L-selectin (sL-selectin) in serum and plasma samples from patients with GCA. A cross sectional study was performed on 64 GCA patients at different activity stages and on 35 age and sex matched healthy donors. Thirteen of these patients were evaluated at the time of diagnosis and serially during follow up.
RESULTS—At the time of diagnosis, sICAM-1 concentrations were significantly higher in active GCA patients than in controls (mean (SD) 360.55 (129.78) ng/ml versus 243.25 (47.43) ng/ml, p<0.001). In contrast, sICAM-3, sVCAM-1, sE-selectin, and sL-selectin values did not differ from those obtained in normal donors. With corticosteroid administration, a decrease in sICAM-1 concentrations was observed, reaching normal values when clinical remission was achieved (263.18 (92.7) ng/ml globally, 293.59 (108.39) ng/ml in the group of patients in recent remission, and 236.83 (70.02) ng/ml in those in long term remission). In the 13 patients followed up longitudinally, sICAM-1 values also normalised with clinical remission (225.87 (64.25) ng/ml in patients in recent remission, and 256.29 (75.15) ng/ml in those in long term remission).
CONCLUSIONS—Circulating sICAM-1 concentrations clearly correlate with clinically apparent disease activity in GCA patients. Differences with results previously found in patients with other vasculitides may indicate that different pathogenic mechanisms contribute to vascular inflammation in different disorders.

 Keywords: adhesion molecules; giant cell arteritis; inflammation PMID:10364919

  15. HEMCAM, an adhesion molecule expressed by c-kit+ hemopoietic progenitors

    PubMed Central

    1996-01-01

    We have characterized the adhesion molecule HEMCAM, which is expressed by hemopoietic progenitors of embryonic bone marrow. HEMCAM belongs to the immunoglobulin superfamily and consists of the V-V-C2-C2-C2 Ig domains. There are three mRNA splice variants. One has a short cytoplasmic tail; another has a long tail; while the third seems to lack transmembrane and cytoplasmic regions. Except for the NH2-terminal sequence, HEMCAM is identical to gicerin, a molecular involved in neurite outgrowth and Wilm's kidney tumor progression in the chicken and it is significantly homologous with MUC18 a molecule involved in melanoma progression and metastasis in human beings. In the bone marrow the HEMCAM+ cell population contains c-kit+ subsets. HEMCAM+ cells coexpressing the receptor tyrosine kinase c-kit give rise to T cells at a frequency of 0.17 when injected intrathymically in congenic animals. As HEMCAM+, c-kit+ cells differentiate into myeloid and erythroid CFU's the double-positive cell population seems to contain precursors for multiple lineages. HEMCAM promotes cell-cell adhesion of transfected cells. Cross-linking of murine HEMCAM leads to cell spreading of T- lymphocyte progenitors adhering to the vascular adhesion molecules, PECAM-1 and VCAM-1. Thus, HEMCAM is likely to be involved in cellular adhesion and homing processes. PMID:8978830

  16. Synaptic Cell Adhesion Molecules in Alzheimer's Disease

    PubMed Central

    Leshchyns'ka, Iryna

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβ via interaction with the key enzymes involved in Aβ formation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD. PMID:27242933

  17. NADPH oxidase and lipid raft-associated redox signaling are required for PCB153-induced upregulation of cell adhesion molecules in human brain endothelial cells

    SciTech Connect

    Eum, Sung Yong Andras, Ibolya; Hennig, Bernhard; Toborek, Michal

    2009-10-15

    Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammation and the development of vascular diseases. Because cell adhesion molecules (CAMs) of the cerebrovascular endothelium regulate infiltration of inflammatory cells into the brain, we have explored the molecular mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs), such as PCB153, can upregulate CAMs in brain endothelial cells. Exposure to PCB153 increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as elevated adhesion of leukocytes to brain endothelial cells. These effects were impeded by inhibitors of EGFR, JAKs, or Src activity. In addition, pharmacological inhibition of NADPH oxidase or disruption of lipid rafts by cholesterol depleting agents blocked PCB153-induced phosphorylation of JAK and Src kinases and upregulation of CAMs. In contrast, silencing of caveolin-1 by siRNA interference did not affect upregulation of ICAM-1 and VCAM-1 in brain endothelial cells stimulated by PCB153. Results of the present study indicate that lipid raft-dependent NADPH oxidase/JAK/EGFR signaling mechanisms regulate the expression of CAMs in brain endothelial cells and adhesion of leukocytes to endothelial monolayers. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCB-induced cerebrovascular disorders and neurotoxic effects in the CNS.

  18. Expression of adhesion molecules, chemokines and matrix metallo- proteinases (MMPs) in viable and degenerating stage of Taenia solium metacestode in swine neurocysticercosis.

    PubMed

    Singh, Satyendra K; Singh, Aloukick K; Prasad, Kashi N; Singh, Amrita; Singh, Avinash; Rai, Ravi P; Tripathi, Mukesh; Gupta, Rakesh K; Husain, Nuzhat

    2015-11-30

    Neurocysticercosis (NCC) is a parasitic infection of central nervous system (CNS). Expression of adhesion molecules, chemokines and matrix metalloproteinases (MMPs) were investigated on brain tissues surrounding viable (n=15) and degenerating cysticerci (n=15) of Taenia solium in swine by real-time RT-PCR and ELISA. Gelatin gel zymography was performed for MMPs activity. ICAM-1 (intercellular adhesion molecule-1), E-selectin, MIP-1α (macrophage inflammatory protein-1α), Eotaxin-1 and RANTES (regulated on activation, normal T cell expressed and secreted) were associated with degenerating cysticerci (cysts). However, VCAM-1 (vascular cell adhesion molecule-1), MCP-1 (monocyte chemotactic protein-1), MMP-2 and MMP-9 were associated with both viable and degenerating cysts. In conclusion, viable and degenerating cysticerci have different immune molecule profiles and role of these molecules in disease pathogenesis needs to be investigated. PMID:26412140

  19. Expression of adhesion molecules, chemokines and matrix metallo- proteinases (MMPs) in viable and degenerating stage of Taenia solium metacestode in swine neurocysticercosis.

    PubMed

    Singh, Satyendra K; Singh, Aloukick K; Prasad, Kashi N; Singh, Amrita; Singh, Avinash; Rai, Ravi P; Tripathi, Mukesh; Gupta, Rakesh K; Husain, Nuzhat

    2015-11-30

    Neurocysticercosis (NCC) is a parasitic infection of central nervous system (CNS). Expression of adhesion molecules, chemokines and matrix metalloproteinases (MMPs) were investigated on brain tissues surrounding viable (n=15) and degenerating cysticerci (n=15) of Taenia solium in swine by real-time RT-PCR and ELISA. Gelatin gel zymography was performed for MMPs activity. ICAM-1 (intercellular adhesion molecule-1), E-selectin, MIP-1α (macrophage inflammatory protein-1α), Eotaxin-1 and RANTES (regulated on activation, normal T cell expressed and secreted) were associated with degenerating cysticerci (cysts). However, VCAM-1 (vascular cell adhesion molecule-1), MCP-1 (monocyte chemotactic protein-1), MMP-2 and MMP-9 were associated with both viable and degenerating cysts. In conclusion, viable and degenerating cysticerci have different immune molecule profiles and role of these molecules in disease pathogenesis needs to be investigated.

  20. Cellular Adhesion Molecules in Healthy Subjects: Short Term Variations and Relations to Flow Mediated Dilation.

    PubMed

    Eschen, Ole; Christensen, Jeppe Hagstrup; Dethlefsen, Claus; Schmidt, Erik Berg

    2008-01-01

    The objective was primarily to describe short term intra-individual variation in serum levels of soluble adhesion molecules (sCAMs: E-selectin, P-selectin, intercellular adhesion molecule-1(sICAM-1) and vascular cellular adhesion molecule-1(sVCAM-1)) in healthy subjects. Secondly, sCAMs were correlated to brachial artery flow mediated vasodilation (FMD).Forty healthy subjects aged 24-66 years had sCAMs measured twice with 4 week intervals and short-term intra-individual variation was estimated as variation in the paired measurements after correcting for the analytical precision of the used method. At baseline, brachial FMD was measured.No difference was observed in mean sCAMs in the whole study group. Estimated intra-subject variations in sCAMs were 7.6-11.3%. In a regression analysis, significant negative association was found between sE-selectin and FMD after controlling for possible confounders (p < 0.04) while no significant correlation could be demonstrated between the other sCAMs and FMD.In conclusion, short term intra-individual variations in sCAMs were 7.6-11.3% in healthy subjects. We also found a significant negative association between sE-selectin and FMD, indicating an possible association between inflammation and dysfunction of the vascular endothelium; however further studies are required to confirm this preliminary finding.

  1. Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway

    PubMed Central

    Yang, Huabing; Zhao, Pengjun; Tian, Shiliu

    2016-01-01

    Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKβ/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKβ/AMPK pathway-dependent. PMID:26824050

  2. Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway.

    PubMed

    Yang, Huabing; Zhao, Pengjun; Tian, Shiliu

    2016-01-01

    Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKβ/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKβ/AMPK pathway-dependent. PMID:26824050

  3. IL-18 regulates IL-1β-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1

    PubMed Central

    Vidal-Vanaclocha, Fernando; Fantuzzi, Giamila; Mendoza, Lorea; Fuentes, Angela M.; Anasagasti, Miren J.; Martín, Javier; Carrascal, Teresa; Walsh, Patrick; Reznikov, Leonid L.; Kim, Soo-Hyun; Novick, Daniela; Rubinstein, Menachem; Dinarello, Charles A.

    2000-01-01

    Proinflammatory cytokines, including IL-1β and tumor necrosis factor-α (TNF-α), promote cancer cell adhesion and liver metastases by up-regulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic sinusoidal endothelium (HSE). In this study, hepatic metastasis after intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84–95% in mice with null mutations for either IL-1β or the IL-1β-converting enzyme (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice were dead compared with 19% of either IL-1β or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-α and IL-1β from cultures of primary murine HSE. The effect of B16M-CM on HSE resulted in increased numbers of B16M cells adhering to HSE, which was completely abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein. Exogenous IL-18 added to HSE also increased the number of adhering melanoma cells; however, this was not affected by IL-1 receptor blockade or TNF neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL-1β and IL-18 in the development of hepatic metastases of B16M in vivo. In vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF-α, IL-1β, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells. PMID:10639148

  4. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array

    PubMed Central

    2010-01-01

    Background Preeclampsia is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive arms of the immune system. Cytokines, chemokines and adhesion molecules are central to innate and adaptive immune processes. The purpose of this study was to determine circulating levels of cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia in a comprehensive manner, and to investigate their relationship to the clinical features and laboratory parameters of the study participants, including markers of overall inflammation (C-reactive protein), endothelial activation (von Willebrand factor antigen) and endothelial injury (fibronectin), oxidative stress (malondialdehyde) and trophoblast debris (cell-free fetal DNA). Results Serum levels of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interferon-gamma-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were measured in 60 preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women by multiplex suspension array and ELISA. In normal pregnancy, the relative abundance of circulating IL-18 over IL-12p70 and the relative deficiency of the bioactive IL-12p70 in relation to IL-12p40 might favour Th2-type immunity. Although decreased IL-1ra, TNF-alpha and MCP-1 concentrations of healthy pregnant relative to non-pregnant women reflect anti-inflammatory changes in circulating cytokine profile, their decreased serum IL-10 and increased IP-10 levels might drive pro-inflammatory responses. In addition to a shift towards Th1-type immunity (expressed by the increased IL-2/IL-4 and IFN-gamma/IL-4 ratios), circulating levels of the pro

  5. Differential modulation of IL-1-induced endothelial adhesion molecules and transendothelial migration of granulocytes by G-CSF.

    PubMed

    Eissner, G; Lindner, H; Reisbach, G; Klauke, I; Holler, E

    1997-06-01

    Granulocyte colony stimulating factor (G-CSF) is widely used for mobilization of haemopoietic stem cells into the peripheral blood. However, little is known about the mechanisms involved in mobilization and the immune modulatory effects of this growth factor. In this report we show that G-CSF down-regulated intercellular adhesion molecule 1 (ICAM-1) induced by Interleukin-1 (IL-1) on human endothelial cells. Interestingly, the G-CSF-mediated down-modulation of IL-1-induced ICAM-1 appeared to be biphasic. In pharmacological concentrations (> 300 ng/ml), and in dose ranges of plasma G-CSF levels above that of nonfebrile healthy individuals (30 pg/ml), a significant decrease in surface ICAM-1 could be observed. This could be explained, at least in part, by an increased autocrine G-CSF production by endothelial cells in response to IL-1 and exogenous G-CSF. In contrast to ICAM-1, IL-1-triggered VCAM-1 expression was superinduced by G-CSF with the optimal concentration of 30 pg/ml. To evaluate the functional significance of these findings, 51Cr adhesion assays with peripheral blood mononuclear cells (PBMC) or granulocytes known to lack the VCAM-1 counter-receptor very late antigen 4 (VLA-4) and IL-1-stimulated endothelial cells, in the presence or absence of G-CSF, were performed. G-CSF could not inhibit the IL-1-induced adhesion of PBMC to endothelial cells, which may be due to the differential adhesion molecule modulation. In contrast, granulocyte adhesion induced by IL-1 could effectively be blocked by co-incubation with G-CSF. Finally, G-CSF also inhibited transendothelial migration of granulocytes through IL-1-activated endothelial cells in a concentration-dependent manner.

  6. Intercellular adhesion molecule-1 in the heart.

    PubMed

    Niessen, Hans W M; Krijnen, Paul A J; Visser, Cees A; Meijer, Chris J L M; Hack, C Erik

    2002-11-01

    Intercellular adhesion molecule-1 (ICAM-1) belongs to the superfamily of immunoglobulin-like adhesion molecules. Up-regulation of ICAM-1 occurs in many different pathophysiological processes. Also, cardiomyocytes can express ICAM-1-for example, in acute myocardial infarction. Moreover, inhibition of ICAM-1 expression in the heart dramatically reduces infarct size. Hence, inhibitors of ICAM-1 may provide a novel therapeutic option for acute myocardial infarction.

  7. Association of inflammatory cytokines and endothelial adhesion molecules with immunological, virological, and cardiometabolic disease in HIV-infected individuals.

    PubMed

    Lacerda, Heloísa Ramos; Falcão, Maria da Conceição Correia; de Albuquerque, Valéria Maria Gonçalves; Zírpoli, Josefina Claudia; Miranda-Filho, Demócrito de Barros; de Albuquerque, Maria de Fátima Pessoa Militão; Montarroyos, Ulisses; Ximenes, Ricardo Arraes de Alencar

    2014-05-01

    Elevated levels of inflammatory and endothelial biomarkers are related to chronic diseases, cancers, and cardiovascular disease. This study aimed at evaluating the association of inflammatory cytokines and endothelial adhesion molecules with immunological, virological, and cardiometabolic disease in HIV-infected individuals. A cross-sectional study was initiated to evaluate the association of CD4 lymphocyte count, viral load, antiretroviral therapy, and metabolic and cardiovascular disease with inflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α)], adhesion molecules [soluble intercellular Adhesion Molecule 1 (sICAM) and soluble Vascular Adhesion Molecule 1 (sVCAM)], and highsensitive C-reactive protein (hs-CRP) levels in 125 HIV-infected patients. The associations between independent variables and biomarkers were analyzed by means of multivariate logistic regression. A viral load ≥100,000 copies/mL had a stronger association with high levels of sVCAM-1 (P=0.026; OR=2.54; CI=1.12-5.78) and TNF-α (P=0.048; OR=2.42; CI=1.01-5.85) than the current viral load using a multivariate analysis. Antiretroviral treatment was associated with lower levels of sVCAM-1 (P=0.20; OR=0.20; CI=0.05-0.78), TNF-α (P=0.060; OR=0.22; CI=0.05-1.07), and hs-CRP (P=0.093; OR=0.44; CI=0.17-1.15). CD4 counts <200 cells/mm(3) were associated with high IL-6 levels (P=0.013; OR=3.17; CI=1.27-7.91); however, antiretroviral treatment was not associated with IL-6 levels. Metabolic syndrome was associated with high hs-CRP levels, systolic hypertension was associated with IL-6 levels, and family history of coronary disease was associated with TNF-α levels. High biomarker levels were associated not only with viral and immunological characteristics but also with cardiometabolic factors. The maximum viral load attained was an important risk factor for high levels of TNF-α and sVCAM-1. Treatment protected patients from high biomarker levels, except IL-6.

  8. Glossogyne tenuifolia Extract Inhibits TNF-α-Induced Expression of Adhesion Molecules in Human Umbilical Vein Endothelial Cells via Blocking the NF-kB Signaling Pathway.

    PubMed

    Hsuan, Chin-Feng; Hsu, Hsia-Fen; Tseng, Wei-Kung; Lee, Thung-Lip; Wei, Yu-Feng; Hsu, Kwan-Lih; Wu, Chau-Chung; Houng, Jer-Yiing

    2015-09-17

    Chronic inflammation plays a pivotal role in the development of atherosclerosis, where the pro-inflammatory cytokine-induced expression of endothelial adhesion molecules and the recruitment of monocytes are the crucial events leading to its pathogenesis. Glossogyne tenuifolia ethanol extract (GTE) is shown to have potent anti-inflammatory and antioxidant activities. We evaluated the effects of GTE and its major components, luteolin (lut), luteolin-7-glucoside (lut-7-g), and oleanolic acid (OA) on TNF-α-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). The results demonstrated that GTE, lut, and lut-7-g attenuated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in TNF-α-activated HUVECs, and inhibited the adhesion of monocytes to TNF-α-activated HUVECs. The TNF-α-induced mRNA expression of ICAM-1 and VCAM-1 was also suppressed, revealing their inhibitory effects at the transcriptional level. Furthermore, GTE, lut, and lut-7-g blocked the TNF-α-induced degradation of nuclear factor-kB inhibitor (IkB), an indicator of the activation of nuclear factor-kB (NF-kB). In summary, GTE and its bioactive components were effective in preventing the adhesion of monocytes to cytokine-activated endothelium by the inhibition of expression of adhesion molecules, which in turn is mediated through blocking the activation and nuclear translocation of NF-kB. The current results reveal the therapeutic potential of GTE in atherosclerosis.

  9. Glossogyne tenuifolia Extract Inhibits TNF-α-Induced Expression of Adhesion Molecules in Human Umbilical Vein Endothelial Cells via Blocking the NF-kB Signaling Pathway.

    PubMed

    Hsuan, Chin-Feng; Hsu, Hsia-Fen; Tseng, Wei-Kung; Lee, Thung-Lip; Wei, Yu-Feng; Hsu, Kwan-Lih; Wu, Chau-Chung; Houng, Jer-Yiing

    2015-01-01

    Chronic inflammation plays a pivotal role in the development of atherosclerosis, where the pro-inflammatory cytokine-induced expression of endothelial adhesion molecules and the recruitment of monocytes are the crucial events leading to its pathogenesis. Glossogyne tenuifolia ethanol extract (GTE) is shown to have potent anti-inflammatory and antioxidant activities. We evaluated the effects of GTE and its major components, luteolin (lut), luteolin-7-glucoside (lut-7-g), and oleanolic acid (OA) on TNF-α-induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). The results demonstrated that GTE, lut, and lut-7-g attenuated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in TNF-α-activated HUVECs, and inhibited the adhesion of monocytes to TNF-α-activated HUVECs. The TNF-α-induced mRNA expression of ICAM-1 and VCAM-1 was also suppressed, revealing their inhibitory effects at the transcriptional level. Furthermore, GTE, lut, and lut-7-g blocked the TNF-α-induced degradation of nuclear factor-kB inhibitor (IkB), an indicator of the activation of nuclear factor-kB (NF-kB). In summary, GTE and its bioactive components were effective in preventing the adhesion of monocytes to cytokine-activated endothelium by the inhibition of expression of adhesion molecules, which in turn is mediated through blocking the activation and nuclear translocation of NF-kB. The current results reveal the therapeutic potential of GTE in atherosclerosis. PMID:26393541

  10. Short-term high-fat diet alters postprandial glucose metabolism and circulating vascular cell adhesion molecule-1 in healthy males.

    PubMed

    Numao, Shigeharu; Kawano, Hiroshi; Endo, Naoya; Yamada, Yuka; Takahashi, Masaki; Konishi, Masayuki; Sakamoto, Shizuo

    2016-08-01

    Short-term intake of a high-fat diet aggravates postprandial glucose metabolism; however, the dose-response relationship has not been investigated. We hypothesized that short-term intake of a eucaloric low-carbohydrate/high-fat diet (LCHF) would aggravate postprandial glucose metabolism and circulating adhesion molecules in healthy males. Seven healthy young males (mean ± SE; age: 26 ± 1 years) consumed either a eucaloric control diet (C, approximately 25% fats), a eucaloric intermediate-carbohydrate/intermediate-fat diet (ICIF, approximately 50% fats), or an LCHF (approximately 70% fats) for 3 days. An oral meal tolerance test (MTT) was performed after the 3-day dietary intervention. The concentrations of plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) were determined at rest and during MTT. The incremental area under the curve (iAUC) of plasma glucose concentration during MTT was significantly higher in LCHF than in C (P = 0.009). The first-phase insulin secretion indexes were significantly lower in LCHF than in C (P = 0.04). Moreover, the iAUC of GLP-1 and VCAM-1 concentrations was significantly higher in LCHF than in C (P = 0.014 and P = 0.04, respectively). The metabolites from ICIF and C were not significantly different. In conclusion, short-term intake of eucaloric diet containing a high percentage of fats in healthy males excessively increased postprandial glucose and VCAM-1 concentrations and attenuated first-phase insulin release.

  11. Control of vascular permeability by adhesion molecules

    PubMed Central

    Sarelius, Ingrid H; Glading, Angela J

    2014-01-01

    Vascular permeability is a vital function of the circulatory system that is regulated in large part by the limited flux of solutes, water, and cells through the endothelial cell layer. One major pathway through this barrier is via the inter-endothelial junction, which is driven by the regulation of cadherin-based adhesions. The endothelium also forms attachments with surrounding proteins and cells via 2 classes of adhesion molecules, the integrins and IgCAMs. Integrins and IgCAMs propagate activation of multiple downstream signals that potentially impact cadherin adhesion. Here we discuss the known contributions of integrin and IgCAM signaling to the regulation of cadherin adhesion stability, endothelial barrier function, and vascular permeability. Emphasis is placed on known and prospective crosstalk signaling mechanisms between integrins, the IgCAMs- ICAM-1 and PECAM-1, and inter-endothelial cadherin adhesions, as potential strategic signaling nodes for multipartite regulation of cadherin adhesion. PMID:25838987

  12. Control of vascular permeability by adhesion molecules.

    PubMed

    Sarelius, Ingrid H; Glading, Angela J

    2015-01-01

    Vascular permeability is a vital function of the circulatory system that is regulated in large part by the limited flux of solutes, water, and cells through the endothelial cell layer. One major pathway through this barrier is via the inter-endothelial junction, which is driven by the regulation of cadherin-based adhesions. The endothelium also forms attachments with surrounding proteins and cells via 2 classes of adhesion molecules, the integrins and IgCAMs. Integrins and IgCAMs propagate activation of multiple downstream signals that potentially impact cadherin adhesion. Here we discuss the known contributions of integrin and IgCAM signaling to the regulation of cadherin adhesion stability, endothelial barrier function, and vascular permeability. Emphasis is placed on known and prospective crosstalk signaling mechanisms between integrins, the IgCAMs- ICAM-1 and PECAM-1, and inter-endothelial cadherin adhesions, as potential strategic signaling nodes for multipartite regulation of cadherin adhesion. PMID:25838987

  13. Effect of Thyrotropin on Osteopontin, Integrin αvβ3, and VCAM-1 in the Endothelium via Activation of Akt

    PubMed Central

    Yan, Yumeng; Jiang, Fengwei; Lai, Yaxin; Wang, Haoyu; Liu, Aihua; Wang, Chuyuan; Zhang, Yuanyuan; Teng, Weiping; Shan, Zhongyan

    2016-01-01

    Numerous epidemiological studies have shown that subclinical hypothyroidism (SCH) can impair endothelial function and cause dyslipidemia. Studies have evaluated the effects of thyroid stimulating hormone (TSH) on endothelial cells, but the mechanism underlying the proatherosclerotic effect of increased TSH levels remains unclear. In the present study, SCH rat models were established in thyroidectomized Wistar rats that were given l-T4 daily. The results showed that in vivo, the expression of osteopontin (OPN) vascular cell adhesion molecule (VCAM-1), and levels of integrin αvβ3 in the aortic tissue in SCH and Hypothyroidism (CH) groups was higher than in the control group. However, the effect in the SCH group was higher than in the CH group. In vitro, results showed that different concentration and time gradients of TSH stimulation could increase the expression of OPN, VCAM-1, and integrin αvβ3, and this was accompanied by extracellular signal regulated kinase 1/2 (Erk1/2) and Akt activation in human umbilical vein endothelial cells (HUVECs). TSH induced elevation of these proatherosclerotic factors was partially suppressed by a specific Akt inhibitor but not by a specific Erk inhibitor. Findings suggested that the endothelial dysfunction caused by SCH was related to increased proatherosclerotic factors induced by TSH via Akt activation. PMID:27657042

  14. The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1 expression through interaction with VEGF receptor-2 (KDR/Flk-1).

    PubMed

    Seye, Cheikh I; Yu, Ningpu; González, Fernando A; Erb, Laurie; Weisman, Gary A

    2004-08-20

    UTP stimulates the expression of pro-inflammatory vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells through activation of the P2Y(2) nucleotide receptor P2Y(2)R. Here, we demonstrated that activation of the P2Y(2)R induced rapid tyrosine phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 in human coronary artery endothelial cells (HCAEC). RNA interference targeting VEGFR-2 or inhibition of VEGFR-2 tyrosine kinase activity abolishes P2Y(2)R-mediated VCAM-1 expression. Furthermore, VEGFR-2 and the P2Y(2)R co-localize upon UTP stimulation. Deletion or mutation of two Src homology-3-binding sites in the C-terminal tail of the P2Y(2)R or inhibition of Src kinase activity abolished the P2Y(2)R-mediated transactivation of VEGFR-2 and subsequently inhibited UTP-induced VCAM-1 expression. Moreover, activation of VEGFR-2 by UTP leads to the phosphorylation of Vav2, a guanine nucleotide exchange factor for Rho family GTPases. Using a binding assay to measure the activity of the small GTPases Rho, we found that stimulation of HCAEC by UTP increased the activity of RhoA and Rac1 (but not Cdc42). Significantly, a dominant negative form of RhoA inhibited P2Y(2)R-mediated VCAM-1 expression, whereas expression of dominant negative forms of Cdc42 and Rac1 had no effect. These data indicate a novel mechanism whereby a nucleotide receptor transactivates a receptor tyrosine kinase to generate an inflammatory response associated with atherosclerosis.

  15. Tumor necrosis factor-{alpha} enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway

    SciTech Connect

    Song, Kai; Zhu, Fei; Zhang, Han-zhong; Shang, Zheng-jun

    2012-08-15

    Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-{alpha}-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer-endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-{alpha} could enhance cancer-endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer-endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis. -- Highlights: Black-Right-Pointing-Pointer Spontaneous oral cancer-endothelial cell fusion. Black-Right-Pointing-Pointer TNF-{alpha} enhanced cell fusions. Black-Right-Pointing-Pointer VCAM-1/VLA-4 expressed in oral cancer. Black-Right-Pointing-Pointer TNF-{alpha} increased expression of VCAM-1 on endothelial cells. Black

  16. Inhibition of VCAM-1 expression on mouse vascular smooth muscle cells by lobastin via downregulation of p38, ERK 1/2 and NF-κB signaling pathways.

    PubMed

    Lee, Kyoungran; Yim, Joung-Han; Lee, Hong-Kum; Pyo, Suhkneung

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease, the progression of which is associated with the increased expression of cell adhesion molecules on vascular smooth muscle cells (VSMCs). Lobastin is a new pseudodepsidone isolated from Stereocaulon alpinum, Antarctic lichen, which is known to have antioxidant and antibacterial activities. However, the nature of the biological effects of lobastin still remains unclear. In the present study, we examine the effect of lobastin on the expression of vascular cell adhesion molecules (VCAM-1) induced by TNF-α in the cultured mouse VSMC cell line, MOVAS-1. Pretreatment of VSMCs for 2 h with lobastin (0.1-10 μg/ml) concentration-dependently inhibited TNF-α-induced protein expression of VCAM-1. Lobastin also inhibited TNF-α-induced production of intracellular reactive oxygen species (ROS). Lobastin abrogated TNF-α-induced phosphorylation of p38 and ERK 1/2, but not JNK, and also inhibited TNF-α-induced NK-κB activation. In addition, lobastin suppressed TNF-α-induced IκB kinase activation, subsequent degradation of IκBα and nuclear translocation of p65 NF-κB. Our results indicate that lobastin downregulates the TNF-α-mediated induction of VCAM-1 in VSMC by inhibiting the p38, ERK 1/2 and NF-κB signaling pathways and intracellular ROS generation. Thus, lobastin may be an important regulator of inflammation in the atherosclerotic lesion and a novel therapeutic drug for the treatment of atherosclerosis.

  17. Dual role of melanoma cell adhesion molecule (MCAM)/CD146 in lymphocyte endothelium interaction: MCAM/CD146 promotes rolling via microvilli induction in lymphocyte and is an endothelial adhesion receptor.

    PubMed

    Guezguez, Borhane; Vigneron, Pascale; Lamerant, Nathalie; Kieda, Claudine; Jaffredo, Thierry; Dunon, Dominique

    2007-11-15

    The melanoma cell adhesion molecule (MCAM)/CD146 is expressed as two isoforms differing by their cytoplasmic domain (MCAM long (MCAM-l) and MCAM short (MCAM-s)). MCAM being expressed by endothelial cells and activated T cells, we analyzed its involvement in lymphocyte trafficking. The NK cell line NKL1 was transfected by MCAM isoforms and submitted to adhesion on both the endothelial cell monolayer and recombinant molecules under shear stress. MCAM-l transfection reduced rolling velocity and increased NKL1 adhesion on the endothelial cell monolayer and VCAM-1. Scanning electron microscopy revealed that MCAM-l induced microvilli formation and extension. In contrast, MCAM short or mock transfection had no effect on adhesion of NKL1 cells and microvilli formation. As shown by mutagenesis, serine 32 of the MCAM-l cytoplasmic tail, belonging to a putative protein kinase C phosphorylation site, was necessary for MCAM-l-actin cytoskeleton interaction and microvilli induction. Accordingly, chelerythrine chloride, a protein kinase C inhibitor, abolished MCAM-l-induced microvilli and rolling of MCAM-l-transfected NKL1 cells. Inhibition of adhesion under shear stress by anti-MCAM Abs suggested that both lymphoid MCAM-l and endothelial MCAM were also directly involved in lymphocyte endothelium interaction. MCAM-l-transfected NKL1 and activated CD4 T cells adhered to rMCAM under shear stress whereas anti-MCAM Ab treatment inhibited this process. Taken together, these data establish that MCAM is involved in the initial steps of lymphocyte endothelium interaction. By promoting the rolling on the inflammation marker VCAM-1 via microvilli induction and displaying adhesion receptor activity involving possible homophilic MCAM-l-MCAM-l interactions, MCAM might be involved in the recruitment of activated T cells to inflammation sites.

  18. Single-molecule mechanics of mussel adhesion

    NASA Astrophysics Data System (ADS)

    Lee, Haeshin; Scherer, Norbert F.; Messersmith, Phillip B.

    2006-08-01

    The glue proteins secreted by marine mussels bind strongly to virtually all inorganic and organic surfaces in aqueous environments in which most adhesives function poorly. Studies of these functionally unique proteins have revealed the presence of the unusual amino acid 3,4-dihydroxy-L-phenylalanine (dopa), which is formed by posttranslational modification of tyrosine. However, the detailed binding mechanisms of dopa remain unknown, and the chemical basis for mussels' ability to adhere to both inorganic and organic surfaces has never been fully explained. Herein, we report a single-molecule study of the substrate and oxidation-dependent adhesive properties of dopa. Atomic force microscopy (AFM) measurements of a single dopa residue contacting a wet metal oxide surface reveal a surprisingly high strength yet fully reversible, noncovalent interaction. The magnitude of the bond dissociation energy as well as the inability to observe this interaction with tyrosine suggests that dopa is critical to adhesion and that the binding mechanism is not hydrogen bond formation. Oxidation of dopa, as occurs during curing of the secreted mussel glue, dramatically reduces the strength of the interaction to metal oxide but results in high strength irreversible covalent bond formation to an organic surface. A new picture of the interfacial adhesive role of dopa emerges from these studies, in which dopa exploits a remarkable combination of high strength and chemical multifunctionality to accomplish adhesion to substrates of widely varying composition from organic to metallic. 3,4-dihydroxylphenylalanine | atomic force microscopy | mussel adhesive protein

  19. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity.

    PubMed

    Turner, G D; Ly, V C; Nguyen, T H; Tran, T H; Nguyen, H P; Bethell, D; Wyllie, S; Louwrier, K; Fox, S B; Gatter, K C; Day, N P; Tran, T H; White, N J; Berendt, A R

    1998-06-01

    Fatal Plasmodium falciparum malaria is accompanied by systemic endothelial activation. To study endothelial activation directly during malaria and sepsis in vivo, the expression of cell adhesion molecules on dermal microvascular endothelium was examined in skin biopsies and correlated with plasma levels of soluble (circulating) ICAM-1, E-selectin, and VCAM-1 and the cytokine tumor necrosis factor (TNF)-alpha. Skin biopsies were obtained from 61 cases of severe malaria, 42 cases of uncomplicated malaria, 10 cases of severe systemic sepsis, and 17 uninfected controls. Systemic endothelial activation, represented by the up-regulation of inducible cell adhesion molecules (CAMs) on endothelium and increased levels of soluble CAMs (sCAMs), were seen in both severe and uncomplicated malaria and sepsis when compared with uninfected controls. Plasma levels of sICAM-1, sVCAM-1, and sE-selectin correlated positively with the severity of malaria whereas TNF-alpha was raised nonspecifically in malaria and sepsis. Immunohistochemical evidence of endothelial activation in skin biopsies did not correlate with sCAM levels or disease severity. This indicates a background of systemic endothelial activation, which occurs in both mild and severe malaria and sepsis. The levels of sCAMs in malaria are thus not an accurate reflection of endothelial cell expression of CAMs in a particular vascular bed, and other factors must influence their levels during disease.

  20. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity.

    PubMed Central

    Turner, G. D.; Ly, V. C.; Nguyen, T. H.; Tran, T. H.; Nguyen, H. P.; Bethell, D.; Wyllie, S.; Louwrier, K.; Fox, S. B.; Gatter, K. C.; Day, N. P.; Tran, T. H.; White, N. J.; Berendt, A. R.

    1998-01-01

    Fatal Plasmodium falciparum malaria is accompanied by systemic endothelial activation. To study endothelial activation directly during malaria and sepsis in vivo, the expression of cell adhesion molecules on dermal microvascular endothelium was examined in skin biopsies and correlated with plasma levels of soluble (circulating) ICAM-1, E-selectin, and VCAM-1 and the cytokine tumor necrosis factor (TNF)-alpha. Skin biopsies were obtained from 61 cases of severe malaria, 42 cases of uncomplicated malaria, 10 cases of severe systemic sepsis, and 17 uninfected controls. Systemic endothelial activation, represented by the up-regulation of inducible cell adhesion molecules (CAMs) on endothelium and increased levels of soluble CAMs (sCAMs), were seen in both severe and uncomplicated malaria and sepsis when compared with uninfected controls. Plasma levels of sICAM-1, sVCAM-1, and sE-selectin correlated positively with the severity of malaria whereas TNF-alpha was raised nonspecifically in malaria and sepsis. Immunohistochemical evidence of endothelial activation in skin biopsies did not correlate with sCAM levels or disease severity. This indicates a background of systemic endothelial activation, which occurs in both mild and severe malaria and sepsis. The levels of sCAMs in malaria are thus not an accurate reflection of endothelial cell expression of CAMs in a particular vascular bed, and other factors must influence their levels during disease. Images Figure 1 PMID:9626052

  1. Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily

    PubMed Central

    Casasnovas, José M.; Pieroni, Cristiana; Springer, Timothy A.

    1999-01-01

    The crystal structure of intercellular adhesion molecule-2 (ICAM-2) revealed significant differences in the presentation of the critical acidic residue important for integrin binding between I and non-I-domain integrin ligands. Based on this crystal structure, we mutagenized ICAM-2 to localize the binding site for the integrin lymphocyte function-associated antigen-1 (LFA-1). The integrin binding site runs diagonally across the GFC β-sheet and includes residues on the CD edge of the β-sandwich. The site is oblong and runs along a flat ridge on the upper half of domain 1, which is proposed to dock to a groove in the I domain of LFA-1, with the critical Glu-37 residue ligating the Mg2+ in the I domain. Previous mutagenesis of ICAM-1 and ICAM-3, interpreted in light of the recently determined ICAM-1 and ICAM-2 structures, suggests similar binding sites. By contrast, major differences are seen with vascular cell adhesion molecule-1 (VCAM-1), which binds α4 integrins that lack an I domain. The binding site on VCAM-1 includes the lower portion of domain 1 and the upper part of domain 2, whereas the LFA-1 binding site on ICAM is confined to the upper part of domain 1. PMID:10077629

  2. Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily.

    PubMed

    Casasnovas, J M; Pieroni, C; Springer, T A

    1999-03-16

    The crystal structure of intercellular adhesion molecule-2 (ICAM-2) revealed significant differences in the presentation of the critical acidic residue important for integrin binding between I and non-I-domain integrin ligands. Based on this crystal structure, we mutagenized ICAM-2 to localize the binding site for the integrin lymphocyte function-associated antigen-1 (LFA-1). The integrin binding site runs diagonally across the GFC beta-sheet and includes residues on the CD edge of the beta-sandwich. The site is oblong and runs along a flat ridge on the upper half of domain 1, which is proposed to dock to a groove in the I domain of LFA-1, with the critical Glu-37 residue ligating the Mg2+ in the I domain. Previous mutagenesis of ICAM-1 and ICAM-3, interpreted in light of the recently determined ICAM-1 and ICAM-2 structures, suggests similar binding sites. By contrast, major differences are seen with vascular cell adhesion molecule-1 (VCAM-1), which binds alpha4 integrins that lack an I domain. The binding site on VCAM-1 includes the lower portion of domain 1 and the upper part of domain 2, whereas the LFA-1 binding site on ICAM is confined to the upper part of domain 1. PMID:10077629

  3. Expression profile of vascular cell adhesion molecule-1 (CD106) in inflammatory foci using rhenium-188 labelled monoclonal antibody in mice.

    PubMed

    Kairemo, K J; Strömberg, S; Nikula, T K; Karonen, S L

    1998-06-01

    Rhenium (Re)-188 is a generator (W-188/Re-188) produced high energy beta-emitter suitable for radionuclide therapy (T1/2 is 16.9 hrs and Emax 2.1 MeV (range 11 mm)). We have labelled monoclonal antibody (MAb) raised against vascular cell adhesion molecule-1 (VCAM-1) with Re-188 using glucoheptonate chelation technique and SnCl2 as reducing agent. The labelling efficiency, free perrhenate and reduced Re were controlled with thin layer chromatography and the purification of Re-188-MoAbs was performed using gel filtration. Our results indicate that Re-188-labelled antibodies remain in vitro stable and the labelling purity is > 90%. We also have applied these Re-188-MoAbs for detection of inflammatory disease in a mouse. The effective half-lives of organs of interest after an injection of Re-188-anti-VCAM1 were as follows: blood 5.2 hr, kidney 4.7 hr, and liver 9.6 hr. Re-188-anti-VCAM-1 was found to accumulate mainly in kidney and liver. One hour after the injection, the kidney contained in average as high as 12.5% and the liver 2.8 ID/g tissue. After 6 hr, the kidney contained 5.5% ID/g and the liver 2.6% ID/g. At 24 hr, the kidney uptake was 0.5% ID/g and the liver uptake 0.8% ID/g, respectively. The inflamed foci, subcutaneous lesions in the footpad skin, were visualized using gamma camera. From the distribution data the uptakes in the inflamed foci as follows: at 1 hr 2.18 (inflammation) and 1.72% ID/g (control), at 6 hr 1.42 (inflammation) and 0.85% ID/g (control), and at 24 hr 0.17 (inflammation) and 0.084% ID/g (control), respectively. Anti-VCAM-1 MAb showed better targeting as compared to control MoAbs in inflammation (caused by E.coli lipoplysaccaride). In conclusion, Re-188 is suitable for MAb labelling, and MAb against VCAM-1 may be used for detection of local inflammatory disease. PMID:9762472

  4. Intercellular adhesion molecule 1 is the major adhesion molecule expressed during schistosome granuloma formation.

    PubMed Central

    Ritter, D M; McKerrow, J H

    1996-01-01

    Endothelial cell adhesion molecules play a key role in inflammation by initiating leukocyte trafficking. One of the most complex inflammatory responses is the formation of a cellular granuloma. Expression of adhesion molecules during granuloma formation was investigated by using the murine host reaction to schistosome parasite eggs deposited in the liver as a model. By both immunohistochemistry and lymphocyte adhesion assays, the predominant interaction identified was between intercellular adhesion molecule 1 (ICAM-1) and its cognate integrin, leukocyte functional antigen 1 (LFA-1). ICAM-1 expression on sinusoidal endothelium was induced when eggs were first deposited in the liver, peaked in parallel with granuloma size, and was downregulated with modulation of the granuloma. Polyacrylamide beads coated with soluble parasite egg antigens could induce ICAM-1 expression on endothelial cells in vitro only in the presence of tumor necrosis factor alpha, a cytokine previously shown to be key to granuloma formation. A role for ICAM-1 in recruiting lymphocytes to the hepatic granuloma was also supported by the observation that lymphocytes preincubated with anti-LFA-1 antibody did not bind to granulomas in tissue sections. While ICAM-1 is the predominant adhesion molecule in schistosome egg granuloma formation in wild-type mice, when the ICAM-1 gene is knocked out, vascular cell adhesion molecule 1 is upregulated and granuloma formation is preserved. PMID:8890229

  5. Effects of marine n-3 fatty acids on circulating levels of soluble adhesion molecules in patients with chronic heart failure.

    PubMed

    Eschen, O; Christensen, J H; LA Rovere, M T; Romano, P; Sala, P; Schmidt, E B

    2010-01-01

    Inflammatory markers as circulating soluble cellular adhesion molecules (sCAMs) and high sensitive C-reactive protein (hsCRP) are elevated in patients with chronic heart failure (CHF), and may constitute an increased risk of adverse outcome. Marine n-3 polyunsaturated fatty acids ( n-3 PUFA) may have anti-inflammatory effect and reduce levels of sCAMs (soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), P-selectin) and hsCRP. In a randomized, controlled trial, 138 patients with NYHA class II-III CHF were allocated to receive a daily supplement of 0.9 g of n-3 PUFA or olive oil for 24 weeks. After supplementation, no significant changes occurred in sCAMs or hsCRP after adjusting for possible confounders. However, a significant reduction was observed in sP-selectin in patients receiving n-3 PUFA, but this result was only of borderline significance in a between-group analysis. In conclusion, a daily supplement with 0.9 g of n-3 PUFA does not significantly affect plasma levels of sCAMs or hs-CRP in patients with CHF. n-3 PUFA may reduce sP-selectin, indicating a possible effect on platelet (and endothelial) activation. The results also indicate that the low dose of n-3 PUFA used in many intervention trials does not have deleterious effects on sCAMs or hsCRP.

  6. Effects of Antioxidant Supplementation on Insulin Sensitivity, Endothelial Adhesion Molecules and Oxidative Stress in Normal Weight and Overweight Young Adults

    PubMed Central

    Vincent, Heather K.; Bourguignon, Cheryl M.; Weltman, Arthur L.; Vincent, Kevin R.; Barrett, Eugene; Innes, Karen E.; Taylor, Ann G.

    2012-01-01

    Objective To determine whether short-term antioxidant supplementation affects insulin sensitivity, endothelial adhesion molecule levels, and oxidative stress in overweight young adults. Methods and Procedures A randomized, double-blind, controlled study tested the effects of antioxidants (AOX) on measures of insulin sensitivity (homeostasis model assessment, HOMA and QUICKI), endothelial adhesion molecules (sICAM-1, sVCAM-1, sE-selectin), adiponectin and oxidative stress (lipid hydroperoxides, PEROX) in overweight and normal weight individuals (N=48, 18-30 years). Participants received either AOX (vitamin E 800IU, vitamin C 500mg, β-carotene 10mg) or placebo (PLC) for 8 weeks. Results HOMA values were initially higher in the overweight subjects and were lowered with AOX by week 8 (15% reduction, p=0.02). Adiponectin increased in both AOX groups. sICAM-1 and sE-selectin decreased in overweight AOX treated groups by 6% and 13%, respectively (p<0.05). Plasma PEROX were reduced by 0.31 and 0.70 nmol/ml in the normal weight and overweight AOX treated groups, respectively, by week 8 (p<0.05). Discussion AOX supplementation moderately lowers HOMA and endothelial adhesion molecule levels in overweight young adults. A potential mechanism to explain this finding is the reduction in oxidative stress by AOX. Long term studies are needed to determine whether AOX are effective in suppressing diabetes or vascular activation over time. PMID:19154960

  7. Pentosan polysulfate treatment ameliorates motor function with increased serum soluble vascular cell adhesion molecule-1 in HTLV-1-associated neurologic disease.

    PubMed

    Nakamura, Tatsufumi; Satoh, Katsuya; Fukuda, Taku; Kinoshita, Ikuo; Nishiura, Yoshihiro; Nagasato, Kunihiko; Yamauchi, Atsushi; Kataoka, Yasufumi; Nakamura, Tadahiro; Sasaki, Hitoshi; Kumagai, Kenji; Niwa, Masami; Noguchi, Mitsuru; Nakamura, Hideki; Nishida, Noriyuki; Kawakami, Atsushi

    2014-06-01

    The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

  8. VCAM-1-targeting gold nanoshell probe for photoacoustic imaging of atherosclerotic plaque in mice.

    PubMed

    Rouleau, Leonie; Berti, Romain; Ng, Vanessa W K; Matteau-Pelletier, Carl; Lam, Tina; Saboural, Pierre; Kakkar, Ashok K; Lesage, Frédéric; Rhéaume, Eric; Tardif, Jean-Claude

    2013-01-01

    The development of molecular probes and novel imaging modalities, allowing better resolution and specificity, is associated with an increased potential for molecular imaging of atherosclerotic plaques especially in basic and pre-clinical research applications. In that context, a photoacoustic molecular probe based on gold nanoshells targeting VCAM-1 in mice (immunonanoshells) was designed. The molecular probe was validated in vitro and in vivo, showing no noticeable acute toxic effects. We performed the conjugation of gold nanoshells displaying near-infrared absorption properties with VCAM-1 antibody molecules and PEG to increase their biocompatibility. The resulting immunonanoshells obtained under different conditions of conjugation were then assessed for specificity and sensitivity. Photoacoustic tomography was performed to determine the ability to distinguish gold nanoshells from blood both in phantoms and in vivo. Ex vivo optical projection tomography of hearts and aortas from atherosclerotic and control mice confirmed the selective accumulation of the immunonanoshells in atherosclerotic-prone regions in mice, thus validating the utility of the probe in vivo in small animals for pre-clinical research. These immunonanoshells represent an adequate mean to target atherosclerotic plaques in small animals, leading to new tools to follow the effect of therapies on the progression or regression of the disease. PMID:23109390

  9. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation.

    PubMed

    Park, So Youn; Lee, Jeong Hyun; Kim, Yong Ki; Kim, Chi Dae; Rhim, Byung Yong; Lee, Won Suk; Hong, Ki Whan

    2005-03-01

    This study shows cilostazol effect to prevent remnant lipoprotein particle (RLP)-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). Upon incubation of HUVECs with RLP (50 microg/ml), adherent monocytes significantly increased by 3.3-fold with increased cell surface expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, E-selectin, and monocyte chemoattractant protein-1 (MCP-1). Cilostazol ( approximately 1-100 microM) concentration dependently repressed these variables as did (E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 microM), a specific nuclear factor-kappaB (NF-kappaB) inhibitor. Cilostazol effects were significantly antagonized by iberiotoxin (1 microM), a maxi-K channel blocker. RLP significantly increased expression of lectin-like receptor for oxidized low-density lipoprotein (LDL) (LOX-1) receptor protein. Upon transfection with antisense LOX-1 oligodeoxynucleotide (As-LOX-1), LOX-1 receptor expression was reduced, whereas HUVECs with sense LOX-1 oligodeoxynucleotide did express high LOX-1 receptor. RLP-stimulated superoxide and tumor necrosis factor-alpha levels were significantly lowered with decreased expression of VCAM-1 and MCP-1 by transfection with As-LOX-1 as did polyinosinic acid (10 microg/ml, a LOX-1 receptor inhibitor). RLP significantly degraded inhibitory kappaBalpha in the cytoplasm and activated nuclear factor-kappaB (NF-kappaB) p65 in the nucleus of HUVECs with increased luciferase activity of NF-kappaB, all of which were reversed by cilostazol (10 microM), BAY 11-7085, and polyinosinic acid. Together, cilostazol suppresses RLP-stimulated increased monocyte adhesion to HUVECs by suppression of LOX-1 receptor-coupled NF-kappaB-dependent nuclear transcription via mediation of the maxi-K channel opening.

  10. Cell-adhesion molecules in memory formation.

    PubMed

    Schmidt, R

    1995-01-23

    After learning events the CNS of higher organisms selects, which acquired informations are permanently stored as a memory trace. This period of memory consolidation is susceptible to interference by biochemical inhibitors of transcription and translation. Ependymin is a specific CNS glycoprotein functionally involved in memory consolidation in goldfish: after active shock-avoidance conditioning ependymin mRNA is rapidly induced in meningeal fibroblasts followed by enhanced synthesis and secretion of several closely related forms of the protein. Intracranial injections of anti-ependymin antisera or antisense oligodeoxynucleotides interfere specifically with memory consolidation, indicating that only de novo synthesized ependymin molecules are involved. Ependymin is capable of directing the growth of central axons in vitro and participates in neuronal regeneration in situ, presumably by its HNK-1 cell-adhesion epitope. Experiments reviewed in this article suggest a model that involves two regulation mechanisms for the function of ependymin in behavioural plasticity: while hormones appear to determine, how much of this cell adhesion molecule is synthesized after learning, local changes of metal cation concentrations in the micro-environment of activated neurons may polymerize ependymin at those synapses, that have to be consolidated to improve their efficacy for future use.

  11. Lactones from Ligusticum chuanxiong Hort. reduces atherosclerotic lesions in apoE-deficient mice via inhibiting over expression of NF-kB-dependent adhesion molecules.

    PubMed

    Xiao, Yang; Wang, Ying-Chao; Li, Lai-Lai; Jin, Ye-Cheng; Sironi, Luigi; Wang, Yi; Wang, Yi

    2014-06-01

    The present study aims to investigate the anti-atherosclerotic effects of lactones extracted from Ligusticum chuanxiong Hort (LLC) in apoE-deficient mice (ApoE(-/-) mice) and proclaim its underlying mechanisms. Expression of endothelial adhesion molecules and NF-κB around the atherosclerotic lesions was detected by immunohistochemistry (IHC). To further validate the mechanism, effect of LLC on the secretion of ICAM-1 and VCAM-1 of human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor α (TNF-α) was measured by ELISA. And the activation of NF-κB was detected by western blot. Mice treated with LLC showed significant reduction in lesion sizes of thoracic segments of the aorta (p<0.01). Meanwhile, LLC treatments lead to decreases of serum TG, TC and LDL-C contents, respectively. LLC also decreased the expression of CD31, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor-kappa B (NF-κB) in the atherosclerotic plaque. Moreover, LLC at 3.125-25 μg/mL can dose-dependently attenuate the expression of ICAM-1 and VCAM-1 in TNF-α stimulated HUVECs. Western blot result indicated LLC inhibited activation of NF-κB. These results suggested that LLC could ameliorate atherosclerosis in ApoE(-/-) mice. The mechanism of action of LLC on anti-atherosclerotic effect may be attributed to the suppression of the production of NF-κB-dependent adhesion molecules. PMID:24594239

  12. Potent anti-inflammatory effect of dioscin mediated by suppression of TNF-α-induced VCAM-1, ICAM-1and EL expression via the NF-κB pathway.

    PubMed

    Wu, Shan; Xu, Hui; Peng, Jinyong; Wang, Changyuan; Jin, Yue; Liu, Kexin; Sun, Huijun; Qin, Jianhua

    2015-03-01

    The modulation of adhesion molecule expression and the reduction of aberrant leukocyte adhesion to the endothelium are attractive approaches for treating inflammation-related vascular complications, including atherosclerosis. Dioscin has a variety of biological activities including anti-inflammatory activity. However, the molecular mechanisms behind dioscin's anti-inflammatory effects are not fully understood. In this study, we investigated the molecular mechanism involved in the effects of dioscin on inflammatory mediators in tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs). In vitro, dioscin decreased monocyte adhesion to TNF-α-treated HUVECs by reducing vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression and inhibiting endothelial lipase (EL) expression in TNF-α-treated HUVECs and macrophages by blocking the nuclear factor-κB (NF-κB) pathway. Thus, dioscin might inhibit inflammation by interrupting the NF-κB signaling pathway and could potentially contribute to treatments for inflammatory diseases and atherosclerosis. PMID:25577996

  13. [A mechanism for the anti-inflammatory effect of nedocromil; inhibition of both adhesion molecule expression on eosinophils and endothelial cells, and eosinophil chemotactic activities].

    PubMed

    Okada, T; Sagara, H; Nakano, Y; Hiyama, T; Fukuda, T

    1999-12-01

    The accumulation of eosinophils in the airway is one of the characteristics seen in patients with bronchial asthma. One of the newly developed anti-asthma drugs (controller), nedocromil sodium (nedocromil) is known to suppress the influx of eosinophils into allergic lesions. However, little is known about this mechanism. Therefore, in this report we investigated the effects of nedocromil on Mac-1 expression on PAF-stimulated eosinophils, and adhesion molecule expression on endothelial cells stimulated by either IL-1 beta or IL-4. We also investigated the eosinophil chemotaxis. A significant suppression of the Mac-1 expression on PAF-induced eosinophils was observed at both concentrations of 10(-5) and 10(-7) M of nedocromil. The expression of adhesion molecules, particularly ICAM-1 and E-selectin, on IL-1 beta-stimulated human umbilical vascular endothelial cells (HUVEC) was significantly suppressed at these concentrations, whereas the VCAM-1 expression was not changed. No significant suppression of VCAM-1 expression on IL-4-stimulated HUVEC was observed, although there was a tendency of suppression at these concentrations. On the other hand, the expression of the E-selectin molecule was significantly suppressed by nedocromil even under resting (non-stimulated) condition. PAF-induced eosinophil chemotactic activities were also suppressed at these concentrations in a dose-dependent manner. These results suggested that nedocromil suppressed the influx of eosinophils to inflammatory lesions by inhibiting not only the expression of the Mac-1 on eosinophils and of E-selectin and ICAM-1 molecules on HUVEC, but also the eosinophil chemotactic activities.

  14. [Effect of erythromycin on neutrophil adhesion molecules].

    PubMed

    Kusano, S; Mukae, H; Morikawa, T; Asai, T; Sawa, H; Morikawa, N; Oda, H; Sakito, O; Shukuwa, C; Senju, R

    1993-01-01

    The mechanisms of erythromycin (EM) in chronic lower respiratory tract diseases including diffuse panbronchiolitis (DPB) has been reported. In this study we investigated the effect of EM on peripheral neutrophil adhesion molecules such as LFA-1 and Mac-1 obtained from six healthy subjects. Pretreatment of neutrophils with each concentration (10 ng/ml approximately 100 micrograms/ml) of EM resulted in no significant reduction in the expression of LFA-1 alpha, beta and Mac-1. Moreover, EM had no capability of reducing these expressions even when neutrophils were pretreated with 1 microgram/ml of EM at time from 0 to 60 min. These findings indicate that EM does not directly reduce the expression of LFA-1 alpha, beta and Mac-1 on peripheral neutrophil obtained from healthy subjects. PMID:8450276

  15. The Anti-Atherosclerotic Effect of Naringin Is Associated with Reduced Expressions of Cell Adhesion Molecules and Chemokines through NF-κB Pathway.

    PubMed

    Hsueh, Tun-Pin; Sheen, Jer-Ming; Pang, Jong-Hwei S; Bi, Kuo-Wei; Huang, Chao-Chun; Wu, Hsiao-Ting; Huang, Sheng-Teng

    2016-02-05

    Naringin has been reported to have an anti-atherosclerosis effect but the underlying mechanism is not fully understood. The aim of this study is to investigate the impact of naringin on the TNF-α-induced expressions of cell adhesion molecules, chemokines and NF-κB signaling pathway in human umbilical vein endothelial cells (HUVECs). The experiments revealed that naringin, at concentrations without cytotoxicity, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated HUVECs. The TNF-α-induced expressions of cell adhesion molecules, including VCAM-1, ICAM-1 and E-selectin, at both the mRNA and protein levels, were significantly suppressed by naringin in a dose dependent manner. In addition, the TNF-α-induced mRNA and protein levels of chemokines, including fractalkine/CX3CL1, MCP-1 and RANTES, were also reduced by naringin. Naringin significantly inhibited TNF-α-induced nuclear translocation of NF-κB, which resulted from the inhibited phosphorylation of IKKα/β, IκB-α and NF-κB. Altogether, we proposed that naringin modulated TNF-α-induced expressions of cell adhesion molecules and chemokines through the inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway to exert the anti-atherosclerotic effect.

  16. Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor.

    PubMed

    Honda, S; Campbell, J J; Andrew, D P; Engelhardt, B; Butcher, B A; Warnock, R A; Ye, R D; Butcher, E C

    1994-04-15

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

  17. Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor.

    PubMed

    Honda, S; Campbell, J J; Andrew, D P; Engelhardt, B; Butcher, B A; Warnock, R A; Ye, R D; Butcher, E C

    1994-04-15

    Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands. PMID:7511663

  18. Circulating adhesion molecules in obstructive sleep apnea and cardiovascular disease.

    PubMed

    Pak, Victoria M; Grandner, Michael A; Pack, Allan I

    2014-02-01

    Over 20 years of evidence indicates a strong association between obstructive sleep apnea (OSA) and cardiovascular disease. Although inflammatory processes have been heavily implicated as an important link between the two, the mechanism for this has not been conclusively established. Atherosclerosis may be one of the mechanisms linking OSA to cardiovascular morbidity. This review addresses the role of circulating adhesion molecules in patients with OSA, and how these may be part of the link between cardiovascular disease and OSA. There is evidence for the role of adhesion molecules in cardiovascular disease risk. Some studies, albeit with small sample sizes, also show higher levels of adhesion molecules in patients with OSA compared to controls. There are also studies that show that levels of adhesion molecules diminish with continuous positive airway pressure therapy. Limitations of these studies include small sample sizes, cross-sectional sampling, and inconsistent control for confounding variables known to influence adhesion molecule levels. There are potential novel therapies to reduce circulating adhesion molecules in patients with OSA to diminish cardiovascular disease. Understanding the role of cell adhesion molecules generated in OSA will help elucidate one mechanistic link to cardiovascular disease in patients with OSA.

  19. Cell adhesion molecules and in vitro fertilization.

    PubMed

    Simopoulou, Maria; Nikolopoulou, Elena; Dimakakos, Andreas; Charalabopoulos, Konstantinos; Koutsilieris, Michael

    2014-01-01

    This review addresses issues regarding the need in the in vitro fertilization (IVF) field for further predictive markers enhancing the standing embryo selection criteria. It aims to serve as a source of defining information for an audience interested in factors related to the wide range of multiple roles played by cell adhesion molecules (CAMs) in several aspects of IVF ultimately associated with the success of an IVF cycle. We begin by stressing the importance of enriching the standing embryo selection criteria available aiming for the golden standard: "extract as much information as possible focusing on non-invasive techniques" so as to guide us towards selecting the embryo with the highest implantation potential. We briefly describe the latest trends on how to best select the right embryo, moving closer towards elective single embryo transfer. These trends are: frozen embryo transfer for all, preimplantation genetic screening, non-invasive selection criteria, and time-lapse imaging. The main part of this review is dedicated to categorizing and presenting published research studies focused on the involvement of CAMs in IVF and its final outcome. Specifically, we discuss the association of CAMs with conditions and complications that arise from performing assisted reproductive techniques, such as ovarian hyperstimulation syndrome, the state of the endometrium, and tubal pregnancies, as well as the levels of CAMs in biological materials available in the IVF laboratory such as follicular fluid, trophectoderm, ovarian granulosa cells, oocytes, and embryos. To conclude, since CAMs have been successfully employed as a diagnostic tool in several pathologies in routine clinical work, we suggest that their multi-faceted nature could serve as a prognostic marker in assisted reproduction, aiming to enrich the list of non-invasive selection and predictive criteria in the IVF setting. We propose that in light of the well-documented involvement of CAMs in the developmental

  20. Effect of vitamin C and iron chelation on diesel exhaust particle and carbon black induced oxidative damage and cell adhesion molecule expression in human endothelial cells.

    PubMed

    Frikke-Schmidt, Henriette; Roursgaard, Martin; Lykkesfeldt, Jens; Loft, Steffen; Nøjgaard, Jacob Klenø; Møller, Peter

    2011-06-24

    Exposure to particulate matter is associated with oxidative stress and risk of cardiovascular diseases. We investigated if vitamin C and desferrioxamine (iron chelator) altered the levels of oxidative stress and expression of cell adhesion molecules upon exposure to diesel exhaust particles (DEP) and carbon black in cultured human umbilical vein endothelial cells (HUVECs). We found that the particles were only slightly cytotoxic in the high concentration ranges. Particle-induced intracellular reactive oxygen species (ROS) production was attenuated by vitamin C administration or iron chelation and particularly when combined (p<0.001). Only desferrioxamine protected the DNA from oxidative damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sensitive sites induced by carbon black (p<0.01). Carbon black and small sized DEP generated from an Euro4 engine increased the surface expression of VCAM-1 and ICAM-1, whereas DEP from an engine representing an old combustion type engine (SRM2975) with larger particles did not affect the expression of cell adhesion molecules. These effects were also attenuated by desferrioxamine but not vitamin C. The study shows that exposure to carbon black and DEP in HUVECs can generate both oxidative stress and expression of cell surface adhesion molecules and that these effects can in part be attenuated by vitamin C and desferrioxamine.

  1. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain.

    PubMed

    Sawicki, C M; McKim, D B; Wohleb, E S; Jarrett, B L; Reader, B F; Norden, D M; Godbout, J P; Sheridan, J F

    2015-08-27

    Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD-induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.

  2. Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts.

    PubMed

    Edwards, J C; Leigh, R D; Cambridge, G

    1997-06-01

    The synovitis of rheumatoid arthritis (RA) is one of few pathological lesions in which B lymphocyte accumulation progresses to the extent of germinal centre formation. The present study was designed to assess the ability of synovial fibroblasts to express molecules implicated in B lymphocyte survival and differentiation, both in vivo, and in response to cytokines in vitro. Normal and diseased synovia were examined by indirect immunofluorescence. In all tissues synovial intimal fibroblasts showed co-expression of vascular cell adhesion molecule-1 (VCAM-1) and complement decay-accelerating factor (DAF) comparable to that of follicular dendritic cells (FDC), but not complement receptor 2 (CR2). In rheumatoid synovia, subintimal cells showed variable expression of VCAM-1 and DAF, with bright co-expression of VCAM-1, DAF and CR2 in lymphoid follicle centres. B lymphocytes, some of which were proliferating cell nuclear antigen-positive, were present in contact with subintimal cells expressing VCAM-1 with or without DAF or CR2. B lymphocytes were rarely present in the intimal layer, and, where present, showed fragmentation. In vitro, synovial fibroblasts exposed to tumour necrosis factor-alpha (TNF-alpha) in combination with interferon-gamma (IFN-gamma) showed enhanced expression of VCAM-1, in comparison with fibroblasts from skin and lung and, unlike skin and lung fibroblasts, also expressed DAF and CR2. These findings support the hypothesis that synovial targeting in RA involves an enhanced ability of synovial fibroblasts to support B lymphocyte survival. This appears to be dependent, not on the constitutive expression of VCAM-1 and DAF on intimal cells, but on the increased ability of subintimal cells to respond to proinflammatory cytokines, perhaps critically in the expression of VCAM-1.

  3. Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts.

    PubMed

    Edwards, J C; Leigh, R D; Cambridge, G

    1997-06-01

    The synovitis of rheumatoid arthritis (RA) is one of few pathological lesions in which B lymphocyte accumulation progresses to the extent of germinal centre formation. The present study was designed to assess the ability of synovial fibroblasts to express molecules implicated in B lymphocyte survival and differentiation, both in vivo, and in response to cytokines in vitro. Normal and diseased synovia were examined by indirect immunofluorescence. In all tissues synovial intimal fibroblasts showed co-expression of vascular cell adhesion molecule-1 (VCAM-1) and complement decay-accelerating factor (DAF) comparable to that of follicular dendritic cells (FDC), but not complement receptor 2 (CR2). In rheumatoid synovia, subintimal cells showed variable expression of VCAM-1 and DAF, with bright co-expression of VCAM-1, DAF and CR2 in lymphoid follicle centres. B lymphocytes, some of which were proliferating cell nuclear antigen-positive, were present in contact with subintimal cells expressing VCAM-1 with or without DAF or CR2. B lymphocytes were rarely present in the intimal layer, and, where present, showed fragmentation. In vitro, synovial fibroblasts exposed to tumour necrosis factor-alpha (TNF-alpha) in combination with interferon-gamma (IFN-gamma) showed enhanced expression of VCAM-1, in comparison with fibroblasts from skin and lung and, unlike skin and lung fibroblasts, also expressed DAF and CR2. These findings support the hypothesis that synovial targeting in RA involves an enhanced ability of synovial fibroblasts to support B lymphocyte survival. This appears to be dependent, not on the constitutive expression of VCAM-1 and DAF on intimal cells, but on the increased ability of subintimal cells to respond to proinflammatory cytokines, perhaps critically in the expression of VCAM-1. PMID:9182884

  4. Cell adhesion molecules and in vitro fertilization.

    PubMed

    Simopoulou, Maria; Nikolopoulou, Elena; Dimakakos, Andreas; Charalabopoulos, Konstantinos; Koutsilieris, Michael

    2014-01-01

    This review addresses issues regarding the need in the in vitro fertilization (IVF) field for further predictive markers enhancing the standing embryo selection criteria. It aims to serve as a source of defining information for an audience interested in factors related to the wide range of multiple roles played by cell adhesion molecules (CAMs) in several aspects of IVF ultimately associated with the success of an IVF cycle. We begin by stressing the importance of enriching the standing embryo selection criteria available aiming for the golden standard: "extract as much information as possible focusing on non-invasive techniques" so as to guide us towards selecting the embryo with the highest implantation potential. We briefly describe the latest trends on how to best select the right embryo, moving closer towards elective single embryo transfer. These trends are: frozen embryo transfer for all, preimplantation genetic screening, non-invasive selection criteria, and time-lapse imaging. The main part of this review is dedicated to categorizing and presenting published research studies focused on the involvement of CAMs in IVF and its final outcome. Specifically, we discuss the association of CAMs with conditions and complications that arise from performing assisted reproductive techniques, such as ovarian hyperstimulation syndrome, the state of the endometrium, and tubal pregnancies, as well as the levels of CAMs in biological materials available in the IVF laboratory such as follicular fluid, trophectoderm, ovarian granulosa cells, oocytes, and embryos. To conclude, since CAMs have been successfully employed as a diagnostic tool in several pathologies in routine clinical work, we suggest that their multi-faceted nature could serve as a prognostic marker in assisted reproduction, aiming to enrich the list of non-invasive selection and predictive criteria in the IVF setting. We propose that in light of the well-documented involvement of CAMs in the developmental

  5. Expression sequences of cell adhesion molecules.

    PubMed Central

    Crossin, K L; Chuong, C M; Edelman, G M

    1985-01-01

    A reexamination of the expression of cell adhesion molecules (CAMs) during the development of the chicken embryo was carried out using more sensitive immunocytochemical techniques than had been used previously. While the previously determined sequence of CAM expression was confirmed, neural CAM (N-CAM) was also detected on endodermal structures such as the lung epithelium, gut epithelium, and pancreas and on budding structures such as the pancreatic duct and gall bladder. It was also found on ectodermal derivatives of the skin. In most of these sites, N-CAM expression was transient, but in the chicken embryo lung, the epithelium remained positive for N-CAM and liver CAM (L-CAM) into adult life. Thus, at one time or another, both of these primary CAMs can be expressed on derivatives of all three germ layers. At sites of embryonic induction, epithelial cells expressing both L-CAM and N-CAM, or L-CAM only, were apposed to mesenchymal cells expressing N-CAM. Examples included epiblast (NL) and notochord (N); endodermal epithelium (NL) and lung mesenchyme (N); Wolffian duct (NL) and mesonephric mesenchyme (N); apical ectodermal ridge (NL) and limb mesenchyme (N); and feather placode (L) and dermal condensation (N). The cumulative observations indicate that cell surface modulation of the primary CAMs at induction sites can be classified into two modes. In mode I, expression of N-CAM (or both CAMs) in mesenchyme decreases to low amounts at the cell surface, and then N-CAM is reexpressed. In mode II, one or the other CAM disappears from epithelia expressing both CAMs. As a result of the primary processes of development, collectives of cells linked by N-CAM and undergoing modulation mode I are brought into the proximity of collectives of cells linked by L-CAM plus N-CAM or by L-CAM undergoing modulation mode II. Such adjoining cell collectives or CAM couples were found at all sites of embryonic induction examined. Images PMID:3863135

  6. Cell adhesion molecules: detection with univalent second antibody

    PubMed Central

    1980-01-01

    Identification of cell surface molecules that play a role in cell-cell adhesion (here called cell adhesion molecules) has been achieved by demonstrating the inhibitory effect of univalent antibodies that bind these molecules in an in vitro assay of cell-cell adhesion. A more convenient reagent, intact (divalent) antibody, has been avoided because it might agglutinate the cells rather than blocking cell-cell adhesion. In this report, we show that intact rabbit immunoglobulin directed against certain cell surface molecules of Dictyostelium discoideum blocks cell-cell adhesion when the in vitro assay is performed in the presence of univalent goat anti-rabbit antibody. Under appropriate experimental conditions, the univalent second antibody blocks agglutination induced by the rabbit antibody without significantly interfering with its effect on cell-cell adhesion. This method promises to be useful for screening monoclonal antibodies raised against potential cell adhesion molecules because: (a) it allows for the screening of large numbers of antibody samples without preparation of univalent fragments; and (b) it requires much less antibody because of the greater affinity of divalent antibodies for antigens. PMID:6970200

  7. Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation.

    PubMed

    Pagoto, Amerigo; Stefania, Rachele; Garello, Francesca; Arena, Francesca; Digilio, Giuseppe; Aime, Silvio; Terreno, Enzo

    2016-08-17

    Inflammation is signaled by the overexpression of epitopes on the vascular endothelium that primarily aim at recruiting immune cells into the inflamed area. The intravascular localization of these biomarkers makes them suitable targets for the MRI visualization of inflammation. Phospholipid-based nanosystems appear excellent candidates in virtue of their good biocompatibility, ability to deliver a high number of imaging units at the target site, and for the easy functionalization with targeting vectors. In this work, phospholipid-based micelles (hydrodynamic diameter of 20 nm) loaded with the amphiphilic Gd(III)-complex Gd-DOTAMA(C18)2 were vectorized with a small peptide able to specifically bind VCAM-1 receptors. The micelles displayed a high longitudinal relaxivity (36.4 s(-1)mmolGd(-1) at 25 °C and 0.7 T). A (1)H- and (17)O-water relaxometry study indicated that the paramagnetic complex embedded in the nanoparticles adopted two isomeric conformations, likely reflecting the well-known square antiprismatic (SAP) and twisted square antiprismatic (TSAP) configurations typically observed in DOTA-like lanthanide complexes. Interestingly, the TSAP structure, showing a much faster exchange rate for the water molecule coordinated to the metal ion, was the most abundant, thus explaining the high relaxivity of the micellar agent. The systemic administration of the micelles into a lipopolysaccharide-induced murine model of acute inflammation successfully demonstrated the ability of the targeting agents to detect the diseased area by T1 contrast enhanced MRI. PMID:27315634

  8. Increased plasma sVCAM-1 is associated with severity in IgA nephropathy

    PubMed Central

    2013-01-01

    Background A considerable proportion of IgAN patients present with histological vasculitic/crescentic lesions in glomeruli, indicating activation of vascular inflammation. Using sVCAM-1, a well-proven marker for endothelial injury under inflammatory processes, we investigated vascular injury and its association with clinical and pathological manifestations in IgAN patients. Methods In this study, 327 biopsy-proven IgAN patients and 55 healthy controls were enrolled. The Oxford classification and two variables, Active Crescentic Lesion Percentage (ACLP) and Chronic Glomerular Lesion Percentage (CGLP), were used for evaluating pathological lesions. Human Umbilical Vein Endothelial Cells were treated with 25-400 ug/ml IgA1. sVCAM-1 in plasma and culture supernatant were measured by ELISA. Results Plasma sVCAM-1 in IgAN patients was significantly higher than healthy controls. In patients with IgAN, plasma sVCAM-1 was significantly correlated with eGFR, 24h urine protein excretion, tubular atrophy/interstitial fibrosis lesion and ACLP, but not CGLP. Meanwhile, compared to healthy volunteers, IgA1 from IgAN patients showed a tendency to increase the HUVECs supernatant sVCAM-1 expression. And IgA1 induced the sVCAM-1 increasing from HUVECs in time- and dose-dependent manner. Conclusions We found increased plasma sVCAM-1 in IgAN patients and its association with severe clinical and pathological manifestations, which might be partly resulted from effect of IgA1 to endothelial cells. PMID:23336423

  9. Dehydrodiconiferyl alcohol suppresses monocyte adhesion to endothelial cells by attenuation of JNK signaling pathway.

    PubMed

    Tsuneyoshi, Tadamitsu; Kanamori, Yuta; Matsutomo, Toshiaki; Morihara, Naoaki

    2015-09-25

    Several clinical studies have shown that the intake of aged garlic extract improves endothelial dysfunction. Lignan compounds, (+)-(2S,3R)-dehydrodiconiferyl alcohol (DDC) and (-)-(2R,3S)-dihydrodehydrodiconiferyl alcohol (DDDC), have been isolated as antioxidants in aged garlic extract. There is evidence showing the importance of oxidative stress in endothelial dysfunction. In the present study, we examined whether DDC and DDDC enhance endothelial cell function in vitro. Cell adhesion assay was performed using THP-1 monocyte and human umbilical vein endothelial cells (HUVECs) which were activated by lipopolysaccharide (LPS) or advanced glycation end products (AGEs)-BSA. Cellular ELISA method was used for the evaluation of vascular cell adhesion molecule 1 (VCAM-1) expression on HUVECs. DDC and DDDC suppressed the adhesion of THP-1 to HUVECs which was activated by LPS or AGEs-BSA. DDC and DDDC also inhibited VCAM-1 expression induced by LPS or AGEs-BSA, but DDDC was less effective than DDC. In addition, the inhibitory effect of DDC on VCAM-1 expression involved suppressing JNK/c-Jun pathway rather than NF-κB pathway. DDC has an inhibitory effect on VCAM-1 expression via JNK pathway in endothelial cells and therefore may serve as a novel pharmacological agent to improve endothelial dysfunction. PMID:26271597

  10. Adhesion Proteins - An Impact on Skeletal Myoblast Differentiation

    PubMed Central

    Przewoźniak, Marta; Czaplicka, Iwona; Czerwińska, Areta M.; Markowska-Zagrajek, Agnieszka; Moraczewski, Jerzy; Stremińska, Władysława; Jańczyk-Ilach, Katarzyna; Ciemerych, Maria A.; Brzoska, Edyta

    2013-01-01

    Formation of mammalian skeletal muscle myofibers, that takes place during embryogenesis, muscle growth or regeneration, requires precise regulation of myoblast adhesion and fusion. There are few evidences showing that adhesion proteins play important role in both processes. To follow the function of these molecules in myoblast differentiation we analysed integrin alpha3, integrin beta1, ADAM12, CD9, CD81, M-cadherin, and VCAM-1 during muscle regeneration. We showed that increase in the expression of these proteins accompanies myoblast fusion and myotube formation in vivo. We also showed that during myoblast fusion in vitro integrin alpha3 associates with integrin beta1 and ADAM12, and also CD9 and CD81, but not with M-cadherin or VCAM-1. Moreover, we documented that experimental modification in the expression of integrin alpha3 lead to the modification of myoblast fusion in vitro. Underexpression of integrin alpha3 decreased myoblasts' ability to fuse. This phenomenon was not related to the modifications in the expression of other adhesion proteins, i.e. integrin beta1, CD9, CD81, ADAM12, M-cadherin, or VCAM-1. Apparently, aberrant expression only of one partner of multiprotein adhesion complexes necessary for myoblast fusion, in this case integrin alpha3, prevents its proper function. Summarizing, we demonstrated the importance of analysed adhesion proteins in myoblast fusion both in vivo and in vitro. PMID:23671573

  11. Regulation of endothelial VCAM-1 expression in murine cardiac grafts. Roles for TNF and IL4.

    PubMed Central

    Bergese, S.; Pelletier, R.; Vallera, D.; Widmer, M.; Orosz, C.

    1995-01-01

    The in vivo mechanisms of vascular endothelial activation and VCAM-1 expression were studied in murine heterotopic cardiac grafts. Preliminary studies demonstrated that cardiac allograft endothelia develop reactivity with MECA-32 monoclonal antibody (MAb) and M/K-2 (anti-VCAM-1) MAb within 3 days of transplantation, whereas cardiac isografts develop MECA-32 reactivity but no M/K-2 reactivity. Additional studies demonstrated that a single treatment of cardiac isograft recipients with the anti-CD3 MAb 145-2C11 induces VCAM-1 expression on isograft microvascular endothelia within 24 hours. We have used this experimental system to identify the cytokines responsible for expression of VCAM-1 and MECA-32 MAb reactivity on graft vascular endothelia. We report that the expression of VCAM-1 on isograft endothelia that was induced with anti-CD3 MAb was blocked by simultaneous treatment with either pentoxifylline, soluble tumor necrosis factor (TNF) receptor (TNFR-Fc), anti-IL4 MAb, or soluble IL4R, but not by anti-IFN-gamma MAb. Alternatively, a similar pattern of isograft endothelial VCAM-1 expression was stimulated in the absence of anti-CD3 MAbs with a single injection of human recombinant TNF-alpha, or with recombinant murine IL4 provided as IL4/anti-IL4 MAb complexes. In addition, the IL4-induced VCAM-1 expression was completely blocked by a single intravenous treatment of the isograft recipients with TNFR:Fc. This suggests that high concentrations of TNF-alpha can stimulate endothelial VCAM-1 expression, but these concentrations are apparently not achieved in cardiac isografts. In the absence of an inducing agent such as anti-CD3 MAb, the stimulation of VCAM-1 expression with exogenous IL4 may reflect functional interaction between endogenous TNF and exogenous IL4, as suggested by the blocking experiments with TNFR:Fc. Although cardiac isograft endothelia normally develop reactivity with MECA-32 MAb within 3 days of transplantation, treatment of cardiac isograft

  12. Cell Adhesion Molecules and Ubiquitination—Functions and Significance

    PubMed Central

    Homrich, Mirka; Gotthard, Ingo; Wobst, Hilke; Diestel, Simone

    2015-01-01

    Cell adhesion molecules of the immunoglobulin (Ig) superfamily represent the biggest group of cell adhesion molecules. They have been analyzed since approximately 40 years ago and most of them have been shown to play a role in tumor progression and in the nervous system. All members of the Ig superfamily are intensively posttranslationally modified. However, many aspects of their cellular functions are not yet known. Since a few years ago it is known that some of the Ig superfamily members are modified by ubiquitin. Ubiquitination has classically been described as a proteasomal degradation signal but during the last years it became obvious that it can regulate many other processes including internalization of cell surface molecules and lysosomal sorting. The purpose of this review is to summarize the current knowledge about the ubiquitination of cell adhesion molecules of the Ig superfamily and to discuss its potential physiological roles in tumorigenesis and in the nervous system. PMID:26703751

  13. Evaluation of ICAM-1 and VCAM-1 Gene Polymorphisms in Patients with Periodontal Disease

    PubMed Central

    Wang, Li; Li, Xiao-Hong; Ning, Wan-Chen

    2016-01-01

    Background We aimed to investigate the potential genetic relationships between the polymorphisms of gene rs5498 ICAM-1 and rs1041163 VCAM-1 and chronic periodontitis in a Chinese population within Heilongjiang. Material/Methods Genomic DNA was extracted from oral mucosa cells of 584 periodontal patients and 182 healthy individuals. Genotyping of the rs5498 ICAM-1 and rs1041163 VCAM-1 gene polymorphisms was performed with the Multiplex SNaPshot technique. Results Statistically significant associations were identified between the chronic periodontal patients and the controls in the gene polymorphisms of rs5498 ICAM-1 (P=0.007) and rs1041163 VCAM-1 (P=0.029). The distribution of rs5498 (P=0.029) and rs1041163 (P=0.049) differed significantly across the mild, moderate, and severe groups of periodontitis. Conclusions Our findings indicate that ICAM-1 rs5498 and VCAM-1 rs1041163 polymorphisms contribute to chronic periodontitis, and ICAM-1 rs5498 and VCAM-1 rs1041163 gene polymorphisms might be associated with periodontitis severity in the Heilongjiang Chinese population. Further studies should be conducted to determine whether these polymorphisms could be used as biomarkers of periodontitis. PMID:27391418

  14. Evaluation of ICAM-1 and VCAM-1 Gene Polymorphisms in Patients with Periodontal Disease.

    PubMed

    Wang, Li; Li, Xiao-Hong; Ning, Wan-Chen

    2016-01-01

    BACKGROUND We aimed to investigate the potential genetic relationships between the polymorphisms of gene rs5498 ICAM-1 and rs1041163 VCAM-1 and chronic periodontitis in a Chinese population within Heilongjiang. MATERIAL AND METHODS Genomic DNA was extracted from oral mucosa cells of 584 periodontal patients and 182 healthy individuals. Genotyping of the rs5498 ICAM-1 and rs1041163 VCAM-1 gene polymorphisms was performed with the Multiplex SNaPshot technique. RESULTS Statistically significant associations were identified between the chronic periodontal patients and the controls in the gene polymorphisms of rs5498 ICAM-1 (P=0.007) and rs1041163 VCAM-1 (P=0.029). The distribution of rs5498 (P=0.029) and rs1041163 (P=0.049) differed significantly across the mild, moderate, and severe groups of periodontitis. CONCLUSIONS Our findings indicate that ICAM-1 rs5498 and VCAM-1 rs1041163 polymorphisms contribute to chronic periodontitis, and ICAM-1 rs5498 and VCAM-1 rs1041163 gene polymorphisms might be associated with periodontitis severity in the Heilongjiang Chinese population. Further studies should be conducted to determine whether these polymorphisms could be used as biomarkers of periodontitis. PMID:27391418

  15. Adhesion Molecules: Master Controllers of the Circulatory System.

    PubMed

    Schmidt, Eric P; Kuebler, Wolfgang M; Lee, Warren L; Downey, Gregory P

    2016-03-15

    This manuscript will review our current understanding of cellular adhesion molecules (CAMs) relevant to the circulatory system, their physiological role in control of vascular homeostasis, innate and adaptive immune responses, and their importance in pathophysiological (disease) processes such as acute lung injury, atherosclerosis, and pulmonary hypertension. This is a complex and rapidly changing area of research that is incompletely understood. By design, we will begin with a brief overview of the structure and classification of the major groups of adhesion molecules and their physiological functions including cellular adhesion and signaling. The role of specific CAMs in the process of platelet aggregation and hemostasis and leukocyte adhesion and transendothelial migration will be reviewed as examples of the complex and cooperative interplay between CAMs during physiological and pathophysiological processes. The role of the endothelial glycocalyx and the glycobiology of this complex system related to inflammatory states such as sepsis will be reviewed. We will then focus on the role of adhesion molecules in the pathogenesis of specific disease processes involving the lungs and cardiovascular system. The potential of targeting adhesion molecules in the treatment of immune and inflammatory diseases will be highlighted in the relevant sections throughout the manuscript.

  16. Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR.

    PubMed

    Banerjee, Nivedita; Kim, Hyemee; Talcott, Stephen; Mertens-Talcott, Susanne

    2013-12-01

    The antitumorigenic activities of polyphenols such as ellagitannins and anthocyanins in pomegranate (Punica granatum L.) have been previously studied where cytotoxic, anti-inflammatory and antioxidant effects were evident in various cancer models. The objective of this study was to investigate the role of miR-126/vascular cell adhesion molecule 1 (VCAM-1) and miR-126/phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) in pomegranate-mediated anti-inflammatory and anticarcinogenic effects in vivo and in vitro. Sprague-Dawley rats (n = 10 per group) received pomegranate juice (2504.74 mg gallic acid equivalents/l) or a polyphenol-free control beverage ad libitum for 10 weeks and were injected with azoxymethane (AOM) subcutaneously (15mg/kg) at weeks 2 and 3. Consumption of pomegranate juice suppressed the number of aberrant crypt foci (ACF) and dysplastic ACF by 29 and 53.5% (P = 0.05 and 0.04), respectively, and significantly lowered proliferation of mucosa cells. Pomegranate juice significantly downregulated proinflammatory enzymes nitric oxide synthase and cyclooxygenase-2 messenger RNA (mRNA) and protein expression. In addition, it suppressed nuclear factor-κB and VCAM-1 mRNA and protein expression in AOM-treated rats. Pomegranate also inhibited phosphorylation of PI3K/AKT and mTOR expression and increased the expression of miR-126. The specific target and functions of miR-126 were investigated in HT-29 colon cancer cell lines. In vitro, the involvement of miR-126 was confirmed using the antagomiR for miR-126, where pomegranate reversed the effects of the antagomiR on the expression of miR-126, VCAM-1 and PI3K p85β. In summary, therapeutic potentials of pomegranate in colon tumorigenesis were due in part to targeting miR-126-regulated pathways, which contributes in the underlying anti-inflammatory mechanisms.

  17. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    SciTech Connect

    Zhang, Feng; Ren, Jingyi; Chan, Kenneth; Chen, Hong

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  18. Sida rhomboidea.Roxb aqueous extract down-regulates in vivo expression of vascular cell adhesion molecules in atherogenic rats and inhibits in vitro macrophage differentiation and foam cell formation.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Salunke, Sunita P; Devkar, Ranjitsinh V; Ramachandran, A V

    2012-10-01

    The present study evaluates efficacy of Sida rhomboidea.Roxb (SR) leaves extract in ameliorating experimental atherosclerosis using in vitro and in vivo experimental models. Atherogenic (ATH) diet fed rats recorded significant increment in the serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very LDL (VLDL), autoantibody against oxidized LDL (Ox-LDL), markers of LDL oxidation and decrement in high-density lipoprotein (HDL) along with increment in aortic TC and TG. The ex vivo LDL oxidation assay revealed an increased susceptibility of LDL isolated from ATH rats to undergo copper mediated oxidation. These set of changes were minimized by simultaneous co-supplementation of SR extract to ATH diet fed rats. Histopathology of aorta and immunolocalization studies recorded pronounced atheromatous plaque formation, vascular calcification, significant elastin derangements and higher expression of macrophage surface marker (F4/80), vascular cell adhesion molecule-1 (VCAM-1) and p-selectin in ATH rats. Whereas, ATH+SR rats depicted minimal evidence of atheromatous plaque formation, calcium deposition, distortion/defragmentation of elastin and accumulation of macrophages along with lowered expression of VCAM-1 and P-selectin compared to ATH rats. Further, monocyte to macrophage differentiation and in vitro foam cell formation were significantly attenuated in presence of SR extract. In conclusion, SR extract has the potency of controlling experimental atherosclerosis and can be used as promising herbal supplement in combating atherosclerosis.

  19. Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia

    PubMed Central

    2011-01-01

    Objective In this study, we determined circulating levels of C-reactive protein, several cytokines, chemokines, adhesion molecules and angiogenic factors along with those of leptin in healthy non-pregnant and pregnant women and preeclamptic patients, and investigated whether serum leptin levels were related to the clinical characteristics and measured laboratory parameters of the study participants. Methods Sixty preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Levels of leptin and transforming growth factor (TGF)-beta1 in maternal sera were assessed by ELISA. Serum levels of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interferon-gamma-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were determined by multiplex suspension array. Serum C-reactive protein (CRP) concentrations were measured by an autoanalyzer. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were determined by electrochemiluminescence immunoassay. For statistical analyses, non-parametric methods were applied. Results There were significant differences in most of the measured laboratory parameters among the three study groups except for serum IL-1beta and TGF-beta1 levels. Serum leptin levels were significantly higher in preeclamptic patients and healthy pregnant women than in healthy non-pregnant women. Additionally, preeclamptic patients had significantly higher leptin levels as compared to healthy pregnant women. Serum leptin levels were independently associated with BMI in healthy non-pregnant women. In healthy pregnant women, both BMI and serum CRP concentrations showed significant positive linear association with leptin

  20. Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro.

    PubMed

    Wang, Yue; Cao, Jiatian; Fan, Yuqi; Xie, Yushui; Xu, Zuojun; Yin, Zhaofang; Gao, Lin; Wang, Changqian

    2016-06-01

    The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-α (TNF-α)-stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-α-stimulated HUVECs. In addition, the nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-α-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-α stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-κB and MAPK signaling pathways. Furthermore, Bay 11-7082 significantly decreased the phosphorylation of levels extracellular signal-regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-α-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-α-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions. PMID:27122190

  1. Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro

    PubMed Central

    WANG, YUE; CAO, JIATIAN; FAN, YUQI; XIE, YUSHUI; XU, ZUOJUN; YIN, ZHAOFANG; GAO, LIN; WANG, CHANGQIAN

    2016-01-01

    The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-α (TNF-α)-stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-α-stimulated HUVECs. In addition, the nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-α-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-α stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-κB and MAPK signaling pathways. Furthermore, Bay 11-7082 significantly decreased the phosphorylation of levels extracellular signal-regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-α-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-α-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions. PMID:27122190

  2. Specific biomembrane adhesion -Indirect lateral interactions between bound receptor molecules

    NASA Astrophysics Data System (ADS)

    Maier, C. W.; Behrisch, A.; Kloboucek, A.; Simson, D. A.; Merkel, R.

    We studied biomembrane adhesion using the micropipet aspiration technique. Adhesion was caused by contact site A, a laterally mobile and highly specific cell adhesion molecule from Dictyostelium discoideum, reconstituted in lipid vesicles of DOPC (L-α-dioleoylphosphatidylcholine) with an addition of 5 mol % DOPE-PEG{2000} (1,2-diacyl-sn-glycero-3-phosphatidylethanolamine-N-[poly(ethyleneglycol) 2000]). The "fuzzy" membrane mimics the cellular plasma membrane including the glycocalyx. We found adhesion and subsequent receptor migration into the contact zone. Using membrane tension jumps to probe the equation of state of the two-dimensional "gas" of bound receptor pairs within the contact zone, we found strong, attractive lateral interactions.

  3. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1

    PubMed Central

    1995-01-01

    Selectins have previously been shown to tether a flowing leukocyte to a vessel wall and mediate rolling. Here, we report that an intergrin, VLA- 4, can also support tethering and rolling. Blood T lymphocytes and alpha 4 integrin-transfected cells can tether in shear flow, and then roll, through binding of the intergrin VLA-4 to purified VCAM-1 on the wall of a flow chamber. VLA-4 transfectants showed similar tethering and rolling on TNF-stimulated endothelium. Tethering efficiency, rolling velocity, and resistance to detachment are related to VCAM-1 density. Tethering and rolling did not occur on ICAM-1, fibronectin, or fibronectin fragments, and tethering did not require integrin activation or the presence of an alpha 4 cytoplasmic domain. Arrest of rolling cells on VCAM-1 occurred spontaneously, and/or was triggered by integrin activating agents Mn2+, phorbol ester, and mAb TS2/16. These agents, and the alpha 4 cytoplasmic domain, promoted increased resistance to detachment. Together the results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1. PMID:7534768

  4. Effect of Linomide on adhesion molecules, TNF-alpha, nitrogen oxide, and cell adhesion.

    PubMed

    Abdul-Hai, A; Hershkoviz, R; Weiss, L; Lider, O; Slavin, S

    2005-02-01

    Linomide (quinoline-3-carboxamide) is an immunomodulator with anti-inflammatory effects in rodents with autoimmune diseases. Its mode of action still remains to be elucidated. We hypothesized that an investigation of T cell interactions with the extracellular matrix (ECM), composed of glycoproteins such as fibronectin (FN) and laminin (LN), might provide better understanding of their in vivo mode of action in extravascular inflammatory sites. We examined the effect of Linomide on T cell adhesion to intact ECM, and separately to LN, and FN, and on the release and production of tumor necrosis factor (TNFalpha) and nitrogen oxide (NO) in relation to adhesive molecules in non-obese diabetic (NOD) female spleen cells, focusing on intracellular adhesion molecule-1 (ICAM-1) and CD44. NOD female mice that developed spontaneous autoimmune insulitis, which destroys pancreatic islets and subsequently leads to insulin-deficient diabetes mellitus, were studied. Linomide, given in the drinking water or added to tissue cultures in vitro, inhibited the beta1 integrin-mediated adhesion of T cells to ECM, FN and LN, as well as the production and release of TNFalpha and NO, which play a major role in the induction and propagation of T cell-mediated insulitis. In addition, exposure of T cells to Linomide resulted in increased expression of CD44 and ICAM-1 molecules on spleen cells of Linomide-treated mice; such an increase in adhesion molecule expression may lead to more effective arrest of T cell migration in vivo. The regulation of T-cell adhesion, adhesion receptor expression, and inhibition of TNFalpha and NO secretion by Linomide may explain its beneficial role and provide a new tool for suppressing self-reactive T cell-dependent autoimmune diseases. PMID:15652754

  5. Ionizing radiation increases adhesiveness of human aortic endothelial cells via a chemokine-dependent mechanism.

    PubMed

    Khaled, Saman; Gupta, Kiran B; Kucik, Dennis F

    2012-05-01

    Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Since radiation also induces inflammation, a possible mechanism is a change in the adhesiveness of vascular endothelial cells, triggering pro-atherogenic accumulation of leukocytes. To investigate this mechanism at the cellular level, the effect of X rays on adhesiveness of cultured human aortic endothelial cells (HAECs) was determined. HAECs were grown as monolayers and exposed to 0 to 30 Gy X rays, followed by measurement of adhesiveness under physiological shear stress using a flow chamber adhesion assay. Twenty-four hours after irradiation, HAEC adhesiveness was increased, with a peak effect at 15 Gy. Radiation had no significant effect on surface expression of the endothelial adhesion molecules ICAM-1 and VCAM-1. Antibody blockade of the leukocyte integrin receptors for ICAM-1 and VCAM-1, however, abolished the radiation-induced adhesiveness. Since these leukocyte integrins can be activated by chemokines presented on the endothelial cell surface, the effect of pertussis toxin (PTX), an inhibitor of chemokine-mediated integrin activation, was tested. PTX specifically inhibited radiation-induced adhesiveness, with no significant effect on nonirradiated cells. Therefore, radiation induces increased adhesiveness of aortic endothelial cells through chemokine-dependent signaling from endothelial cells to leukocytes, even in the absence of increased expression of the adhesion molecules involved.

  6. Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules neurexin and neuroligin.

    PubMed

    Tanaka, Hiroki; Miyazaki, Naoyuki; Matoba, Kyoko; Nogi, Terukazu; Iwasaki, Kenji; Takagi, Junichi

    2012-07-26

    Polymorphic adhesion molecules neurexin and neuroligin (NL) mediate asymmetric trans-synaptic adhesion, which is crucial for synapse development and function. It is not known whether or how individual synapse function is controlled by the interactions between variants and isoforms of these molecules with differing ectodomain regions. At a physiological concentration of Ca(2+), the ectodomain complex of neurexin-1 β isoform (Nrx1β) and NL1 spontaneously assembled into crystals of a lateral sheet-like superstructure topologically compatible with transcellular adhesion. Correlative light-electron microscopy confirmed extracellular sheet formation at the junctions between Nrx1β- and NL1-expressing non-neuronal cells, mimicking the close, parallel synaptic membrane apposition. The same NL1-expressing cells, however, did not form this higher-order architecture with cells expressing the much longer neurexin-1 α isoform, suggesting a functional discrimination mechanism between synaptic contacts made by different isoforms of neurexin variants.

  7. Differential adhesiveness between blood and marrow leukemic cells having similar pattern of VLA adhesion molecule expression.

    PubMed

    Thomas, X; Anglaret, B; Bailly, M; Maritaz, O; Magaud, J P; Archimbaud, E

    1998-10-01

    Functional adhesion of blood and marrow leukemic cells from 14 acute myeloid leukemia patients presenting with hyperleukocytosis was evaluated by performing cytoadhesion assays on purified (extracellular matrix proteins) and non-purified supports (MRC5 fibroblastic cell line). Results, in 30-min chromium release assay, show a mean +/- S.D. adhesion to fibronectin, collagen, and laminin respectively of 30 +/- 17%, 20 +/- 13%, 25 +/- 17% for blood leukemic cells and 18 +/- 11%, 11 +/- 10%, 11 +/- 8% for marrow leukemic cells. These differences between blood and marrow cells were statistically significant (respectively P = 0.005, P = 0.01 and P = 0.002), while no difference was noted regarding adhesion to non-purified supports. The higher adhesion of blood blast cells to purified supports was observed regardless of CD34 expression. No significant difference was observed in the expression of cell surface VLA-molecules (CD29, CD49b, CD49d, CD49e, CD49f) between blood and marrow blast cells. The addition of GM-CSF or G-CSF induced increased adhesion of marrow blasts and decreased adhesion of blood blasts leading to a loss of the difference between blood and marrow cells. In a 60-min chromium release assay, marrow blasts adhered even more than blood leukemic cells to fibronectin. In contrast, marrow blasts from 'aleukemic' acute myeloid leukemia patients did not show any modification regarding their adhesion to extracellular matrix proteins when co-cultured with growth factors. PMID:9766756

  8. Characterization of a Distinct Population of Circulating Human Non-Adherent Endothelial Forming Cells and Their Recruitment via Intercellular Adhesion Molecule-3

    PubMed Central

    Thompson, Emma J.; Barrett, Jeffrey M.; Tooley, Katie; Sen, Shaundeep; Sun, Wai Yan; Grose, Randall; Nicholson, Ian; Levina, Vitalina; Cooke, Ira; Talbo, Gert; Lopez, Angel F.; Bonder, Claudine S.

    2012-01-01

    Circulating vascular progenitor cells contribute to the pathological vasculogenesis of cancer whilst on the other hand offer much promise in therapeutic revascularization in post-occlusion intervention in cardiovascular disease. However, their characterization has been hampered by the many variables to produce them as well as their described phenotypic and functional heterogeneity. Herein we have isolated, enriched for and then characterized a human umbilical cord blood derived CD133+ population of non-adherent endothelial forming cells (naEFCs) which expressed the hematopoietic progenitor cell markers (CD133, CD34, CD117, CD90 and CD38) together with mature endothelial cell markers (VEGFR2, CD144 and CD31). These cells also expressed low levels of CD45 but did not express the lymphoid markers (CD3, CD4, CD8) or myeloid markers (CD11b and CD14) which distinguishes them from ‘early’ endothelial progenitor cells (EPCs). Functional studies demonstrated that these naEFCs (i) bound Ulex europaeus lectin, (ii) demonstrated acetylated-low density lipoprotein uptake, (iii) increased vascular cell adhesion molecule (VCAM-1) surface expression in response to tumor necrosis factor and (iv) in co-culture with mature endothelial cells increased the number of tubes, tubule branching and loops in a 3-dimensional in vitro matrix. More importantly, naEFCs placed in vivo generated new lumen containing vasculature lined by CD144 expressing human endothelial cells (ECs). Extensive genomic and proteomic analyses of the naEFCs showed that intercellular adhesion molecule (ICAM)-3 is expressed on their cell surface but not on mature endothelial cells. Furthermore, functional analysis demonstrated that ICAM-3 mediated the rolling and adhesive events of the naEFCs under shear stress. We suggest that the distinct population of naEFCs identified and characterized here represents a new valuable therapeutic target to control aberrant vasculogenesis. PMID:23144795

  9. The ubiquitous neural cell adhesion molecule (N-CAM).

    PubMed

    Weledji, Elroy P; Assob, Jules C

    2014-09-01

    Adhesive interactions are important for cell trafficking, differentiation, function and tissue differentiation. Neural cell adhesion molecule (NCAM) is involved in a diverse range of contact-mediated interactions among neurons, astrocytes, oligodendrocytes, and myotubes. It is widely but transiently expressed in many tissues early in embryogenesis. Four main isoforms exist but there are many other variants resulting from alternative splicing and post-translational modifications. This review discusses the actions and association of N-CAM and variants, PSA CAM. L1CAM and receptor tyrosine kinase. Their interactions with the interstitial cells of Cajal - the pacemaker cells of the gut in the manifestation of gut motility disorders, expression in carcinomas and mesenchymal tumours are discussed. PMID:25568792

  10. P2Y2 Nucleotide Receptor Activation Up-regulates Vascular Cell Adhesion Molecular-1 Expression and Enhances Lymphocyte Adherence to a Human Submandibular Gland Cell Line

    PubMed Central

    Baker, Olga J.; Camden, Jean M.; Rome, Danny E.; Seye, Cheikh I.; Weisman, Gary A.

    2007-01-01

    Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease that causes salivary and lacrimal gland tissue destruction resulting in impaired secretory function. Although lymphocytic infiltration of salivary epithelium is associated with SS, the mechanisms involved have not been adequately elucidated. Our previous studies have shown that the G protein-coupled P2Y2 nucleotide receptor (P2Y2R) is up-regulated in response to damage or stress of salivary gland epithelium, and in salivary glands of the NOD.B10 mouse model of SS-like autoimmune exocrinopathy. Additionally, we have shown that P2Y2R activation up-regulates vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells leading to the binding of monocytes. The present study demonstrates that activation of the P2Y2R in dispersed cell aggregates from rat submandibular gland (SMG) and in human submandibular gland ductal cells (HSG) up-regulates the expression of VCAM-1. Furthermore, P2Y2R activation mediated the up-regulation of VCAM-1 expression in HSG cells leading to increased adherence of lymphocytic cells. Inhibitors of EGFR phosphorylation and metalloprotease activity abolished P2Y2R-mediated VCAM-1 expression and decreased lymphocyte binding to HSG cells. Moreover, silencing of EGFR expression abolished UTP-induced VCAM-1 up-regulation in HSG cells. These results suggest that P2Y2R activation in salivary gland cells increases the EGFR-dependent expression of VCAM-1 and the binding of lymphocytes, a pathway relevant to inflammation associated with SS. PMID:17599409

  11. Genetic variation in CD36, HBA, NOS3 and VCAM1 is associated with chronic haemolysis level in sickle cell anaemia: a longitudinal study.

    PubMed

    Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Nunes, Baltazar; Ferreira, Emanuel; Picanço, Isabel; Faustino, Paula; Lavinha, João

    2014-03-01

    Chronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P < 0.05) association was observed, the following ones were confirmed upon correction for multiple comparisons: (i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.

  12. Carotid Endothelial VCAM-1 Is an Early Marker of Carotid Atherosclerosis and Predicts Coronary Artery Disease in Swine

    PubMed Central

    Masseau, I.; Bowles, D. K.

    2015-01-01

    Objective The aim was to determine if endothelial VCAM-1 (eVCAM-1) expression in the common carotid artery (CCA) would correlate with predictive markers of atherosclerotic disease, would precede reduction of markers of endothelial cell function and would predict coronary artery disease (CAD). Methods and results Carotid arterial segments (bifurcation, proximal and distal CCA) were harvested from 14 and 24 month-old male castrated familial hypercholesterolemic (FH) swine, a model of spontaneous atherosclerosis. Quantification of local expression of eVCAM-1, intimal macrophage accumulation, oxidative stress, intima-media (I/M) ratio, intima-media thickness (IMT), endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) in selected regions of the carotids revealed a relationship between local inflammation and atheroscle-rotic plaque progression. Importantly, inflammation was not uniform throughout the CCA. Endo-thelial VCAM-1 expression was the greatest at the bifurcation and increased with age. Finally, eV-CAM-1 best estimated the severity of CAD compared to blood levels of glucose, hypercholestero-lemia, carotid IMT, and p-eNOS. Conclusion Our data suggested that eVCAM-1 was closely associated with atherosclerotic plaque progression and preceded impairment of EDD. Thus, this study supported the use of carotid VCAM-1 targeting agents to estimate the severity of CAD. PMID:26702331

  13. Analysis of Adhesion Molecules and Basement Membrane Contributions to Synaptic Adhesion at the Drosophila Embryonic NMJ

    PubMed Central

    Koper, Andre; Schenck, Annette; Prokop, Andreas

    2012-01-01

    Synapse formation and maintenance crucially underlie brain function in health and disease. Both processes are believed to depend on cell adhesion molecules (CAMs). Many different classes of CAMs localise to synapses, including cadherins, protocadherins, neuroligins, neurexins, integrins, and immunoglobulin adhesion proteins, and further contributions come from the extracellular matrix and its receptors. Most of these factors have been scrutinised by loss-of-function analyses in animal models. However, which adhesion factors establish the essential physical links across synaptic clefts and allow the assembly of synaptic machineries at the contact site in vivo is still unclear. To investigate these key questions, we have used the neuromuscular junction (NMJ) of Drosophila embryos as a genetically amenable model synapse. Our ultrastructural analyses of NMJs lacking different classes of CAMs revealed that loss of all neurexins, all classical cadherins or all glutamate receptors, as well as combinations between these or with a Laminin deficiency, failed to reveal structural phenotypes. These results are compatible with a view that these CAMs might have no structural role at this model synapse. However, we consider it far more likely that they operate in a redundant or well buffered context. We propose a model based on a multi-adaptor principle to explain this phenomenon. Furthermore, we report a new CAM-independent adhesion mechanism that involves the basement membranes (BM) covering neuromuscular terminals. Thus, motorneuronal terminals show strong partial detachment of the junction when BM-to-cell surface attachment is impaired by removing Laminin A, or when BMs lose their structural integrity upon loss of type IV collagens. We conclude that BMs are essential to tie embryonic motorneuronal terminals to the muscle surface, lending CAM-independent structural support to their adhesion. Therefore, future developmental studies of these synaptic junctions in Drosophila need

  14. Expression of intercellular adhesion molecule-1 in rat heart with ischemia/reperfusion and limitation of infarct size by treatment with antibodies against cell adhesion molecules.

    PubMed Central

    Yamazaki, T.; Seko, Y.; Tamatani, T.; Miyasaka, M.; Yagita, H.; Okumura, K.; Nagai, R.; Yazaki, Y.

    1993-01-01

    To elucidate the mechanism(s) of myocardial reperfusion injury, we investigated the roles of cell adhesion molecules on both leukocytes and vascular endothelial cells in the reperfused myocardia. We found that within 2 hours after reperfusion leukocytes began to infiltrate into the rat myocardia subjected to 30 minutes of ischemia and clarified, for the first time, that the expression of intercellular adhesion molecule-1 was enhanced on the capillary and venous endothelial cells from 8 to 96 hours after the start of reperfusion. Furthermore, pretreatment with individual monoclonal antibodies against cell adhesion molecules (CD11a, CD11bc, CD18, and intercellular adhesion molecule-1) reduced not only the infiltration of leukocytes but also the area of infarction in the reperfused hearts. These observations suggest that cell adhesion molecules play a critical role in the pathogenesis of myocardial reperfusion injury. Images Figure 2 Figure 3 Figure 4 PMID:8102030

  15. Both common and specialty mushrooms inhibit adhesion molecule expression and in vitro binding of monocytes to human aortic endothelial cells in a pro-inflammatory environment

    PubMed Central

    2010-01-01

    Background Cardiovascular disease (CVD) is a leading cause of mortality in the United States as well as globally. Epidemiological studies show that regular fruit and vegetable consumption reduces CVD risk, in part, due to antioxidant activity and immunomodulation since oxidative stress and inflammation are features of atherogenesis. Accumulating evidence also shows that dietary fungi, viz., mushrooms, can protect against chronic disease by altering inflammatory environments such as those associated with CVD although most research has focused on specialty mushrooms. In this study, we tested the ability of both common and specialty mushrooms to inhibit cellular processes associated with CVD. Methods Human aortic endothelial cells (HAEC) were incubated overnight with control media with dimethylsulfoxide (DMSO) vehicle (1% v/v) or containing DMSO extracts of whole dehydrated mushrooms (0.1 mg/mL), which included Agaricus bisporus (white button and crimini), Lentinula edodes (shiitake), Pleurotus ostreatus (oyster), and Grifola frondosa (maitake). Monolayers were subsequently washed and incubated with medium alone or containing the pro-inflammatory cytokine IL-1β (5 ng/mL) for 6 h to upregulate pro-atherosclerotic adhesion molecules (AM). AM expression was assayed by ELISA and binding of U937 human monocytes pre-loaded with fluorescent dye was determined. Results White button mushrooms consistently reduced (p < 0.05) VCAM-1, ICAM-1, and E-selectin-1 expression, whereas other test mushrooms significantly modulated AM expression singly, collectively, or combinatorially. All mushrooms, however, significantly reduced binding of monocytes to both quiescent and cytokine-stimulated monolayers. Conclusion These data provide evidence that dietary mushrooms can inhibit cellular processes such as adhesion molecule expression and ultimate binding of monocytes to the endothelium under pro-inflammatory conditions, which are associated with CVD. As a result, these findings support

  16. Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts.

    PubMed

    Sotnikov, Ilya; Hershkoviz, Rami; Grabovsky, Valentin; Ilan, Neta; Cahalon, Liora; Vlodavsky, Israel; Alon, Ronen; Lider, Ofer

    2004-05-01

    During their migration into inflammatory sites, immune cells, such as T cells, secrete extracellular matrix (ECM)-degrading enzymes, such as heparanase, which, under mildly acidic conditions, degrade heparan sulfate proteoglycans (HSPG). We have previously shown that at pH 7.2, human placental heparanase loses its enzymatic activity, while retaining its ability to bind HSPG and promote T cell adhesion to unfractionated ECM. We now demonstrate that the 65-kDa recombinant human heparanase, which is devoid of enzymatic activity, but can still bind HSPG, captures T cells under shear flow conditions and mediates their rolling and arrest, in the absence or presence of stromal cell-derived factor 1 alpha (SDF-1 alpha; CXCL12), in an alpha(4)beta(1)-VCAM-1-dependent manner. Furthermore, heparanase binds to and induces T cell adhesion to key ECM components, like fibronectin and hyaluronic acid, in beta(1) integrin- and CD44-specific manners, respectively, via the activation of the protein kinase C and phosphatidylinositol 3-kinase intracellular signaling machineries. Although the nature of the putative T cell heparanase-binding moiety is unknown, it appears that heparanase exerts its proadhesive activity by interacting with the T cells' surface HSPG, because pretreatment of the cells with heparinase abolished their subsequent response to heparanase. Also, heparanase augmented the SDF-1 alpha-triggered phosphorylation of Pyk-2 and extracellular signal-regulated kinase-2 implicated in integrin functioning. Moreover, heparanase, which had no chemotactic effect on T cells on its own, augmented the SDF-1 alpha-induced T cell chemotaxis across fibronectin. These findings add another dimension to the known versatility of heparanase as a key regulator of T cell activities during inflammation, both in the context of the vasculature and at extravascular sites. PMID:15100255

  17. Direct observation of catch bonds involving cell-adhesion molecules

    NASA Astrophysics Data System (ADS)

    Marshall, Bryan T.; Long, Mian; Piper, James W.; Yago, Tadayuki; McEver, Rodger P.; Zhu, Cheng

    2003-05-01

    Bonds between adhesion molecules are often mechanically stressed. A striking example is the tensile force applied to selectin-ligand bonds, which mediate the tethering and rolling of flowing leukocytes on vascular surfaces. It has been suggested that force could either shorten bond lifetimes, because work done by the force could lower the energy barrier between the bound and free states (`slip'), or prolong bond lifetimes by deforming the molecules such that they lock more tightly (`catch'). Whereas slip bonds have been widely observed, catch bonds have not been demonstrated experimentally. Here, using atomic force microscopy and flow-chamber experiments, we show that increasing force first prolonged and then shortened the lifetimes of P-selectin complexes with P-selectin glycoprotein ligand-1, revealing both catch and slip bond behaviour. Transitions between catch and slip bonds might explain why leukocyte rolling on selectins first increases and then decreases as wall shear stress increases. This dual response to force provides a mechanism for regulating cell adhesion under conditions of variable mechanical stress.

  18. Glatiramer acetate (GA) prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway

    SciTech Connect

    Wei, Guoqian; Zhang, Xueyan; Su, Zhendong; Li, Xueqi

    2015-01-30

    Highlights: • GA inhibited TNF-α-induced binding of monocytes to endothelial cells. • GA inhibited the induction of adhesion molecules MCP-1, VCAM-1 and E-selectin. • GA inhibits NF-κB p65 nuclear translocation and transcriptional activity. • GA inhibits TNF-α-induced IκBα degradation. - Abstract: Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of endothelial dysfunction. Exposure to TNF-α induces the expression of a number of proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1), and adhesion molecules, including vascular adhesion molecule-1 (VCAM-1) and E-selectin, which mediate the interaction of invading monocytes with vascular endothelial cells. Glatiramer acetate (GA) is a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). The effects of GA in vascular disease have not shown before. In this study, we found that GA significantly inhibited TNF-α-induced binding of monocytes to endothelial cells. Mechanistically, we found that GA ameliorated the upregulation of MCP-1, VCAM-1, and E-selectin induced by TNF-α. Notably, this process is mediated by inhibiting the nuclear translocation and activation of NF-κB. Our results also indicate that GA pretreatment attenuates the up-regulation of COX-2 and iNOS. These data suggest that GA might have a potential benefit in therapeutic endothelial dysfunction related diseases.

  19. Cooperative inhibitory effects of antisense oligonucleotide of cell adhesion molecules and cimetidine on cancer cell adhesion

    PubMed Central

    Tang, Nan-Hong; Chen, Yan-Ling; Wang, Xiao-Qian; Li, Xiu-Jin; Yin, Feng-Zhi; Wang, Xiao-Zhong

    2004-01-01

    AIM: To explore the cooperative effects of antisense oligonucleotide (ASON) of cell adhesion molecules and cimetidine on the expression of E-selectin and ICAM-1 in endothelial cells and their adhesion to tumor cells. METHODS: After treatment of endothelial cells with ASON and/or cimetidine and induction with TNF-α, the protein and mRNA changes of E-selectin and ICAM-1 in endothelial cells were examined by flow cytometry and RT-PCR, respectively. The adhesion rates of endothelial cells to tumor cells were measured by cell adhesion experiment. RESULTS: In comparison with TNF-α inducing group, lipo-ASON and lipo-ASON/cimetidine could significantly decrease the protein and mRNA levels of E-selectin and ICAM-1 in endothelial cells, and lipo-ASON/cimetidine had most significant inhibitory effect on E-selectin expression (from 36.37 ± 1.56% to 14.23 ± 1.07%, P < 0.001). Meanwhile, cimetidine alone could inhibit the expression of E-selectin (36.37 ± 1.56% vs 27.2 ± 1.31%, P < 0.001), but not ICAM-1 (69.34 ± 2.50% vs 68.07 ± 2.10%, P > 0.05)and the two kinds of mRNA, either. Compared with TNF-α inducing group, the rate of adhesion was markedly decreased in lipo-E-selectin ASON and lipo-E-selectin ASON/cimetidine treated groups(P < 0.05), and lipo-E-selectin ASON/cimetidine worked better than lipo-E-selectin ASON alone except for HepG2/ECV304 group (P < 0.05). However, the decrease of adhesion was not significant in lipo-ICAM-1 ASON and lipo-ICAM-1 ASON/cimetidine treated groups except for HepG2/ECV304 group (P > 0.05). CONCLUSION: These data demonstrate that ASON in combination with cimetidine in vitro can significantly reduce the adhesion between endothelial cells and hepatic or colorectal cancer cells, which is stronger than ASON or cimetidine alone. This study provides some useful proofs for gene therapy of antiadhesion. PMID:14695770

  20. Exenatide Alters Gene Expression of Neural Cell Adhesion Molecule (NCAM), Intercellular Cell Adhesion Molecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) in the Hippocampus of Type 2 Diabetic Model Mice.

    PubMed

    Gumuslu, Esen; Cine, Naci; Ertan Gökbayrak, Merve; Mutlu, Oguz; Komsuoglu Celikyurt, Ipek; Ulak, Guner

    2016-01-01

    BACKGROUND Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. MATERIAL AND METHODS The present study demonstrated the effects of exenatide treatment (0.1 µg/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. RESULTS The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. CONCLUSIONS Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM. PMID:27465247

  1. Exenatide Alters Gene Expression of Neural Cell Adhesion Molecule (NCAM), Intercellular Cell Adhesion Molecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) in the Hippocampus of Type 2 Diabetic Model Mice

    PubMed Central

    Gumuslu, Esen; Cine, Naci; Gökbayrak, Merve Ertan; Mutlu, Oguz; Celikyurt, Ipek Komsuoglu; Ulak, Guner

    2016-01-01

    Background Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. Material/Methods The present study demonstrated the effects of exenatide treatment (0.1 μg/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. Results The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. Conclusions Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM. PMID:27465247

  2. Carbohydrate ligands for endothelial - Leukocyte adhesion molecule 1

    SciTech Connect

    Tiemeyer, M.; Swiedler, S.J.; Ishihara, Masayuki; Moreland, M.; Schweingruber, H.; Hirtzer, P.; Brandley, B.K. )

    1991-02-15

    The acute inflammatory response requires that circulating leukocytes bind to and penetrate the vascular wall to access the site of injury. Several receptors have been implicated in this interaction, including a family of putative carbohydrate-binding proteins. The authors report here the identification of an endogenous carbohydrate ligand for one of these receptors, endothelial-leukocyte adhesion molecule 1 (ELAM-1). Radiolabeled COS cells transfected with a plasmid containing the cDNA for ELAM-1 were used as probes to screen glycolipids extracted from human leukocytes. COS cells transfected with this plasmid adhered to a subset of sialylated glycolipids resolved on TLC plates or adsorbed on polyvinyl chloride microtiter wells. Adhesion to these glycolipids required calcium but was not inhibited by heparin, chondroitin sulfate, keratan sulfate, or yeast phosphomannan. Monosaccharide composition, linkage analysis, and fast atom bombardment mass spectrometry of the glycolipids indicate that the ligands for ELAM-1 are terminally sialylated lactosylceramides with a variable number of N-acetyllactosamine repeats and at least one fucosylated N-acetylglucosamine residue.

  3. Cell adhesion molecule control of planar spindle orientation.

    PubMed

    Tuncay, Hüseyin; Ebnet, Klaus

    2016-03-01

    Polarized epithelial cells align the mitotic spindle in the plane of the sheet to maintain tissue integrity and to prevent malignant transformation. The orientation of the spindle apparatus is regulated by the immobilization of the astral microtubules at the lateral cortex and depends on the precise localization of the dynein-dynactin motor protein complex which captures microtubule plus ends and generates pulling forces towards the centrosomes. Recent developments indicate that signals derived from intercellular junctions are required for the stable interaction of the dynein-dynactin complex with the cortex. Here, we review the molecular mechanisms that regulate planar spindle orientation in polarized epithelial cells and we illustrate how different cell adhesion molecules through distinct and non-overlapping mechanisms instruct the cells to align the mitotic spindle in the plane of the sheet. PMID:26698907

  4. The role of endothelial cell adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 in leucocyte recruitment induced by exogenous methylglyoxal.

    PubMed

    Su, Yang; Lei, Xi; Wu, Lingyun; Liu, Lixin

    2012-09-01

    Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In hyperglycaemic conditions, increased MG level has been linked to the development of diabetes and its vascular complications at the macrovascular and microvascular levels where inflammation plays a role. To study the mechanism of MG-induced inflammation in vivo, we applied MG locally to healthy mice and used intravital microscopy to investigate the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in cremasteric microvasculature. Administration of MG (25 and 50 mg/kg) to the tissue dose-dependently induced leucocyte recruitment at 4.0-5.5 hr, with 84-92% recruited cells being neutrophils. Such MG treatment up-regulated the expression of endothelial cell adhesion molecules P-selectin, E-selectin, intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1. Activation of the nuclear factor-κB signalling pathway contributed to MG-induced up-regulation of these adhesion molecules and leucocyte recruitment. The role of the up-regulated endothelial cell adhesion molecules in MG-induced leucocyte recruitment was determined by applying specific functional blocking antibodies to MG-treated animals and observing changes in leucocyte recruitment parameters. Our data demonstrate that the up-regulation of P-selectin, E-selectin and intercellular adhesion molecule-1 contributes to the increased leucocyte rolling flux, reduced leucocyte rolling velocity, and increased leucocyte adhesion, respectively. Our results reveal the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in microvasculature, an inflammatory condition related to diabetic vascular complications.

  5. The role of endothelial cell adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 in leucocyte recruitment induced by exogenous methylglyoxal

    PubMed Central

    Su, Yang; Lei, Xi; Wu, Lingyun; Liu, Lixin

    2012-01-01

    Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In hyperglycaemic conditions, increased MG level has been linked to the development of diabetes and its vascular complications at the macrovascular and microvascular levels where inflammation plays a role. To study the mechanism of MG-induced inflammation in vivo, we applied MG locally to healthy mice and used intravital microscopy to investigate the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in cremasteric microvasculature. Administration of MG (25 and 50 mg/kg) to the tissue dose-dependently induced leucocyte recruitment at 4·0–5·5 hr, with 84–92% recruited cells being neutrophils. Such MG treatment up-regulated the expression of endothelial cell adhesion molecules P-selectin, E-selectin, intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1. Activation of the nuclear factor-κB signalling pathway contributed to MG-induced up-regulation of these adhesion molecules and leucocyte recruitment. The role of the up-regulated endothelial cell adhesion molecules in MG-induced leucocyte recruitment was determined by applying specific functional blocking antibodies to MG-treated animals and observing changes in leucocyte recruitment parameters. Our data demonstrate that the up-regulation of P-selectin, E-selectin and intercellular adhesion molecule-1 contributes to the increased leucocyte rolling flux, reduced leucocyte rolling velocity, and increased leucocyte adhesion, respectively. Our results reveal the role of endothelial cell adhesion molecules in MG-induced leucocyte recruitment in microvasculature, an inflammatory condition related to diabetic vascular complications. PMID:22681228

  6. An extracellular adhesion molecule complex patterns dendritic branching and morphogenesis.

    PubMed

    Dong, Xintong; Liu, Oliver W; Howell, Audrey S; Shen, Kang

    2013-10-10

    Robust dendrite morphogenesis is a critical step in the development of reproducible neural circuits. However, little is known about the extracellular cues that pattern complex dendrite morphologies. In the model nematode Caenorhabditis elegans, the sensory neuron PVD establishes stereotypical, highly branched dendrite morphology. Here, we report the identification of a tripartite ligand-receptor complex of membrane adhesion molecules that is both necessary and sufficient to instruct spatially restricted growth and branching of PVD dendrites. The ligand complex SAX-7/L1CAM and MNR-1 function at defined locations in the surrounding hypodermal tissue, whereas DMA-1 acts as the cognate receptor on PVD. Mutations in this complex lead to dramatic defects in the formation, stabilization, and organization of the dendritic arbor. Ectopic expression of SAX-7 and MNR-1 generates a predictable, unnaturally patterned dendritic tree in a DMA-1-dependent manner. Both in vivo and in vitro experiments indicate that all three molecules are needed for interaction. PMID:24120131

  7. Adhesion Molecule Expression in Human Endothelial Cells under Simulated Microgravity

    NASA Astrophysics Data System (ADS)

    Rudimov, E. G.; Andreeva, E. R.; Buravkova, L. B.

    2013-02-01

    High gravisensitivity of endothelium is now well recognized. Therefore, the microgravity can be one of the main factors affecting the endothelium in space flight. In this work we studied the effects of gravity vector randomization (3D-clinorotation in RPM) on the viability of endothelial cells from human umbilical vein (HUVEC) and the expression of adhesion molecules on its surface. After RPM exposure, HUVEC conditioning medium was collected for cytokines evaluation, a part of vials was used for immunocytochemistry and other one - for cytofluorimetric analysis of ICAM-I, VCAM-I, PECAM-I, E-selectin, Endoglin, VE-cadherin expression. The viability of HUVEC and constitutive expression of EC marker molecules PECAM-I and Endoglin were similar in all experimental groups both after 6 and 24 hrs of exposure. There were no differences in ICAM-I and E-selectin expression on HUVEC in 3 groups after 6 hrs of exposure. 24 hrs incubation has provoked decrease in ICAM-I and E-selectin expression. Thus, gravity vector randomization can lead to the disruption of ECs monolayer.

  8. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.

    PubMed

    Tichet, Mélanie; Prod'Homme, Virginie; Fenouille, Nina; Ambrosetti, Damien; Mallavialle, Aude; Cerezo, Michael; Ohanna, Mickaël; Audebert, Stéphane; Rocchi, Stéphane; Giacchero, Damien; Boukari, Fériel; Allegra, Maryline; Chambard, Jean-Claude; Lacour, Jean-Philippe; Michiels, Jean-François; Borg, Jean-Paul; Deckert, Marcel; Tartare-Deckert, Sophie

    2015-04-30

    Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

  9. Differential Role of a NF-kappaB Transcriptional Response Element in Endothelial versus Intimal Cell VCAM-1 Expression

    PubMed Central

    Milstone, David S.; Ilyama, Motoi; Chen, Mian; O’Donnell, Peter; Davis, Vannessa M.; Plutzky, Jorge; Brown, Jonathan D.; Haldar, Saptarsi M.; Siu, Allan; Lau, Andrew C.; Zhu, Su-Ning; Basheer, Mayada F.; Collins, Tucker; Jongstra-Bilen, Jenny; Cybulsky, Myron I.

    2016-01-01

    Rationale Human and murine Vcam1 promoters contain 2 adjacent NF-κB-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown. Objective Determine the role of the 5′ NF-κB binding element in expression of the endogenous Vcam1 gene. Methods and Results Homologous recombination in embryonic stem cells was used to inactivate the 5′ NF-κB element in the Vcam1 promoter and alter three nucleotides in the 5′ untranslated region to allow direct comparison of wild type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (LPS) induced lower expression of the mutant allele relative to wild type by endothelial cells in the aorta, heart and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/LDL receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished LPS-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild type alleles was comparable in intimal cells of wire-injured carotid artery and 4 to 12-week atherosclerotic lesions. Conclusions This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial VCAM-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries. PMID:26034041

  10. Heterogeneity of cell adhesion molecules in the developing nervous system

    SciTech Connect

    Williams, R.K.

    1985-01-01

    Cell-surface molecules, especially glycoproteins, are believed to mediate interactions between developing neurons and their environment. These interactions include pathfinding by growing processes, recognition of appropriate targets, and formation of synaptic structures. In order to identify neuronal cell-surface molecules, monoclonal antibodies (Mab's) were prepared against synaptic fractions from adult rat brain. From this group three monoclonal antibodies, designated 3C5.59, 3G5.34, and 3G6.41, that react with cell-surface antigens of embryonic neurons were selected for further study. In immunofluoresence experiments each of these antibodies strongly reacted with the processes of cultured granule cell neurons, the major class of small cerebellar neurons, cultured from developing rat cerebellum. Mab's 3C5.59 and 3G5.34 reacted only with neurons in the cerebellar cultures. Mab 3G6.41, however, also reacted with cultured brain astrocytes. On frozen sections Mab's 3G5.34 and 3G6.41 also strongly stained the molecular layer, the site of active granule cell axon growth, in the developing cerebellum. Monoclonal and polyclonal antibodies specific for the neural cell adhesion molecule (N-CAM) were used to compare the two glycoproteins recognized by Mab 3G6.41 with N-CAM. Band 1, another large neuronal cell-surface glycoprotein was originally identified in mouse N18 neuroblastoma cells. In this study /sup 125/I-labeled N18-derived band 1 was tested for binding to 9 plant lectins and Limulus polyphemus agglutinin coupled to agarose beads. Band 1 solubilized from brain also specifically bound to LCA-agarose, indicating that mannose containing sugar moieties are present on band 1 from brain.

  11. Purification, composition, and structure of macrophage adhesion molecule

    SciTech Connect

    Remold-O'Donnell, E.; Savage, B.

    1988-01-12

    Macrophage adhesion molecule (MAM) is a surface heterodimer consisting of the trypsin- and plasmin-sensitive glycopeptide gp160 (MAM-..cap alpha..) and the glycopeptide gp93 (MAM-..beta..). MAM, which is the guinea pig analog of Mo1 and Mac-1, was purified from detergent lysates of peritoneal neutrophils by lentil lectin chromatography and M2-antibody chromatography. The pure heterodimer molecule was dissociated by acidic conditions (pH 3.5), and MAM-..cap alpha.. and MAM-..beta.. were separated by M7-antibody chromatography. MAM-..beta.. is an approx. 640 amino acid residue polypeptide with exceptionally high cysteine content. At 7.2 residues per 100 amino acids, Cys/2 of MAM-..beta.. is more than 3 times the mean for 200 purified proteins. Reactivity with six ..beta..-subunit-specific /sup 125/I-labeled monoclonal antibodies recognizing at least four epitopes demonstrated that intrapeptide disulfide bonds are required to maintain the structure of MAM-..beta... All six antibodies failed to react when MAM-..beta.. was treated with reducing agents. MAM-..beta.. is 18% carbohydrate; the major monosaccharides are mannose, N-acetylglucosamine, galactose, and sialic acid. MAM-..beta.. is estimated to contain five to six N-linked carbohydrate units. MAM-..cap alpha.. is an approx. 1100-residue polypeptide with lower Cys/2 content (2.0 residues per 100 amino acid residues). MAM-..cap alpha.. is 21% carbohydrate. The major monosaccharides are mannose, N-acetylglucosamine, galactose, and sialic acid; the mannose content is higher in MAM-..cap alpha.. than MAM-..beta.. is estimated to contain 12 N-linked carbohydrate units.

  12. Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα

    PubMed Central

    Chen, Po-Jen; Wang, Yu-Ling; Kuo, Liang-Mou; Lin, Chwan-Fwu; Chen, Chun-Yu; Tsai, Yung-Fong; Shen, Jiann-Jong; Hwang, Tsong-Long

    2016-01-01

    Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α–induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin–ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation. PMID:27212040

  13. Increases in oxidized low-density lipoprotein and other inflammatory and adhesion molecules with a concomitant decrease in high-density lipoprotein in the individuals exposed to arsenic in Bangladesh.

    PubMed

    Karim, Md Rezaul; Rahman, Mashiur; Islam, Khairul; Mamun, Abdullah Al; Hossain, Shakhawoat; Hossain, Ekhtear; Aziz, Abdul; Yeasmin, Fouzia; Agarwal, Smita; Hossain, Md Imam; Saud, Zahangir Alam; Nikkon, Farjana; Hossain, Mostaque; Mandal, Abul; Jenkins, Richard O; Haris, Parvez I; Miyataka, Hideki; Himeno, Seiichiro; Hossain, Khaled

    2013-09-01

    Elevated exposure to arsenic has been suggested to be associated with atherosclerosis leading to cardiovascular disease (CVD). However, biochemical events underlying the arsenic-induced atherosclerosis have not yet been fully documented. The aim of this study was to investigate the associations of circulating molecules involved in atherosclerosis with arsenic exposure in the individuals exposed to arsenic in Bangladesh. A total of 324 study subjects, 218 from arsenic-endemic areas and 106 from nonendemic areas in Bangladesh, were recruited. Drinking water, hair, nail, and blood samples were collected from the study subjects for analysis. Total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels were lower in arsenic-endemic subjects than those of nonendemic subjects. Oxidized LDL (Ox-LDL), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were significantly higher in arsenic-endemic subjects than those in nonendemic subjects. All these circulating molecules showed significant correlations with arsenic exposure (water, hair, and nail arsenic concentrations), and all these relations were significant before and after adjusting for relevant covariates. Among the circulating molecules tested in this study, HDL, Ox-LDL, and CRP showed dose-response relationships with arsenic exposure. Ox-LDL/HDL ratios were increased with the increasing concentrations of arsenic in the water, hair, and nails. Furthermore, non-HDL cholesterol and TC/HDL ratios were significantly correlated with arsenic exposure before and after adjusting for relevant covariates. Thus, all the observed associations may be the major features of arsenic exposure-related atherosclerosis leading to CVD.

  14. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

    PubMed

    Kataria, Hardeep; Lutz, David; Chaudhary, Harshita; Schachner, Melitta; Loers, Gabriele

    2016-09-01

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries. PMID:26253722

  15. IRF-1 and miRNA126 modulate inflammatory VCAM-1 expression in response to a high fat meal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rationale: High-fat diets accompanied by hypertriglyceridemia increase an individual’s risk for developing atherosclerosis. An early event in this process is monocyte recruitment through binding to VCAM-1 on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide...

  16. New families of adhesion molecules play a vital role in platelet functions.

    PubMed

    Parmentier, S; Kaplan, C; Catimel, B; McGregor, J L

    1990-07-01

    Adhesion molecules play a crucial part in cell-matrix and in cell-cell interactions. These interactions, which are essential to the body's defense processes, involve adhesion molecules belonging to different families: integrins, immunoglobulins and selectins. Integrins are expressed by a large number of tissues, whereas other adhesion molecule families are restricted to a small number of cell types. A recent symposium dealt with the recruitment of circulating platelets at specific sites, their adhesion to extracellular matrix components and their activation by agonists leading to aggregation or attachment to other cells. These events, supporting hemostasis and thrombosis, involve integrins, selectins and other adhesion molecules. This report focuses on newly reported integrins (GPIa, GPIc, GPIIa), selectins (GMP-140) and GPIIIb, previously known as 'minor' surface oriented platelet glycoproteins. Major membrane glycoproteins such as GPIIb-IIIa (an integrin) and GPIb, which also play a vital role in platelet functions, have been extensively reviewed elsewhere.

  17. Reciprocal Interactions between Cell Adhesion Molecules of the Immunoglobulin Superfamily and the Cytoskeleton in Neurons

    PubMed Central

    Leshchyns'ka, Iryna; Sytnyk, Vladimir

    2016-01-01

    Cell adhesion molecules of the immunoglobulin superfamily (IgSF) including the neural cell adhesion molecule (NCAM) and members of the L1 family of neuronal cell adhesion molecules play important functions in the developing nervous system by regulating formation, growth and branching of neurites, and establishment of the synaptic contacts between neurons. In the mature brain, members of IgSF regulate synapse composition, function, and plasticity required for learning and memory. The intracellular domains of IgSF cell adhesion molecules interact with the components of the cytoskeleton including the submembrane actin-spectrin meshwork, actin microfilaments, and microtubules. In this review, we summarize current data indicating that interactions between IgSF cell adhesion molecules and the cytoskeleton are reciprocal, and that while IgSF cell adhesion molecules regulate the assembly of the cytoskeleton, the cytoskeleton plays an important role in regulation of the functions of IgSF cell adhesion molecules. Reciprocal interactions between NCAM and L1 family members and the cytoskeleton and their role in neuronal differentiation and synapse formation are discussed in detail. PMID:26909348

  18. Reciprocal Interactions between Cell Adhesion Molecules of the Immunoglobulin Superfamily and the Cytoskeleton in Neurons.

    PubMed

    Leshchyns'ka, Iryna; Sytnyk, Vladimir

    2016-01-01

    Cell adhesion molecules of the immunoglobulin superfamily (IgSF) including the neural cell adhesion molecule (NCAM) and members of the L1 family of neuronal cell adhesion molecules play important functions in the developing nervous system by regulating formation, growth and branching of neurites, and establishment of the synaptic contacts between neurons. In the mature brain, members of IgSF regulate synapse composition, function, and plasticity required for learning and memory. The intracellular domains of IgSF cell adhesion molecules interact with the components of the cytoskeleton including the submembrane actin-spectrin meshwork, actin microfilaments, and microtubules. In this review, we summarize current data indicating that interactions between IgSF cell adhesion molecules and the cytoskeleton are reciprocal, and that while IgSF cell adhesion molecules regulate the assembly of the cytoskeleton, the cytoskeleton plays an important role in regulation of the functions of IgSF cell adhesion molecules. Reciprocal interactions between NCAM and L1 family members and the cytoskeleton and their role in neuronal differentiation and synapse formation are discussed in detail. PMID:26909348

  19. A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury.

    PubMed

    Mishra, Amarjit; Guo, Yujie; Zhang, Li; More, Sunil; Weng, Tingting; Chintagari, Narendranath Reddy; Huang, Chaoqun; Liang, Yurong; Pushparaj, Samuel; Gou, Deming; Breshears, Melanie; Liu, Lin

    2016-10-01

    Pulmonary neutrophils are the initial inflammatory cells that are recruited during lung injury and are crucial for innate immunity. However, pathological recruitment of neutrophils results in lung injury. The objective of this study is to determine whether the novel neutrophil chemoattractant, soluble VCAM-1 (sVCAM-1), recruits pathological levels of neutrophils to injury sites and amplifies lung inflammation during acute lung injury. The mice with P2X7 receptor deficiency, or treated with a P2X7 receptor inhibitor or anti-VCAM-1 Abs, were subjected to a clinically relevant two-hit LPS and mechanical ventilation-induced acute lung injury. Neutrophil infiltration and lung inflammation were measured. Neutrophil chemotactic activities were determined by a chemotaxis assay. VCAM-1 shedding and signaling pathways were assessed in isolated lung epithelial cells. Ab neutralization of sVCAM-1 or deficiency or antagonism of P2X7R reduced neutrophil infiltration and proinflammatory cytokine levels. The ligands for sVCAM-1 were increased during acute lung injury. sVCAM-1 had neutrophil chemotactic activities and activated alveolar macrophages. VCAM-1 is released into the alveolar airspace from alveolar epithelial type I cells through P2X7 receptor-mediated activation of the metalloproteinase ADAM-17. In conclusion, sVCAM-1 is a novel chemoattractant for neutrophils and an activator for alveolar macrophages. Targeting sVCAM-1 provides a therapeutic intervention that could block pathological neutrophil recruitment, without interfering with the physiological recruitment of neutrophils, thus avoiding the impairment of host defenses. PMID:27559050

  20. Homophilic Adhesion Mechanism of Neurofascin, a Member of the L1 Family of Neural Cell Adhesion Molecules

    SciTech Connect

    Liu, Heli; Focia, Pamela J.; He, Xiaolin

    2012-02-13

    The L1 family neural cell adhesion molecules play key roles in specifying the formation and remodeling of the neural network, but their homophilic interaction that mediates adhesion is not well understood. We report two crystal structures of a dimeric form of the headpiece of neurofascin, an L1 family member. The four N-terminal Ig-like domains of neurofascin form a horseshoe shape, akin to several other immunoglobulin superfamily cell adhesion molecules such as hemolin, axonin, and Dscam. The neurofascin dimer, captured in two crystal forms with independent packing patterns, reveals a pair of horseshoes in trans-synaptic adhesion mode. The adhesion interaction is mediated mostly by the second Ig-like domain, which features an intermolecular {beta}-sheet formed by the joining of two individual GFC {beta}-sheets and a large but loosely packed hydrophobic cluster. Mutagenesis combined with gel filtration assays suggested that the side chain hydrogen bonds at the intermolecular {beta}-sheet are essential for the homophilic interaction and that the residues at the hydrophobic cluster play supplementary roles. Our structures reveal a conserved homophilic adhesion mode for the L1 family and also shed light on how the pathological mutations of L1 affect its structure and function.

  1. Homophilic adhesion mechanism of neurofascin, a member of the L1 family of neural cell adhesion molecules.

    PubMed

    Liu, Heli; Focia, Pamela J; He, Xiaolin

    2011-01-01

    The L1 family neural cell adhesion molecules play key roles in specifying the formation and remodeling of the neural network, but their homophilic interaction that mediates adhesion is not well understood. We report two crystal structures of a dimeric form of the headpiece of neurofascin, an L1 family member. The four N-terminal Ig-like domains of neurofascin form a horseshoe shape, akin to several other immunoglobulin superfamily cell adhesion molecules such as hemolin, axonin, and Dscam. The neurofascin dimer, captured in two crystal forms with independent packing patterns, reveals a pair of horseshoes in trans-synaptic adhesion mode. The adhesion interaction is mediated mostly by the second Ig-like domain, which features an intermolecular β-sheet formed by the joining of two individual GFC β-sheets and a large but loosely packed hydrophobic cluster. Mutagenesis combined with gel filtration assays suggested that the side chain hydrogen bonds at the intermolecular β-sheet are essential for the homophilic interaction and that the residues at the hydrophobic cluster play supplementary roles. Our structures reveal a conserved homophilic adhesion mode for the L1 family and also shed light on how the pathological mutations of L1 affect its structure and function. PMID:21047790

  2. Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial adhesion and lesion macrophage accumulation

    PubMed Central

    Ding, Yinyuan; Huang, Linzhang; Xian, Xunde; Yuhanna, Ivan S.; Wasser, Catherine R.; Frotscher, Michael; Mineo, Chieko; Shaul, Philip W.; Herz, Joachim

    2016-01-01

    The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to Apolipoprotein E receptor-2 (Apoer2) and very low-density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr−/−) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM-1, VCAM-1 and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing the activity of NF-kB in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease. PMID:26980442

  3. Modulation of lens cell adhesion molecules by particle beams

    NASA Technical Reports Server (NTRS)

    McNamara, M. P.; Bjornstad, K. A.; Chang, P. Y.; Chou, W.; Lockett, S. J.; Blakely, E. A.

    2001-01-01

    Cell adhesion molecules (CAMs) are proteins which anchor cells to each other and to the extracellular matrix (ECM), but whose functions also include signal transduction, differentiation, and apoptosis. We are testing a hypothesis that particle radiations modulate CAM expression and this contributes to radiation-induced lens opacification. We observed dose-dependent changes in the expression of beta 1-integrin and ICAM-1 in exponentially-growing and confluent cells of a differentiating human lens epithelial cell model after exposure to particle beams. Human lens epithelial (HLE) cells, less than 10 passages after their initial culture from fetal tissue, were grown on bovine corneal endothelial cell-derived ECM in medium containing 15% fetal bovine serum and supplemented with 5 ng/ml basic fibroblast growth factor (FGF-2). Multiple cell populations at three different stages of differentiation were prepared for experiment: cells in exponential growth, and cells at 5 and 10 days post-confluence. The differentiation status of cells was characterized morphologically by digital image analysis, and biochemically by Western blotting using lens epithelial and fiber cell-specific markers. Cultures were irradiated with single doses (4, 8 or 12 Gy) of 55 MeV protons and, along with unirradiated control samples, were fixed using -20 degrees C methanol at 6 hours after exposure. Replicate experiments and similar experiments with helium ions are in progress. The intracellular localization of beta 1-integrin and ICAM-1 was detected by immunofluorescence using monoclonal antibodies specific for each CAM. Cells known to express each CAM were also processed as positive controls. Both exponentially-growing and confluent, differentiating cells demonstrated a dramatic proton-dose-dependent modulation (upregulation for exponential cells, downregulation for confluent cells) and a change in the intracellular distribution of the beta 1-integrin, compared to unirradiated controls. In contrast

  4. Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms

    PubMed Central

    Barreiro, Olga; Zamai, Moreno; Yáñez-Mó, María; Tejera, Emilio; López-Romero, Pedro; Monk, Peter N.; Gratton, Enrico; Caiolfa, Valeria R.; Sánchez-Madrid, Francisco

    2008-01-01

    VCAM-1 and ICAM-1, receptors for leukocyte integrins, are recruited to cell–cell contact sites on the apical membrane of activated endothelial cells. In this study, we show that this recruitment is independent of ligand engagement, actin cytoskeleton anchorage, and heterodimer formation. Instead, VCAM-1 and ICAM-1 are recruited by inclusion within specialized preformed tetraspanin-enriched microdomains, which act as endothelial adhesive platforms (EAPs). Using advanced analytical fluorescence techniques, we have characterized the diffusion properties at the single-molecule level, nanoscale organization, and specific intradomain molecular interactions of EAPs in living primary endothelial cells. This study provides compelling evidence for the existence of EAPs as physical entities at the plasma membrane, distinct from lipid rafts. Scanning electron microscopy of immunogold-labeled samples treated with a specific tetraspanin-blocking peptide identify nanoclustering of VCAM-1 and ICAM-1 within EAPs as a novel mechanism for supramolecular organization that regulates the leukocyte integrin–binding capacity of both endothelial receptors during extravasation. PMID:18955551

  5. Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion

    SciTech Connect

    Cheng, Huiwen; Mollica, Molly Y.; Lee, Shin Hee; Wang, Lei; Velázquez-Martínez, Carlos A.; Wu, Shiyong

    2012-10-15

    A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20–30% and fibronectin by 25–44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (∼ 56%) the activity of β1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion. -- Highlights: ► NONO-naproxen, a novel nitric oxide-releasing NSAID, was synthesized. ► NONO-NSAIDs, but not their parent NSAIDs, reduced melanoma adhesion. ► NONO-naproxen, but not NONO-aspirin and NSAIDs, reduced activity of β1 integrin.

  6. Chinese Herbal Cardiotonic Pill Stabilizes Vulnerable Plaques in Rabbits by Decreasing the Expression of Adhesion Molecules

    PubMed Central

    Chen, Liang; Li, Xiaonan; Li, Changjiang; Rong, Yuanyuan; Xiao, Yawei; Xu, Xinsheng; Yao, Guihua; Jiang, Guihua

    2016-01-01

    Abstract: The cardiotonic pill (CP), consisting of a mixture of Radix Salviae Miltiorrhizae, Radix Notoginseng, and Borneolum Syntheticum, has been widely used in the prevention and treatment of cardiovascular disease. Adhesion molecules, including intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, are involved in the development of vulnerable plaque. We investigated the effect of the CP in a rabbit model of vulnerable plaque established by local transfection with p53 gene. Compared with the control group, rabbits with vulnerable plaque showed a significantly lower intima-media thickness and plaque burden after CP treatment for 12 weeks. Moreover, the reduction in rate of plaque rupture and vulnerability index was similar. On enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry analysis, the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 was inhibited with CP treatment. CP treatment could postpone atherosclerotic plaque development and stabilize vulnerable plaque by inhibiting the expression of adhesion molecules in treatment of cardiovascular disease. PMID:27110743

  7. N-Glycosylation at the SynCAM (Synaptic Cell Adhesion Molecule) Immunoglobulin Interface Modulates Synaptic Adhesion

    SciTech Connect

    A Fogel; Y Li; Q Wang; T Lam; Y Modis; T Biederer

    2011-12-31

    Select adhesion molecules connect pre- and postsynaptic membranes and organize developing synapses. The regulation of these trans-synaptic interactions is an important neurobiological question. We have previously shown that the synaptic cell adhesion molecules (SynCAMs) 1 and 2 engage in homo- and heterophilic interactions and bridge the synaptic cleft to induce presynaptic terminals. Here, we demonstrate that site-specific N-glycosylation impacts the structure and function of adhesive SynCAM interactions. Through crystallographic analysis of SynCAM 2, we identified within the adhesive interface of its Ig1 domain an N-glycan on residue Asn(60). Structural modeling of the corresponding SynCAM 1 Ig1 domain indicates that its glycosylation sites Asn(70)/Asn(104) flank the binding interface of this domain. Mass spectrometric and mutational studies confirm and characterize the modification of these three sites. These site-specific N-glycans affect SynCAM adhesion yet act in a differential manner. Although glycosylation of SynCAM 2 at Asn(60) reduces adhesion, N-glycans at Asn(70)/Asn(104) of SynCAM 1 increase its interactions. The modification of SynCAM 1 with sialic acids contributes to the glycan-dependent strengthening of its binding. Functionally, N-glycosylation promotes the trans-synaptic interactions of SynCAM 1 and is required for synapse induction. These results demonstrate that N-glycosylation of SynCAM proteins differentially affects their binding interface and implicate post-translational modification as a mechanism to regulate trans-synaptic adhesion.

  8. Bead Aggregation Assays for the Characterization of Putative Cell Adhesion Molecules

    PubMed Central

    Emond, Michelle R.; Jontes, James D.

    2014-01-01

    Cell-cell adhesion is fundamental to multicellular life and is mediated by a diverse array of cell surface proteins. However, the adhesive interactions for many of these proteins are poorly understood. Here we present a simple, rapid method for characterizing the adhesive properties of putative homophilic cell adhesion molecules. Cultured HEK293 cells are transfected with DNA plasmid encoding a secreted, epitope-tagged ectodomain of a cell surface protein. Using functionalized beads specific for the epitope tag, the soluble, secreted fusion protein is captured from the culture medium. The coated beads can then be used directly in bead aggregation assays or in fluorescent bead sorting assays to test for homophilic adhesion. If desired, mutagenesis can then be used to elucidate the specific amino acids or domains required for adhesion. This assay requires only small amounts of expressed protein, does not require the production of stable cell lines, and can be accomplished in 4 days. PMID:25350770

  9. Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study

    PubMed Central

    Ashander, Liam M.; Appukuttan, Binoy; Ma, Yuefang; Gardner-Stephen, Dione; Smith, Justine R.

    2016-01-01

    Targeting the endothelial adhesion molecules that control leukocyte trafficking into a tissue has been explored as a biological therapy for inflammatory diseases. However, these molecules also participate in leukocyte migration for immune surveillance, and inhibiting the physiological level of an adhesion molecule might promote infection or malignancy. We explored the concept of targeting endothelial adhesion molecule transcription during inflammation in a human system. Intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte migration across the retinal endothelium in noninfectious posterior uveitis. We observed an increase in the transcription factor, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), in parallel with ICAM-1, in human retinal endothelial cells treated with tumor necrosis factor-alpha (TNF-α), and identified putative binding sites for NF-κB1 within the ICAM-1 regulatory region. We targeted induced NF-κB1 expression in endothelial cells with small interfering (si)RNA. Knockdown of NF-κB1 significantly decreased cell surface expression of ICAM-1 protein induced by TNF-α but did not reduce constitutive ICAM-1 expression. Consistently, NF-κB1 knockdown significantly reduced leukocyte binding to cell monolayers in the presence of TNF-α but did not impact baseline binding. Findings of this proof-of-concept study indicate that induced transcription of endothelial adhesion molecules might be targeted therapeutically for inflammatory disease in humans. PMID:27293321

  10. [The expression level of adhesion molecules on neutrophils depending at segmentation of their nuclei].

    PubMed

    Kashutin, S L; Danilov, S I; Vereshchagina, E N; Kluchareva, S V

    2013-11-01

    The article deals with results of detection of expression level of adhesion molecules on neutrophils and segmentation of their nuclei. It is established that in conditions of absence of antigen stimulation neutrophils of circulating pool express molecules of L-selectin in 53.34%, LFA-1 molecules in 65.64%, ICAM-1 in 40.51%, LE4-3 in 58.72% and PECAM-1 in 59.74%. The full readiness to realization of phase of sliding, strong adhesion and immediately transmigration itselfis detected in neutrophils with five segments in nucleus.

  11. Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation.

    PubMed

    Ding, Yinyuan; Huang, Linzhang; Xian, Xunde; Yuhanna, Ivan S; Wasser, Catherine R; Frotscher, Michael; Mineo, Chieko; Shaul, Philip W; Herz, Joachim

    2016-03-15

    The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor κB (NF-κB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

  12. Adhesion molecules involved in hepoxilin A3-mediated neutrophil transepithelial migration

    PubMed Central

    Hurley, B P; Sin, A; McCormick, B A

    2008-01-01

    A common feature underlying active states of inflammation is the migration of neutrophils (PMNs) from the circulation and across a number of tissue barriers in response to chemoattractant stimuli. Although our group has recently established a discreet role for the PMN chemoattractant, hepoxilin A3 (HXA3) in the process of PMN recruitment, very little is known regarding the interaction of HXA3 with PMNs. To characterize further the event of HXA3-induced PMN transepithelial migration, we sought to determine the adhesion molecules required for migration across different epithelial surfaces (T84 intestinal and A549 airway cells) relative to two well-studied PMN chemoattractants, formyl-methionyl-leucyl-phenylalanine (fMLP) and leukotriene B4 (LTB4). Our findings reveal that the adhesion interaction profile of PMN transepithelial migration in response to HXA3 differs from the adhesion interaction profile exhibited by the structurally related eicosanoid LTB4. Furthermore, unique to PMN transepithelial migration induced by gradients of HXA3 was the critical dependency of all four major surface adhesion molecules examined (i.e. CD18, CD47, CD44 and CD55). Our results suggest that the particular chemoattractant gradient imposed, as well as the type of epithelial cell monolayer, each plays a role in determining the adhesion molecules involved in transepithelial migration. Given the complexities of these interactions, our findings are important to consider with respect to adhesion molecules that may be targeted for potential drug development. PMID:18005361

  13. Lymphocyte subpopulations and the expression of intercellular adhesion molecules in chronic periodontitis.

    PubMed

    Cindrić, Gordan; Aurer, Andrej; Plancak, Darije; Ljerka, Jindra; Girotto, Miljena

    2004-12-01

    Immunological responses to invading bacteria play a major role in the course of inflammatory periodontal diseases, such as CP. It was suggested that one of the major elements in determining the course of the disease is the expression of cellular adhesion molecules. We therefore investigated the expression of cellular adhesion molecules, ICAM-1 and beta-1 integrins, capillary density and lymphocyte subpopulations in gingival biopsies obtained from 20 patients with CP who responded and 21 patient who failed to respond to initial treatment using immunohistochemical methods. We found no differences between the two groups in capillary density, ICAM-1 and beta-1 integrin expression. Patients who responded to treatment had a lymphocytic inflammatory infiltrate consisting predominantly of T cells, while those who failed to respond had an approximately equal number of T and B cells. Our findings support the role of host immunological mechanisms in determining the outcome of CP and argue against a major role of differential cellular adhesion molecule expression.

  14. Curcumin attenuates adhesion molecules and matrix metalloproteinase expression in hypercholesterolemic rabbits.

    PubMed

    Um, Min Young; Hwang, Kwang Hyun; Choi, Won Hee; Ahn, Jiyun; Jung, Chang Hwa; Ha, Tae Youl

    2014-10-01

    Curcumin, the yellow substance found in turmeric, possesses antioxidant, anti-inflammation, anticancer, and lipid-lowering properties. Because we hypothesized that curcumin could ameliorate the development of atherosclerosis, the present study focused on the effects and potential mechanisms of curcumin consumption on high-cholesterol diet-induced atherosclerosis in rabbits. During our study, New Zealand white rabbits were fed 1 of 3 experimental diets: a normal diet, a normal diet enriched with 1% cholesterol (HCD), or an HCD supplemented with 0.2% curcumin. At the end of 8 weeks, blood samples were collected to determine the levels of serum lipids, cytokines, and soluble adhesion molecule levels. Gene expression of adhesion molecules and matrix metalloproteinases (MMPs) in aortas were measured by quantitative real-time polymerase chain reaction and Western blot. Compared with the HCD group, rabbits fed an HCD supplemented with 0.2% curcumin had significantly less aortic lesion areas and neointima thickening. Curcumin reduced the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and oxidized low-density lipoprotein cholesterol in serum by 30.7%, 41.3%, 30.4%, and 66.9% (all P < .05), respectively, but did not affect high-density lipoprotein cholesterol levels. In addition, curcumin attenuated HCD-induced CD36 expression, circulating inflammatory cytokines, and soluble adhesive molecule levels. Curcumin reduced the mRNA and protein expression of intracellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and monocyte chemotactic protein-1, and it inhibited HCD-induced up-regulation of MMP-1, MMP-2, and MMP-9. Our results demonstrate that curcumin exerts an antiatherosclerotic effect, which is mediated by multiple mechanisms that include lowering serum lipids and oxidized low-density lipoprotein, thus modulating the proinflammatory cytokine levels and altering adhesion molecules and MMP gene expression. PMID

  15. Curcumin attenuates adhesion molecules and matrix metalloproteinase expression in hypercholesterolemic rabbits.

    PubMed

    Um, Min Young; Hwang, Kwang Hyun; Choi, Won Hee; Ahn, Jiyun; Jung, Chang Hwa; Ha, Tae Youl

    2014-10-01

    Curcumin, the yellow substance found in turmeric, possesses antioxidant, anti-inflammation, anticancer, and lipid-lowering properties. Because we hypothesized that curcumin could ameliorate the development of atherosclerosis, the present study focused on the effects and potential mechanisms of curcumin consumption on high-cholesterol diet-induced atherosclerosis in rabbits. During our study, New Zealand white rabbits were fed 1 of 3 experimental diets: a normal diet, a normal diet enriched with 1% cholesterol (HCD), or an HCD supplemented with 0.2% curcumin. At the end of 8 weeks, blood samples were collected to determine the levels of serum lipids, cytokines, and soluble adhesion molecule levels. Gene expression of adhesion molecules and matrix metalloproteinases (MMPs) in aortas were measured by quantitative real-time polymerase chain reaction and Western blot. Compared with the HCD group, rabbits fed an HCD supplemented with 0.2% curcumin had significantly less aortic lesion areas and neointima thickening. Curcumin reduced the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and oxidized low-density lipoprotein cholesterol in serum by 30.7%, 41.3%, 30.4%, and 66.9% (all P < .05), respectively, but did not affect high-density lipoprotein cholesterol levels. In addition, curcumin attenuated HCD-induced CD36 expression, circulating inflammatory cytokines, and soluble adhesive molecule levels. Curcumin reduced the mRNA and protein expression of intracellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and monocyte chemotactic protein-1, and it inhibited HCD-induced up-regulation of MMP-1, MMP-2, and MMP-9. Our results demonstrate that curcumin exerts an antiatherosclerotic effect, which is mediated by multiple mechanisms that include lowering serum lipids and oxidized low-density lipoprotein, thus modulating the proinflammatory cytokine levels and altering adhesion molecules and MMP gene expression.

  16. Molecular Architecture of a Complex between an Adhesion Protein from the Malaria Parasite and Intracellular Adhesion Molecule 1*

    PubMed Central

    Brown, Alan; Turner, Louise; Christoffersen, Stig; Andrews, Katrina A.; Szestak, Tadge; Zhao, Yuguang; Larsen, Sine; Craig, Alister G.; Higgins, Matthew K.

    2013-01-01

    The adhesion of Plasmodium falciparum-infected erythrocytes to human tissues or endothelium is central to the pathology caused by the parasite during malaria. It contributes to the avoidance of parasite clearance by the spleen and to the specific pathologies of cerebral and placental malaria. The PfEMP1 family of adhesive proteins is responsible for this sequestration by mediating interactions with diverse human ligands. In addition, as the primary targets of acquired, protective immunity, the PfEMP1s are potential vaccine candidates. PfEMP1s contain large extracellular ectodomains made from CIDR (cysteine-rich interdomain regions) and DBL (Duffy-binding-like) domains and show extensive variation in sequence, size, and domain organization. Here we use biophysical methods to characterize the entire ∼300-kDa ectodomain from IT4VAR13, a protein that interacts with the host receptor, intercellular adhesion molecule-1 (ICAM-1). We show through small angle x-ray scattering that IT4VAR13 is rigid, elongated, and monomeric. We also show that it interacts with ICAM-1 through the DBLβ domain alone, forming a 1:1 complex. These studies provide a first low resolution structural view of a PfEMP1 ectodomain in complex with its ligand. They show that it combines a modular domain arrangement consisting of individual ligand binding domains, with a defined higher order architecture that exposes the ICAM-1 binding surface to allow adhesion. PMID:23297413

  17. Clematichinenoside inhibits VCAM-1 and ICAM-1 expression in TNF-α-treated endothelial cells via NADPH oxidase-dependent IκB kinase/NF-κB pathway.

    PubMed

    Yan, Simin; Zhang, Xu; Zheng, Haili; Hu, Danhong; Zhang, Yongtian; Guan, Qinghua; Liu, Lifang; Ding, Qilong; Li, Yunman

    2015-01-01

    Proinflammatory cytokine TNF-α-induced adhesion of leukocytes to endothelial cells plays a critical role in the early stage of atherosclerosis. Oxidative stress and redox-sensitive transcription factors are implicated in the process. Thus, compounds that mediate intracellular redox status and regulate transcription factors are of great therapeutic interest. Clematichinenoside (AR), a triterpene saponin isolated from the root of Clematis chinensis Osbeck, was previously demonstrated to have anti-inflammatory and antioxidative properties. However, little is known about the exact mechanism underlying these actions. Thus we performed a detailed study on its effect on leukocytes-endothelial cells adhesion with TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) and cell-free systems. First, we found that AR reduced TNF-α-induced VCAM-1 and ICAM-1 expression and their promoter activity, inhibited translocation of p65 and phosphorylation of IκBα, suppressed IκB kinase-β (IKK-β) activity, lowered O2(∙-) and H2O2 levels, tackled p47(phox) translocation, and decreased NOX4 NADPH oxidase expression. Second, we showed that AR exhibited no direct free radical scavenging ability in cell-free systems at concentrations that were used in intact cells. Besides, AR had no direct effect on the activity of IKK-β that was extracted from TNF-α-stimulated HUVECs. We also found that p47 translocation, NOX4 expression, and reactive oxygen species (ROS) levels were up-regulated before IκB phosphorylation in TNF-α-induced HUVECs. Moreover, TNF-α-enhanced IKK-β activity was also inhibited by (polyethylene glycol) PEG-catalase, N-acetylcysteine (NAC), and vitamin E. In conclusion, these results suggest that AR reduces VCAM-1 and ICAM-1 expression through NADPH oxidase-dependent IKK/NF-κB pathways in TNF-α-induced HUVECs, which finally suppress monocyte-HUVECs adhesion. This compound is potentially beneficial for early-stage atherosclerosis. PMID:25463279

  18. Wheat proteins enhance stability and function of adhesion molecules in cryopreserved hepatocytes.

    PubMed

    Grondin, Mélanie; Hamel, Francine; Averill-Bates, Diana A; Sarhan, Fathey

    2009-01-01

    Cryopreserved hepatocytes with good hepatospecific functions upon thawing are important for clinical transplantation and for in vitro drug toxicity testing. However, cryopreservation reduces viability and certain hepatospecific functions, but the most pronounced change is diminished attachment efficiency of hepatocytes. Adhesion of cells to the extracellular matrix and cell-cell contacts are crucial for many aspects of cellular function. These processes are partly mediated and controlled by cellular adhesion molecules. The mechanisms responsible for reduced attachment efficiency of cryopreserved hepatocytes are not well understood. To address this question, we investigated the effect of a new cryopreservation procedure, using wheat proteins (WPs) or mixtures of recombinant forms of wheat freezing tolerance-associated proteins, on the stability of three important adhesion molecules (beta1-integrin, E-cadherin, and beta-catenin). Immunoblot analyses revealed that the levels of beta1-integrin, E-cadherin, and beta-catenin were much lower in cryopreserved rat hepatocytes, when compared to fresh cells. Protein expression of the adhesion molecules was generally lower in cells cryopreserved with DMSO, compared to WPs. Moreover, the stability of the adhesion molecules was not affected by cryopreservation to the same degree, with more pronounced decreases occurring for beta1-integrin (62-74%) > beta-catenin (51-58%) > E-cadherin (21-37%). However, when hepatocytes were cryopreserved with partially purified WPs (SulWPE, AcWPE) or with mixtures of recombinant wheat proteins, there was a clear protective effect against the loss of protein expression of beta1-integrin, E-cadherin, and beta-catenin. Protein expression was only 10-20% lower than that observed in fresh hepatocytes. These findings clearly demonstrate that WPs, and more particularly, partially purified WPs and recombinant wheat proteins, were more efficient for cryopreservation of rat hepatocytes by maintaining good

  19. Matrine inhibits the expression of adhesion molecules in activated vascular smooth muscle cells.

    PubMed

    Liu, Jun; Zhang, Lihua; Ren, Yingang; Gao, Yanli; Kang, Li; Lu, Shaoping

    2016-03-01

    Atherosclerosis is a chronic inflammatory disease associated with increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Matrine is a main active ingredient of Sophora flavescens roots, which are used to treat inflammatory diseases. However, the effects of matrine on the expression of adhesion molecules in VSMCs have largely remained elusive. Therefore, the present study investigated the effects of matrine on the expression of adhesion molecules in tumor necrosis factor (TNF)‑α‑stimulated human aortic smooth muscle cells (HASMCs). The results showed that matrine inhibited the expression of vascular cell adhesion molecule‑1 (VCAM‑1) and intercellular adhesion molecule‑1 (ICAM‑1) in TNF‑α‑stimulated HASMCs. Matrine markedly inhibited the TNF‑α‑induced expression of nuclear factor (NF)‑κB p65 and prevented the TNF‑α‑caused degradation of inhibitor of NF‑κB; it also inhibited TNF‑α‑induced activation of mitogen‑activated protein kinases (MAPKs). Furthermore, matrine inhibited the production of intracellular reactive oxygen species (ROS) in TNF‑α‑stimulated HASMCs. In conclusion, the results of the present study demonstrated that matrine inhibited the expression of VCAM‑1 and ICAM‑1 in TNF‑α‑stimulated HASMCs via the suppression of ROS production as well as NF‑κB and MAPK pathway activation. Therefore, matrine may have a potential therapeutic use for preventing the advancement of atherosclerotic lesions.

  20. Simulated microgravity does not alter epithelial cell adhesion to matrix and other molecules

    NASA Technical Reports Server (NTRS)

    Jessup, J. M.; Brown, K.; Ishii, S.; Ford, R.; Goodwin, T. J.; Spaulding, G.

    1994-01-01

    Microgravity has advantages for the cultivation of tissues with high fidelity; however, tissue formation requires cellular recognition and adhesion. We tested the hypothesis that simulated microgravity does not affect cell adhesion. Human colorectal carcinoma cells were cultured in the NASA Rotating Wall Vessel (RWV) under low shear stress with randomization of the gravity vector that simulates microgravity. After 6 - 7 days, cells were assayed for binding to various substrates and compared to cells grown in standard tissue culture flasks and static suspension cultures. The RWV cultures bound as well to basement membrane proteins and to Carcinoembryonic Antigen (CEA), an intercellular adhesion molecule, as control cultures did. Thus, microgravity does not alter epithelial cell adhesion and may be useful for tissue engineering.

  1. Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options.

    PubMed

    Sluiter, Nina; de Cuba, Erienne; Kwakman, Riom; Kazemier, Geert; Meijer, Gerrit; Te Velde, Elisabeth Atie

    2016-06-01

    Peritoneal dissemination is diagnosed in 10-25 % of colorectal cancer patients. Selected patients are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. For these patients, earlier diagnosis, optimised selection criteria and a personalised approach are warranted. Biomarkers could play a crucial role here. However, little is known about possible candidates. Considering tumour cell adhesion as a key step in peritoneal dissemination, we aim to provide an overview of the functional importance of adhesion molecules in peritoneal dissemination and discuss the prognostic, diagnostic and therapeutic options of these candidate biomarkers. A systematic literature search was conducted according to the PRISMA guidelines. In 132 in vitro, ex vivo and in vivo studies published between 1995 and 2013, we identified twelve possibly relevant adhesion molecules in various cancers that disseminate peritoneally. The most studied molecules in tumour cell adhesion are integrin α2β1, CD44 s and MUC16. Furthermore, L1CAM, EpCAM, MUC1, sLe(x) and Le(x), chemokine receptors, Betaig-H3 and uPAR might be of clinical importance. ICAM1 was found to be less relevant in tumour cell adhesion in the context of peritoneal metastases. Based on currently available data, sLe(a) and MUC16 are the most promising prognostic biomarkers for colorectal peritoneal metastases that may help improve patient selection. Different adhesion molecules appear expressed in haematogenous and transcoelomic spread, indicating two different attachment processes. However, our extensive assessment of available literature reveals that knowledge on metastasis-specific genes and their possible candidates is far from complete. PMID:27074785

  2. A hot water extract of Curcuma longa inhibits adhesion molecule protein expression and monocyte adhesion to TNF-α-stimulated human endothelial cells.

    PubMed

    Kawasaki, Kengo; Muroyama, Koutarou; Yamamoto, Norio; Murosaki, Shinji

    2015-01-01

    The recruitment of arterial leukocytes to endothelial cells is an important step in the progression of various inflammatory diseases. Therefore, its modulation is thought to be a prospective target for the prevention or treatment of such diseases. Adhesion molecules on endothelial cells are induced by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), and contribute to the recruitment of leukocytes. In the present study, we investigated the effect of hot water extract of Curcuma longa (WEC) on the protein expression of adhesion molecules, monocyte adhesion induced by TNF-α in human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with WEC significantly suppressed both TNF-α-induced protein expression of adhesion molecules and monocyte adhesion. WEC also suppressed phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) induced by TNF-α in HUVECs, suggesting that WEC inhibits the NF-κB signaling pathway.

  3. Choice of anesthetic technique on plasma concentrations of interleukins and cell adhesion molecules

    PubMed Central

    2013-01-01

    Background Whether inflammatory responses to surgery are comparably activated during total intravenous anesthesia (TIVA) and during volatile anesthesia remains unclear. We thus compared the perioperative effects of TIVA and isoflurane anesthesia on plasma concentrations of proinflammatory and anti-inflammatory interleukins and cell adhesion molecules. Methods Patients having laparoscopic cholecystectomies were randomly allocated to two groups: 44 were assigned to TIVA and 44 to isoflurane anesthesia. IL-1β, IL-6, IL-8, IL-10, IL-13, and the cellular adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were determined preoperatively, before incision, and at 2 and 24 hours postoperatively. Our primary outcomes were area-under-the-curve cytokine and adhesion molecule concentrations over 24 postoperative hours. Results The only statistically significant difference in area-under-the-curve concentrations was for IL-6, which was greater in patients given isoflurane:78 (95% confidence interval (CI): 52 to 109) pg/ml versus 33 (22 to 50) pg/ml, P= 0.006. Two hours after surgery, IL-6 was significantly greater than baseline in patients assigned to isoflurane: 47 (95% CI: 4 to 216, P<0.001) pg/ml versus 18 (95%CI: 4 to 374, P<0.001) pg/ml in the TIVA group. In contrast, IL-10 was significantly greater in patients assigned to TIVA: 20 (95% CI: 2 to 140, P<0.001) pg/ml versus 12 (95% CI: 3 to 126, P<0.001) pg/ml. By 24 hours after surgery, concentrations were generally similar between study groups and similar to baseline values. Conclusion The only biomarker whose postoperative area-under-the-curve concentrations differed significantly as a function of anesthetic management was IL-6. Two hours after surgery, IL-6 concentrations were significantly greater in patients given isoflurane than TIVA. However, the differences were modest and seem unlikely to prove clinically important. Further studies are needed. PMID:24472144

  4. Effect of PKC-β Signaling Pathway on Expression of MCP-1 and VCAM-1 in Different Cell Models in Response to Advanced Glycation End Products (AGEs)

    PubMed Central

    Rempel, Lisienny C. T.; Finco, Alessandra B.; Maciel, Rayana A. P.; Bosquetti, Bruna; Alvarenga, Larissa M.; Souza, Wesley M.; Pecoits-Filho, Roberto; Stinghen, Andréa E. M.

    2015-01-01

    Advanced glycation end products (AGEs) are compounds classified as uremic toxins in patients with chronic kidney disease that have several pro-inflammatory effects and are implicated in the development of cardiovascular diseases. To explore the mechanisms of AGEs–endothelium interactions through the receptor for AGEs (RAGE) in the PKC-β pathway, we evaluated the production of MCP-1 and VCAM-1 in human endothelial cells (HUVECs), monocytes, and a coculture of both. AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. The effect of AGEs on cell viability was assessed with an MTT assay. The cells were also treated with AGEs with and without a PKC-β inhibitor. MCP-1 and VCAM-1 in the cell supernatants were estimated by ELISA, and RAGE was evaluated by immunocytochemistry. AGEs exposure did not affect cell viability, but AGEs induced RAGE, MCP-1, and VCAM-1 expression in HUVECs. When HUVECs or monocytes were incubated with AGEs and a PKC-β inhibitor, MCP-1 and VCAM-1 expression significantly decreased. However, in the coculture, exposure to AGEs and a PKC-β inhibitor produced no significant effect. This study demonstrates, in vitro, the regulatory mechanisms involved in MCP-1 production in three cellular models and VCAM-1 production in HUVECs, and thus mimics the endothelial dysfunction caused by AGEs in early atherosclerosis. Such mechanisms could serve as therapeutic targets to reduce the harmful effects of AGEs in patients with chronic kidney disease. PMID:26008233

  5. Spatio-Temporally Restricted Expression of Cell Adhesion Molecules during Chicken Embryonic Development

    PubMed Central

    Roy, Priti; Bandyopadhyay, Amitabha

    2014-01-01

    Differential cell adhesive properties are known to regulate important developmental events like cell sorting and cell migration. Cadherins and protocadherins are known to mediate these cellular properties. Though a large number of such molecules have been predicted, their characterization in terms of interactive properties and cellular roles is far from being comprehensive. To narrow down the tissue context and collect correlative evidence for tissue specific roles of these molecules, we have carried out whole-mount in situ hybridization based RNA expression study for seven cadherins and four protocadherins. In developing chicken embryos (HH stages 18, 22, 26 and 28) cadherins and protocadherins are expressed in tissue restricted manner. This expression study elucidates precise expression domains of cell adhesion molecules in the context of developing embryos. These expression domains provide spatio-temporal context in which the function of these genes can be further explored. PMID:24806091

  6. PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity

    SciTech Connect

    Chengye, Zhan; Daixing, Zhou Qiang, Zhong; Shusheng, Li

    2013-09-13

    Highlights: •First time to display that LPS downregulate the expression of PRC. •First time to show that PRC inhibits the induction of VCAM-1 and E-selectin. •First time to show that PRC inhibit monocytes attachment to endothelial cells. •First time to display that PRC inhibits transcriptional activity of NF-κB. •PRC protects the respiration rate and suppresses the glycolysis rate against LPS. -- Abstract: PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor known to activate many of the nuclear genes specifying mitochondrial respiratory function. Endothelial dysfunction is a prominent feature found in many inflammatory diseases. Adhesion molecules, such as VCAM-1, mediate the attachment of monocytes to endothelial cells, thereby playing an important role in endothelial inflammation. The effects of PRC in regards to endothelial inflammation remain unknown. In this study, our findings show that PRC can be inhibited by the inflammatory cytokine LPS in cultured human umbilical vein endothelial cells (HUVECs). In the presence of LPS, the expression of endothelial cell adhesion molecular, such as VCAM1 and E-selectin, is found to be increased. These effects can be negated by overexpression of PRC. Importantly, monocyte adhesion to endothelial cells caused by LPS is significantly attenuated by PRC. In addition, overexpression of PRC protects mitochondrial metabolic function and suppresses the rate of glycolysis against LPS. It is also found that overexpression of PRC decreases the transcriptional activity of NF-κB. These findings suggest that PRC is a negative regulator of endothelial inflammation.

  7. Protective effects of hydrogen-rich medium on lipopolysaccharide-induced monocytic adhesion and vascular endothelial permeability through regulation of vascular endothelial cadherin.

    PubMed

    Yu, Y; Wang, W N; Han, H Z; Xie, K L; Wang, G L; Yu, Y H

    2015-06-11

    We observed the effect of hydrogen-rich medium on lipopolysaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs), hyaline leukocyte conglutination, and permeability of the endothelium. Endotheliocytes were inoculated on 6-well plates and randomly divided into 4 groups: control, H2, LPS, LPS+H2, H2, and LPS+H2 in saturated hydrogen-rich medium. We applied Wright's stain-ing to observe conglutination of hyaline leukocytes and HUVECs, flow cytometry to determine the content of vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), enzyme-linked immunosorbent assay to measure the E-selectin concentration in the cell liquor, the transendothelial electrical resistance (TEER) to test the permeability of endothelial cells, and Western blot and immunofluorescence to test the expression and distribution of vascular endothelial (VE)-cadherin. Compared with control cells, there was an increase in endothelium-hyaline leukocyte conglutination, a reduction in VCAM-1, ICAM-1, and E-selectin, and the TEER value increased obviously. Compared with LPS, there was an obvious reduction in the conglutination of LPS+H2 cells, a reduction in VCAM-1, ICAM-1, and E-selectin levels, and a reduction in the TEER-resistance value, while the expression of VE-cadherin increased. Fluorescence results showed that, compared with control cells, the VE-cadherin in LPS cells was in-complete at the cell joints. Compared with LPS cells, the VE-cadherin in LPS+H2 cells was even and complete at the cell joints. Liquid rich in hydrogen could reduce LPS-induced production of adhesion molecules and endothelium-hyaline leukocyte conglutination, and influence the expression and distribution of VE-cadherin to regulate the permeability of the endothelium.

  8. Cell adhesion molecules and actin cytoskeleton at immune synapses and kinapses.

    PubMed

    Dustin, Michael L

    2007-10-01

    The immunological synapse is a stable adhesive junction between a polarized immune effector cell and an antigen-bearing cell. Immunological synapses are often observed to have a striking radial symmetry in the plane of contact with a prominent central cluster of antigen receptors surrounded by concentric rings of adhesion molecules and actin-rich projections. There is a striking similarity between the radial zones of the immunological synapse and the dynamic actinomyosin modules employed by migrating cells. Breaking the symmetry of an immunological synapse generates a moving adhesive junction that can be defined as a kinapse, which facilitates signal integration by immune cells while moving over the surface of antigen-presenting cells.

  9. Cadherin transfection of Xenopus XTC cells downregulates expression of substrate adhesion molecules.

    PubMed

    Finnemann, S; Kühl, M; Otto, G; Wedlich, D

    1995-09-01

    Cadherins are discussed not in terms of their adhesive function but rather as morphoregulatory proteins. Changes in gene expression following cadherin transfection of cells in culture or by overexpression in embryos have, until now, not been reported. We established a protocol for stable transfection of Xenopus XTC cells and generated cells bearing high levels of membrane-integrated mouse uvomorulin (E-cadherin) or Xenopus XB-cadherin. These cell lines showed drastically impaired substrate adhesion on fibronectin and laminin. In immunoblot and radioimmunoprecipitation experiments, we found that fibronectin and alpha 3/beta 1 integrin are downregulated. The reduced amounts of proteins result from a decrease of the respective mRNAs as proven by RNase protection assays. Coprecipitations revealed that transfected cadherin molecules are complexed with alpha-catenin and beta-catenin at plasma membranes. However, the alpha-catenin present in the XB-cadherin complex differs immunologically from that found in the uvomorulin complex. When a truncated form of XB-cadherin lacking 38 of the most C-terminal amino acids was expressed in XTC cells, complex formation with endogenous catenins was abolished. In these transfectants, substrate adhesion was not affected. These results prove that complex formation of transfected cadherins in XTC cells with endogenous beta-catenin correlates with altered synthesis of certain substrate adhesion molecules.

  10. Integrin VLA-4 enhances sialyl-Lewisx/a-negative melanoma adhesion to and extravasation through the endothelium under low flow conditions

    PubMed Central

    Liang, Shile; Dong, Cheng

    2008-01-01

    During their passage through the circulatory system, tumor cells undergo extensive interactions with various host cells including endothelial cells. The capacity of tumor cells to form metastasis is related to their ability to interact with and extravasate through endothelial cell layers, which involves multiple adhesive interactions between tumor cells and endothelium (EC). Thus it is essential to identify the adhesive receptors on the endothelial and melanoma surface that mediate those specific adhesive interactions. P-selectin and E-selectin have been reported as adhesion molecules that mediate the cell-cell interaction of endothelial cells and melanoma cells. However, not all melanoma cells express ligands for selectins. In this study, we elucidated the molecular constituents involved in the endothelial adhesion and extravasation of sialyl-Lewisx/a-negative melanoma cell lines under flow in the presence and absence of polymorphonuclear neutrophils (PMNs). Results show the interactions of α4β1 (VLA-4) on sialyl-Lewisx/a-negative melanoma cells and vascular adhesion molecule (VCAM-1) on inflamed EC supported melanoma adhesion to and subsequent extravasation through the EC in low shear flow. These findings provide clear evidence for a direct role of the VLA-4/VCAM-1 pathway in melanoma cell adhesion to and extravasation through the vascular endothelium in a shear flow. PMNs facilitated melanoma cell extravasation under both low and high shear conditions via the involvement of distinct molecular mechanisms. In the low shear regime, β2-integrins were sufficient to enhance melanoma cell extravasation, whereas in the high shear regime, selectin ligands and β2-integrins on PMNs were necessary for facilitating the melanoma extravasation process. PMID:18632734

  11. Markedly diminished epidermal keratinocyte expression of intercellular adhesion molecule-1 (ICAM-1) in Sezary syndrome

    SciTech Connect

    Nickoloff, B.J.; Griffiths, E.M.; Baadsgaard, O.; Voorhees, J.J.; Hanson, C.A.; Cooper, K.D. )

    1989-04-21

    In mucosis fungoides the malignant T cells express lymphocyte function-associated antigen-1, which allows them to bind to epidermal keratinocytes expressing the gamma interferon-inducible intercellular adhesion molecule-1. In this report, a patient with leukemic-stage mucosis fungoides (Sezary syndrome) had widespread erythematous dermal infiltrates containing malignant T cells, but without any epidermotropism. The authors discovered that the T cells expressed normal amounts of functional lymphocyte function-associated antigen-1, but the keratinocytes did not express significant levels of intercellular adhesion molecule-1, which was probably due to the inability of the malignant T cells to produce gamma interferon. These results support the concept that the inability of malignant T cells to enter the epidermis may contribute to emergence of more clinically aggressive T-cell clones that are no longer confined to the skin, but infiltrate the blood, lymph nodes, and viscera, as is seen in Sezary syndrome.

  12. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1.

    PubMed Central

    Sligh, J E; Ballantyne, C M; Rich, S S; Hawkins, H K; Smith, C W; Bradley, A; Beaudet, A L

    1993-01-01

    Gene targeting was used to produce mice deficient in intercellular adhesion molecule 1 (ICAM-1) or CD54, an immunoglobulin-like cell adhesion molecule that binds beta 2 integrins. Homozygous deficient animals develop normally, are fertile, and have a moderate granulocytosis. The nature of the mutation, RNA analysis, and immunostaining are consistent with complete loss of surface expression of ICAM-1. Deficient mice exhibit prominent abnormalities of inflammatory responses including impaired neutrophil emigration in response to chemical peritonitis and decreased contact hypersensitivity to 2,4-dinitrofluorobenzene. Mutant cells provided negligible stimulation in the mixed lymphocyte reaction, although they proliferated normally as responder cells. These mutant animals will be extremely valuable for examining the role of ICAM-1 and its counterreceptors in inflammatory disease processes and atherosclerosis. Images Fig. 1 Fig. 2 PMID:8104338

  13. L1 cell adhesion molecule as a therapeutic target in cancer.

    PubMed

    Yu, Xinzhe; Yang, Feng; Fu, De-Liang; Jin, Chen

    2016-01-01

    L1 cell adhesion molecule (L1CAM) is the prototype member of the L1-family of closely related neural adhesion molecules. L1CAM is differentially expressed in the normal nervous system as well as pathological tissues and displays a wide range of biological activities. In human malignancies, L1CAM plays a vital role in tumor growth, invasion and metastasis. Recently, increasing evidence has suggested that L1CAM exerts a variety of functions at different steps of tumor progression through a series of signaling pathways. In addition, L1CAM has been identified as a promising target for cancer therapy by using synthetic and natural inhibitors. In this review, we provide an up-to-date overview of the role of L1CAM involved in cancers and the rationale for L1CAM as a novel molecular target for cancer therapy. PMID:26781307

  14. Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation?

    PubMed

    Hoffman, K B; Martinez, J; Lynch, G

    1998-11-16

    Tissue plasminogen activator (tPA), a serine protease endogenous to hippocampal neurons, is shown to recognize a highly conserved sequence in the extracellular domain of cell adhesion molecules (CAMs). When added to brain homogenates, tPA generated a CAM fragment similar in size to that produced in hippocampal slices by brief periods of NMDA receptor stimulation. The serine protease inhibitor 4-(2-Aminoethyl)-benzenesulfonyl fluoride blocked the effects of tPA with an approximately 50% suppression at 250 microM. The inhibitor at this concentration had no evident effect on synaptic responses but caused long term potentiation to decay back to baseline over a 1 h period. These results suggest that extracellular breakdown of cell adhesion molecules initiated by NMDA receptors and mediated by serine proteases contributes to the formation of stable potentiation.

  15. Intercellular adhesion molecule-1 expression by skeletal muscle cells augments myogenesis.

    PubMed

    Goh, Qingnian; Dearth, Christopher L; Corbett, Jacob T; Pierre, Philippe; Chadee, Deborah N; Pizza, Francis X

    2015-02-15

    We previously demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) by skeletal muscle cells after muscle overload contributes to ensuing regenerative and hypertrophic processes in skeletal muscle. The objective of the present study is to reveal mechanisms through which skeletal muscle cell expression of ICAM-1 augments regenerative and hypertrophic processes of myogenesis. This was accomplished by genetically engineering C2C12 myoblasts to stably express ICAM-1, and by inhibiting the adhesive and signaling functions of ICAM-1 through the use of a neutralizing antibody or cell penetrating peptide, respectively. Expression of ICAM-1 by cultured skeletal muscle cells augmented myoblast-myoblast adhesion, myotube formation, myonuclear number, myotube alignment, myotube-myotube fusion, and myotube size without influencing the ability of myoblasts to proliferate or differentiate. ICAM-1 augmented myotube formation, myonuclear accretion, and myotube alignment through a mechanism involving adhesion-induced activation of ICAM-1 signaling, as these dependent measures were reduced via antibody and peptide inhibition of ICAM-1. The adhesive and signaling functions of ICAM-1 also facilitated myotube hypertrophy through a mechanism involving myotube-myotube fusion, protein synthesis, and Akt/p70s6k signaling. Our findings demonstrate that ICAM-1 expression by skeletal muscle cells augments myogenesis, and establish a novel mechanism through which the inflammatory response facilitates growth processes in skeletal muscle.

  16. Characterization of the inflammatory infiltrate and expression of endothelial cell adhesion molecules in lupus erythematosus tumidus.

    PubMed

    Kuhn, Annegret; Sonntag, Monika; Lehmann, Percy; Megahed, Mosaad; Vestweber, Dietmar; Ruzicka, Thomas

    2002-03-01

    Lupus erythematosus tumidus (LET) is a disease with characteristic clinical and histopathologic features that has not always been considered a subset of cutaneous lupus erythematosus (CLE). Although LET was first mentioned in the literature in 1930, it has rarely been documented, and immunohistochemical studies have never been performed. The aim of the present study was to characterize the inflammatory infiltrate and to analyze the expression of endothelial cell adhesion molecules in skin specimens from patients with LET and to compare the results with those from patients with other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Cryostat sections of lesional skin specimens from ten patients with LET demonstrated an infiltrate composed of more than 75% CD4+, CD8+, and HLA-DR+ cells. Interestingly, CD45RO+ cells, in contrast to CD45RA+ cells, were the prevailing inflammatory cell population. Compared with skin specimens from patients with DLE and SCLE, the mean expression of CD4+ and CD8+ cells was higher (but not significantly so) in LET, and no differences were observed with the other three antibodies. Furthermore, in contrast to controls, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, and P-selectin showed the same expression pattern in skin specimens from patients with DLE, SCLE, and LET. In conclusion, the inflammatory infiltrate of LET primarily consists of CD4+/CD8+ lymphocytes. Furthermore, expression of endothelial cell adhesion molecules was equally upregulated in LET compared with the expression in DLE and SCLE, suggesting a similar immunopathomechanism of these subtypes of CLE. PMID:12071156

  17. The control of tumor vessels: what you would not expect from a neural adhesion molecule.

    PubMed

    Angiolini, Francesca; Cavallaro, Ugo

    2015-01-01

    The neural adhesion molecule L1 is involved in development and plasticity of the nervous system. We recently reported aberrant expression of L1 in the vasculature of various human tumor types. Genetic and functional inactivation of endothelial L1 in a mouse tumor model resulted in decreased tumor angiogenesis and promoted vascular normalization. Thus, endothelial L1 might represent a novel therapeutic target for vessel-targeted treatments of solid tumors. PMID:27308446

  18. Rupture of molecules upon fracture of adhesive joint between two polymer samples

    NASA Astrophysics Data System (ADS)

    Boiko, Yu. M.; Mamalimov, R. I.; Vettegren, V. I.

    2013-07-01

    The surfaces formed after fracture of the joint of two polystyrene (PS) samples have been studied by attenuated total reflection Fourier-transform infrared spectroscopy. The adhesive joint between samples was created by pressing them one against another and holding at a pressure of 0.8 MPa and a temperature of 80°C, which is ˜23°C lower than the glass transition temperature of PS. It has been found that, after the joint fracture, the concentration of molecule ends formed after the rupture of carbon-carbon bonds in the back-bone of the PS molecule increases.

  19. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

    PubMed Central

    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  20. Erythroid Adhesion Molecules in Sickle Cell Anaemia Infants: Insights Into Early Pathophysiology

    PubMed Central

    Brousse, Valentine; Colin, Yves; Pereira, Catia; Arnaud, Cecile; Odièvre, Marie Helene; Boutemy, Anne; Guitton, Corinne; de Montalembert, Mariane; Lapouméroulie, Claudine; Picot, Julien; Le Van Kim, Caroline; El Nemer, Wassim

    2014-01-01

    Sickle cell anaemia (SCA) results from a single mutation in the β globin gene. It is seldom symptomatic in the first semester of life. We analysed the expression pattern of 9 adhesion molecules on red blood cells, in a cohort of 54 SCA and 17 non-SCA very young infants of comparable age (median 144 days, 81–196). Haemoglobin F (HbF) level was unsurprisingly elevated in SCA infants (41.2% ± 11.2) and 2–4 fold higher than in non-SCA infants, yet SCA infants presented significantly decreased Hb level and increased reticulocytosis. Cytometry analysis evidenced a specific expression profile on reticulocytes of SCA infants, with notably an increased expression of the adhesion molecules Lu/BCAM, ICAM-4 and LFA-3, both in percentage of positive cells and in surface density. No significant difference was found on mature red cells. Our findings demonstrate the very early onset of reticulocyte membrane modifications in SCA asymptomatic infants and allow an insight into the first pathological changes with the release of stress reticulocytes expressing a distinctive profile of adhesion molecules. PMID:26137540

  1. Mobilization of NK cells by exercise: downmodulation of adhesion molecules on NK cells by catecholamines.

    PubMed

    Nagao, F; Suzui, M; Takeda, K; Yagita, H; Okumura, K

    2000-10-01

    The change of plasma catecholamine concentration correlates with the change of natural killer (NK) activity and NK cell number in peripheral blood mononuclear cells (PBMC) during and after moderate exercise. We studied the causal relation between exercise-induced catecholamine and expression of adhesion molecules on NK cells during and after exercise. The expression of CD44 and CD18 on CD3(-)CD56(+) NK cells was significantly reduced during exercise (P < 0.01). When PBMC were stimulated with 10(-8)M norepinephrine in vitro, the expression of these adhesion molecules on CD3(-)CD56(+) NK cells was downmodulated within 30 min. The binding capacity of NK cells to a CD44 ligand, hyaluronate, was reduced by the stimulation with norepinephrine (P < 0.01). The intravenous injection of norepinephrine in mice decreased the expression of CD44 and CD18 on CD3(-)NK1.1(+) cells (P < 0.01) and increased the number of CD3(-)NK1.1(+) cells in PBMC (P < 0.01). These findings suggest that exercise-induced catecholamines modulate the expression of adhesion molecules on NK cells, resulting in the mobilization of NK cells into the circulation. PMID:11003990

  2. Differential expression of epithelial cell adhesion molecule in salivary gland neoplasms.

    PubMed

    Phattarataratip, Ekarat; Masorn, Marisa; Jarupoonphol, Werapong; Supatthanayut, Sirinpaporn; Saeoweiang, Pichanee

    2016-10-01

    Epithelial cell adhesion molecule (EpCAM) is the epithelial-specific molecule expressed on various epithelial cell types. The function of EpCAM involves cellular adhesion, proliferation, and signaling in both normal tissues and cancers. The purposes of this study were to investigate the EpCAM expression in salivary gland neoplasms and examine its relationship with pathologic characteristics. Forty-two cases of salivary gland neoplasms, including 20 mucoepidermoid carcinomas (MECs), 11 adenoid cystic carcinomas (ACCs), 9 pleomorphic adenomas (PAs), and 2 polymorphous low-grade adenocarcinomas (PLGAs) were enrolled. Epithelial cell adhesion molecule expression was analyzed immunohistochemically using MOC-31 and BerEP4 antibodies. Results showed that the majority of MECs and all PLGAs showed EpCAM expression in more than 50% of neoplastic cells, whereas most PAs and ACCs did not express this protein. In MECs, most EpCAM-positive neoplastic cells were clear cells, glandular epithelial cells, and intermediate cells, whereas squamous cells and mucous cells were largely negative. The expression was limited to ductal epithelium in EpCAM-positive PAs and ACCs. The decreased EpCAM expression in MECs was significantly associated with microscopically diminished cystic components, the presence of small nest invasion at invasive front, cellular anaplasia, vascular invasion, and high pathologic grade. These data suggested that EpCAM showed different expression pattern among salivary gland neoplasms and in different grades of MECs. PMID:27649957

  3. [Allergens-induced sensitization alters airway epithelial adhesion molecules expression in mice].

    PubMed

    Zeng, Dan; Tan, Mei-Ling; Xiang, Yang; Qin, Xiao-Qun; Zhu, Li-Ming; Dai, Ai-Guo

    2015-12-25

    To explore the relationship between the epithelial adhesion molecules and immune responses of airway epithelium, we observed the expression of integrin β4 and intercellular adhesion molecule-1 (ICAM-1) in the mice airway epithelium after sensitization with allergens. BALB/c mice were sensitized with intraperitoneal injection of ovalbumin (OVA) or house dust mite (HDM) and then developed airway hyper-responsiveness as determined by barometric whole-body plethysmography. Both OVA and HDM sensitization led to increases of the number of peripheral leukocytes as well as inflammatory cells infiltration in lungs. OVA sensitized mice showed more severe inflammatory cells infiltration than HDM sensitized mice. Immunohistochemistry analysis of mice lung tissues revealed that sensitization with both allergens also led to a decrease of integrin β4 expression and an increase of ICAM-1 expression in airway epithelia. OVA sensitized mice showed a more significant increase of ICAM-1 expression compared with HDM sensitized mice. siRNA mediated silencing of integrin β4 gene in 16HBE cells resulted in an up-regulation of ICAM-1 expression. Our results indicate a possible role of airway epithelial adhesion molecules in allergen-induced airway immune responses. PMID:26701635

  4. Micromanipulation of adhesion of phorbol 12-myristate-13-acetate-stimulated T lymphocytes to planar membranes containing intercellular adhesion molecule-1.

    PubMed Central

    Tözeren, A; Mackie, L H; Lawrence, M B; Chan, P Y; Dustin, M L; Springer, T A

    1992-01-01

    This paper presents an analytical and experimental methodology to determine the physical strength of cell adhesion to a planar membrane containing one set of adhesion molecules. In particular, the T lymphocyte adhesion due to the interaction of the lymphocyte function associated molecule 1 on the surface of the cell, with its counter-receptor, intercellular adhesion molecule-1 (ICAM-1), on the planar membrane, was investigated. A micromanipulation method and mathematical analysis of cell deformation were used to determine (a) the area of conjugation between the cell and the substrate and (b) the energy that must be supplied to detach a unit area of the cell membrane from its substrate. T lymphocytes stimulated with phorbol 12-myristate-13-acetate (PMA) conjugated strongly with the planar membrane containing purified ICAM-1. The T lymphocytes attached to the planar membrane deviated occasionally from their round configuration by extending pseudopods but without changing the size of the contact area. These adherent cells were dramatically deformed and then detached when pulled away from the planar membrane by a micropipette. Detachment occurred by a gradual decrease in the radius of the contact area. The physical strength of adhesion between a PMA-stimulated T lymphocyte and a planar membrane containing 1,000 ICAM-1 molecules/micron 2 was comparable to the strength of adhesion between a cytotoxic T cell and its target cell. The comparison of the adhesive energy density, measured at constant cell shape, with the model predictions suggests that the physical strength of cell adhesion may increase significantly when the adhesion bonds in the contact area are immobilized by the actin cytoskeleton. Images FIGURE 2 FIGURE 4 FIGURE 5 FIGURE 8 FIGURE 9 PMID:1358239

  5. EA-1, a novel adhesion molecule involved in the homing of progenitor T lymphocytes to the thymus

    PubMed Central

    1991-01-01

    The mouse progenitor T lymphocyte (pro-T) cell line FTF1 binds in vitro to thymus blood vessels, the thymic capsule, and liver from newborn mice. A mAb, EA-1, raised against an embryonic mouse endothelial cell line, blocked adhesion. The antibody also interfered with pro-T cell adhesion to a thymus-derived mouse endothelial cell line; it had no effect on the adhesion of mature T lymphocytes and myeloid cells. The antigen recognized by EA-1 is located on the vascular endothelium of various mouse tissues and absent on pro-T cells. EA-1 antibody precipitates molecules with apparent molecular weights of 110,000, 140,000, 160,000, and 200,000. Immunoclearing and binding-inhibition studies with antibodies against known adhesion molecules suggest that the EA-1 antigen is a novel adhesion molecule involved in colonization of the embryonic thymus by T cell progenitors. PMID:1874787

  6. Crystal Structure of an Engineered LRRTM2 Synaptic Adhesion Molecule and a Model for Neurexin Binding.

    PubMed

    Paatero, Anja; Rosti, Katja; Shkumatov, Alexander V; Sele, Celeste; Brunello, Cecilia; Kysenius, Kai; Singha, Prosanta; Jokinen, Ville; Huttunen, Henri; Kajander, Tommi

    2016-02-16

    Synaptic adhesion molecules are key components in development of the brain, and in the formation of neuronal circuits, as they are central in the assembly and maturation of chemical synapses. Several families of neuronal adhesion molecules have been identified such as the neuronal cell adhesion molecules, neurexins and neuroligins, and in particular recently several leucine-rich repeat proteins, e.g., Netrin G-ligands, SLITRKs, and LRRTMs. The LRRTMs form a family of four proteins. They have been implicated in excitatory glutamatergic synapse function and were specifically characterized as ligands for neurexins in excitatory synapse formation and maintenance. In addition, LRRTM3 and LRRTM4 have been found to be ligands for heparan sulfate proteoglycans, including glypican. We report here the crystal structure of a thermostabilized mouse LRRTM2, with a Tm 30 °C higher than that of the wild-type protein. We localized the neurexin binding site to the concave surface based on protein engineering, sequence conservation, and prior information about the interaction of the ligand with neurexins, which allowed us to propose a tentative model for the LRRTM-neurexin interaction complex. We also determined affinities of the thermostabilized LRRTM2 and wild-type LRRTM1 and LRRTM2 for neurexin-β1 with and without Ca(2+). Cell culture studies and binding experiments show that the engineered protein is functional and capable of forming synapselike contacts. The structural and functional data presented here provide the first structure of an LRRTM protein and allow us to propose a model for the molecular mechanism of LRRTM function in the synaptic adhesion.

  7. Adhesion

    MedlinePlus

    ... as the shoulder Eyes Inside the abdomen or pelvis Adhesions can become larger or tighter over time. ... Other causes of adhesions in the abdomen or pelvis include: Appendicitis , most often when the appendix breaks ...

  8. Intercellular adhesion molecule-1 expression by skeletal muscle cells augments myogenesis

    SciTech Connect

    Goh, Qingnian; Dearth, Christopher L.; Corbett, Jacob T.; Pierre, Philippe; Chadee, Deborah N.; Pizza, Francis X.

    2015-02-15

    We previously demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) by skeletal muscle cells after muscle overload contributes to ensuing regenerative and hypertrophic processes in skeletal muscle. The objective of the present study is to reveal mechanisms through which skeletal muscle cell expression of ICAM-1 augments regenerative and hypertrophic processes of myogenesis. This was accomplished by genetically engineering C2C12 myoblasts to stably express ICAM-1, and by inhibiting the adhesive and signaling functions of ICAM-1 through the use of a neutralizing antibody or cell penetrating peptide, respectively. Expression of ICAM-1 by cultured skeletal muscle cells augmented myoblast–myoblast adhesion, myotube formation, myonuclear number, myotube alignment, myotube–myotube fusion, and myotube size without influencing the ability of myoblasts to proliferate or differentiate. ICAM-1 augmented myotube formation, myonuclear accretion, and myotube alignment through a mechanism involving adhesion-induced activation of ICAM-1 signaling, as these dependent measures were reduced via antibody and peptide inhibition of ICAM-1. The adhesive and signaling functions of ICAM-1 also facilitated myotube hypertrophy through a mechanism involving myotube–myotube fusion, protein synthesis, and Akt/p70s6k signaling. Our findings demonstrate that ICAM-1 expression by skeletal muscle cells augments myogenesis, and establish a novel mechanism through which the inflammatory response facilitates growth processes in skeletal muscle. - Highlights: • We examined mechanisms through which skeletal muscle cell expression of ICAM-1 facilitates events of in vitro myogenesis. • Expression of ICAM-1 by cultured myoblasts did not influence their ability to proliferate or differentiate. • Skeletal muscle cell expression of ICAM-1 augmented myoblast fusion, myotube alignment, myotube–myotube fusion, and myotube size. • ICAM-1 augmented myogenic processes through

  9. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein.

    PubMed

    Li, Zhijuan; Cheng, Jianxin; Wang, Liping

    2015-10-30

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation.

  10. Adhesion of single polyelectrolyte molecules on silica, mica, and bitumen surfaces.

    PubMed

    Long, Jun; Xu, Zhenghe; Masliyah, Jacob H

    2006-02-14

    In a recent study (Energy Fuels 2005, 19, 936), a partially hydrolyzed polyacrylamide (HPAM) was used as a process aid to recover bitumen from oil sand ores. It was found that HPAM addition at the bitumen extraction step not only improved bitumen recovery but also enhanced fine solids settling in the tailings stream. To understand the role of HPAM, single-molecule force spectroscopy was employed for the first time to measure the desorption/adhesion forces of single HPAM molecules on silica, mica, and bitumen surfaces using an atomic force microscope (AFM). Silicon wafers with an oxidized surface layer and newly cleaved mica were used, respectively, to represent sand grains and clays in oil sands. The force measurements were carried out in deionized water and in commercial plant process water under equilibrium conditions. The desorption/adhesion forces of HPAM obtained on mica, silica, and bitumen surfaces were approximately 200, 40, and 80 pN in deionized water and approximately 100, 50, and 40 pN in the plant process water, respectively. The measured adhesion forces together with the zeta potential values of these surfaces indicate that the polymer would preferentially adsorb onto clay surfaces rather than onto bitumen surfaces. It is the selective adsorption of HPAM that benefits both bitumen recovery and tailings settling when the polymer was added directly to the bitumen extraction process at an appropriate dosage.

  11. Depletion of water molecules during ethanol wet-bonding with etch and rinse dental adhesives.

    PubMed

    Grégoire, Geneviève; Sharrock, Patrick; Delannée, Mathieu; Delisle, Marie-Bernadette

    2013-01-01

    The treatment of demineralized dentin with ethanol has been proposed as a way to improve hydrophobic monomer penetration into otherwise water saturated collagen fibrils. The ethanol rinse is expected to preserve the fibrils from collapsing while optimizing resin constituent infiltration for better long term adhesion. The physico-chemical investigations of demineralized dentin confirmed objectively these working hypotheses. Namely, Differential Scanning Calorimetry (DSC) measurements of the melting point of water molecules pointed to the presence of free and bound water states. Unfreezable water was the main type of water remaining following a rinsing step with absolute ethanol. Two different liquid water phases were also observed by Magic Angle Spinning (MAS) solid state Nuclear magnetic Resonance (NMR) spectroscopy. Infrared spectra of ethanol treated specimens illustrated differences with the fully hydrated specimens concerning the polar carbonyl vibrations. Optical microscopy observations as well as scanning electron microscopy showed an improved dentin-adhesive interface with ethanol wet bonding. The results indicate that water can be confined to strongly bound structural molecules when excess water is removed with ethanol prior to adhesive application. This should preserve collagen from hydrolysis upon aging of the hybrid layer.

  12. The cell adhesion molecule Fasciclin2 regulates brush border length and organization in Drosophila renal tubules

    PubMed Central

    Halberg, Kenneth A.; Rainey, Stephanie M.; Veland, Iben R.; Neuert, Helen; Dornan, Anthony J.; Klämbt, Christian; Davies, Shireen-Anne; Dow, Julian A. T.

    2016-01-01

    Multicellular organisms rely on cell adhesion molecules to coordinate cell–cell interactions, and to provide navigational cues during tissue formation. In Drosophila, Fasciclin 2 (Fas2) has been intensively studied due to its role in nervous system development and maintenance; yet, Fas2 is most abundantly expressed in the adult renal (Malpighian) tubule rather than in neuronal tissues. The role Fas2 serves in this epithelium is unknown. Here we show that Fas2 is essential to brush border maintenance in renal tubules of Drosophila. Fas2 is dynamically expressed during tubule morphogenesis, localizing to the brush border whenever the tissue is transport competent. Genetic manipulations of Fas2 expression levels impact on both microvilli length and organization, which in turn dramatically affect stimulated rates of fluid secretion by the tissue. Consequently, we demonstrate a radically different role for this well-known cell adhesion molecule, and propose that Fas2-mediated intermicrovillar homophilic adhesion complexes help stabilize the brush border. PMID:27072072

  13. The cell adhesion molecule Fasciclin2 regulates brush border length and organization in Drosophila renal tubules.

    PubMed

    Halberg, Kenneth A; Rainey, Stephanie M; Veland, Iben R; Neuert, Helen; Dornan, Anthony J; Klämbt, Christian; Davies, Shireen-Anne; Dow, Julian A T

    2016-01-01

    Multicellular organisms rely on cell adhesion molecules to coordinate cell-cell interactions, and to provide navigational cues during tissue formation. In Drosophila, Fasciclin 2 (Fas2) has been intensively studied due to its role in nervous system development and maintenance; yet, Fas2 is most abundantly expressed in the adult renal (Malpighian) tubule rather than in neuronal tissues. The role Fas2 serves in this epithelium is unknown. Here we show that Fas2 is essential to brush border maintenance in renal tubules of Drosophila. Fas2 is dynamically expressed during tubule morphogenesis, localizing to the brush border whenever the tissue is transport competent. Genetic manipulations of Fas2 expression levels impact on both microvilli length and organization, which in turn dramatically affect stimulated rates of fluid secretion by the tissue. Consequently, we demonstrate a radically different role for this well-known cell adhesion molecule, and propose that Fas2-mediated intermicrovillar homophilic adhesion complexes help stabilize the brush border. PMID:27072072

  14. Theobroma cacao increases cells viability and reduces IL-6 and sVCAM-1 level in endothelial cells induced by plasma from preeclamptic patients.

    PubMed

    Rahayu, Budi; Baktiyani, Siti Candra Windu; Nurdiana, Nurdiana

    2016-01-01

    This study aims to investigate whether an ethanolic extract of Theobroma cacao bean is able to increase cell viability and decrease IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluency, endothelial cells were divided into six groups, which included control (untreated), endothelial cells exposed to plasma from normal pregnancy, endothelial cells exposed to 2% plasma from preeclamptic patients (PP), endothelial cells exposed to PP in the presence of ethanolic extract of T. cacao (PP+TC) at the following three doses: 25, 50, and 100 ppm. The analysis was performed in silico using the Hex 8.0, LigPlus and LigandScout 3.1 software. Analysis on IL-6 and sVCAM-1 levels were done by enzyme linked immunosorbent assay (ELISA). We found that seven of them could bind to the protein NFκB (catechin, leucoanthocyanidin, niacin, phenylethylamine, theobromine, theophylline, and thiamin). This increase in IL-6 was significantly (P<0.05) attenuated by both the 50 and 100 ppm treatments of T. cacao extract. Plasma from PP significantly increased sVCAM-1 levels compared to untreated cells. This increase in sVCAM-1 was significantly attenuated by all doses of the extract. In conclusion, T. cacao extract prohibits the increase in IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Therefore this may provide a herbal therapy for attenuating the endothelial dysfunction found in preeclampsia. PMID:26955771

  15. Nerve growth factor translates stress response and subsequent murine abortion via adhesion molecule-dependent pathways.

    PubMed

    Tometten, Mareike; Blois, Sandra; Kuhlmei, Arne; Stretz, Anna; Klapp, Burghard F; Arck, Petra C

    2006-04-01

    Spontaneous abortion is a frequent threat affecting 10%-25% of human pregnancies. Psychosocial stress has been suggested to be attributable for pregnancy losses by challenging the equilibrium of systems mandatory for pregnancy maintenance, including the nervous, endocrine, and immune system. Strong evidence indicates that stress-triggered abortion is mediated by adhesion molecules, i.e., intercellular adhesion molecule 1 (ICAM1) and leukocyte function associated molecule 1, now being referred to as integrin alpha L (ITGAL), which facilitate recruitment of inflammatory cells to the feto-maternal interface. The neurotrophin beta-nerve growth factor (NGFB), which has been shown to be upregulated in response to stress in multiple experimental settings including in the uterine lining (decidua) during pregnancy, increases ICAM1 expression on endothelial cells. Here, we investigated whether and how NGFB neutralization has a preventive effect on stress-triggered abortion in the murine CBA/J x DBA/2J model. We provide experimental evidence that stress exposure upregulates the frequency of abortion and the expression of uterine NGFB. Further, adhesion molecules ICAM1 and selectin platelet (SELP, formerly P-Selectin) and their ligands ITGAL and SELP ligand (SELPL, formerly P selectin glycoprotein ligand 1) respectively increase in murine deciduas in response to stress. Subsequently, decidual cytokines are biased toward a proinflammatory and abortogenic cytokine profile. Additionally, a decrease of pregnancy protective CD8alpha(+) decidual cells is present. Strikingly, all such uterine stress responses are abrogated by NGFB neutralization. Hence, NGFB acts as a proximal mediator in the hierarchical network of immune rejection by mediating an abortogenic environment comprised of classical signs of neurogenic inflammation. PMID:16371592

  16. Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells.

    PubMed

    Fujiwara, K

    2006-04-01

    Endothelial cells are known to respond to mechanical forces such as fluid shear stress and cyclic stretch, but elucidating the mechanism for mechanosensing has been difficult. Experimental data indicate that there are probably several sensing mechanisms. We have recently proposed a novel mechanoresponse mechanism that involves platelet endothelial cell adhesion molecule-1 (PECAM-1). When endothelial cells are stimulated by fluid shear stress, PECAM-1 is tyrosine phosphorylated and activates the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signalling cascade. The same signalling events occurred when we applied pulling force directly on PECAM-1 on the endothelial cell surface using magnetic beads coated with antibodies against the external domain of PECAM-1. These results appear to indicate that PECAM-1 is a mechanotransduction molecule. To our knowledge, this is the first mammalian molecule that is shown to respond to mechanical force directly exerted to it. PMID:16594905

  17. Adhesion, stretching, and electrical charge assessment of dermatan sulfate molecules by colloidal probes.

    PubMed

    Gonzalez, Rodrigo; Caballero, Leonardo; Pavez, Jorge; Melo, Francisco

    2012-06-26

    Electrical and mechanical properties of dermatan sulfate (DS) molecules are studied in an aqueous environment as a function of pH. DS molecules linked at various points distributed on the surface of mica previously silanizated along with a suitable functionalized microsphere, attached to the cantilever of an atomic force microscope (AFM), provided suitable surfaces for testing interactions through the colloidal probe methodology. The repulsive force between the surfaces indicated that the charge of DS increases with pH as a result of the gradual deprotonation of acidic groups. Pulling experiments revealed increasing adhesion of DS to the monolayer as a function of pH, presumably due both to the electrical nature of the interaction between these molecules and the progressive increase of the charge of DS with pH. Serrations exhibited by the force in pulling experiments indicate that more than a single DS molecule is stretched at the same time. In addition, pulling force remained significant even at extensions that went beyond the average contour length of a single DS molecule, which suggests the existence of a significant link between DS molecules.

  18. Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction.

    PubMed

    Pezzi, Nicole; Assis, Amanda Freire; Cotrim-Sousa, Larissa Cotrim; Lopes, Gabriel Sarti; Mosella, Maritza Salas; Lima, Djalma Sousa; Bombonato-Prado, Karina F; Passos, Geraldo Aleixo

    2016-09-01

    We demonstrate that even a partial reduction of Aire mRNA levels by siRNA-induced Aire knockdown (Aire KD) has important consequences to medullary thymic epithelial cells (mTECs). Aire knockdown is sufficient to reduce Aire protein levels, impair its nuclear location, and cause an imbalance in large-scale gene expression, including genes that encode cell adhesion molecules. These genes drew our attention because adhesion molecules are implicated in the process of mTEC-thymocyte adhesion, which is critical for T cell development and the establishment of central self-tolerance. Accordingly, we consider the following: 1) mTECs contribute to the elimination of self-reactive thymocytes through adhesion; 2) Adhesion molecules play a crucial role during physical contact between these cells; and 3) Aire is an important transcriptional regulator in mTECs. However, its role in controlling mTEC-thymocyte adhesion remains unclear. Because Aire controls adhesion molecule genes, we hypothesized that the disruption of its expression could influence mTEC-thymocyte interaction. To test this hypothesis, we used a murine Aire(+) mTEC cell line as a model system to reproduce mTEC-thymocyte adhesion in vitro. Transcriptome analysis of the mTEC cell line revealed that Aire KD led to the down-modulation of more than 800 genes, including those encoding for proteins involved in cell adhesion, i.e., the extracellular matrix constituent Lama1, the CAM family adhesion molecules Vcam1 and Icam4, and those that encode peripheral tissue antigens. Thymocytes co-cultured with Aire KD mTECs had a significantly reduced capacity to adhere to these cells. This finding is the first direct evidence that Aire also plays a role in controlling mTEC-thymocyte adhesion. PMID:27505711

  19. Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction.

    PubMed

    Pezzi, Nicole; Assis, Amanda Freire; Cotrim-Sousa, Larissa Cotrim; Lopes, Gabriel Sarti; Mosella, Maritza Salas; Lima, Djalma Sousa; Bombonato-Prado, Karina F; Passos, Geraldo Aleixo

    2016-09-01

    We demonstrate that even a partial reduction of Aire mRNA levels by siRNA-induced Aire knockdown (Aire KD) has important consequences to medullary thymic epithelial cells (mTECs). Aire knockdown is sufficient to reduce Aire protein levels, impair its nuclear location, and cause an imbalance in large-scale gene expression, including genes that encode cell adhesion molecules. These genes drew our attention because adhesion molecules are implicated in the process of mTEC-thymocyte adhesion, which is critical for T cell development and the establishment of central self-tolerance. Accordingly, we consider the following: 1) mTECs contribute to the elimination of self-reactive thymocytes through adhesion; 2) Adhesion molecules play a crucial role during physical contact between these cells; and 3) Aire is an important transcriptional regulator in mTECs. However, its role in controlling mTEC-thymocyte adhesion remains unclear. Because Aire controls adhesion molecule genes, we hypothesized that the disruption of its expression could influence mTEC-thymocyte interaction. To test this hypothesis, we used a murine Aire(+) mTEC cell line as a model system to reproduce mTEC-thymocyte adhesion in vitro. Transcriptome analysis of the mTEC cell line revealed that Aire KD led to the down-modulation of more than 800 genes, including those encoding for proteins involved in cell adhesion, i.e., the extracellular matrix constituent Lama1, the CAM family adhesion molecules Vcam1 and Icam4, and those that encode peripheral tissue antigens. Thymocytes co-cultured with Aire KD mTECs had a significantly reduced capacity to adhere to these cells. This finding is the first direct evidence that Aire also plays a role in controlling mTEC-thymocyte adhesion.

  20. Inhalation of Ultrafine Particles Alters Blood Leukocyte Expression of Adhesion Molecules in Humans

    PubMed Central

    Frampton, Mark W.; Stewart, Judith C.; Oberdörster, Günter; Morrow, Paul E.; Chalupa, David; Pietropaoli, Anthony P.; Frasier, Lauren M.; Speers, Donna M.; Cox, Christopher; Huang, Li-Shan; Utell, Mark J.

    2006-01-01

    Ultrafine particles (UFPs; aerodynamic diameter < 100 nm) may contribute to the respiratory and cardiovascular morbidity and mortality associated with particulate air pollution. We tested the hypothesis that inhalation of carbon UFPs has vascular effects in healthy and asthmatic subjects, detectable as alterations in blood leukocyte expression of adhesion molecules. Healthy subjects inhaled filtered air and freshly generated elemental carbon particles (count median diameter ~ 25 nm, geometric standard deviation ~ 1.6), for 2 hr, in three separate protocols: 10 μg/m3 at rest, 10 and 25 μg/m3 with exercise, and 50 μg/m3 with exercise. In a fourth protocol, subjects with asthma inhaled air and 10 μg/m3 UFPs with exercise. Peripheral venous blood was obtained before and at intervals after exposure, and leukocyte expression of surface markers was quantitated using multiparameter flow cytometry. In healthy subjects, particle exposure with exercise reduced expression of adhesion molecules CD54 and CD18 on monocytes and CD18 and CD49d on granulocytes. There were also concentration-related reductions in blood monocytes, basophils, and eosinophils and increased lymphocyte expression of the activation marker CD25. In subjects with asthma, exposure with exercise to 10 μg/m3 UFPs reduced expression of CD11b on monocytes and eosinophils and CD54 on granulocytes. Particle exposure also reduced the percentage of CD4+ T cells, basophils, and eosinophils. Inhalation of elemental carbon UFPs alters peripheral blood leukocyte distribution and expression of adhesion molecules, in a pattern consistent with increased retention of leukocytes in the pulmonary vascular bed. PMID:16393658

  1. Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule.

    PubMed

    Zhu, D Z; Cheng, C F; Pauli, B U

    1991-11-01

    Organ-specific adhesion molecules expressed by vascular endothelial cells have been implicated in the arrest of blood-borne cancer cells in selective, secondary sites. A lung-specific endothelial cell adhesion molecule (Lu-ECAM-1) localized on endothelia of distinct branches of lung blood vessels has been purified by immunoaffinity chromatography from detergent extracts of lung matrix-modulated endothelial cells using monoclonal antibody (mAb) 6D3. It has a molecular mass of 90 kDa and promotes the selective attachment of lung-metastatic B16 melanoma cells. Corresponding with their metastatic performance, B16-F10 tumor cells selected for higher lung colonization bind to Lu-ECAM-1 in significantly higher numbers than their low lung metastatic counterpart B16-F0. Binding of B16-F0 and B16-F10 is reduced with mAb 6D3 to slightly lower levels than B16-F0 bound to Lu-ECAM-1. mAb 6D3 injected into C57BL/6 mice 1 hr prior to an i.v. challenge with B16-F10 causes a 90% reduction in the number of lung colonies compared with animals injected with control mAb (6D8 or 3C6). Lu-ECAM-1 neither binds nor effects metastasis of other lung-colonizing tumor cells (e.g., KLN205). Thus, site-specific metastasis of tumor cells is regulated by similar mechanisms as the homing of lymphocytes--namely, by the ability of blood-borne cancer cells to recognize and adhere to distinct endothelial cell adhesion molecules.

  2. Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule.

    PubMed Central

    Zhu, D Z; Cheng, C F; Pauli, B U

    1991-01-01

    Organ-specific adhesion molecules expressed by vascular endothelial cells have been implicated in the arrest of blood-borne cancer cells in selective, secondary sites. A lung-specific endothelial cell adhesion molecule (Lu-ECAM-1) localized on endothelia of distinct branches of lung blood vessels has been purified by immunoaffinity chromatography from detergent extracts of lung matrix-modulated endothelial cells using monoclonal antibody (mAb) 6D3. It has a molecular mass of 90 kDa and promotes the selective attachment of lung-metastatic B16 melanoma cells. Corresponding with their metastatic performance, B16-F10 tumor cells selected for higher lung colonization bind to Lu-ECAM-1 in significantly higher numbers than their low lung metastatic counterpart B16-F0. Binding of B16-F0 and B16-F10 is reduced with mAb 6D3 to slightly lower levels than B16-F0 bound to Lu-ECAM-1. mAb 6D3 injected into C57BL/6 mice 1 hr prior to an i.v. challenge with B16-F10 causes a 90% reduction in the number of lung colonies compared with animals injected with control mAb (6D8 or 3C6). Lu-ECAM-1 neither binds nor effects metastasis of other lung-colonizing tumor cells (e.g., KLN205). Thus, site-specific metastasis of tumor cells is regulated by similar mechanisms as the homing of lymphocytes--namely, by the ability of blood-borne cancer cells to recognize and adhere to distinct endothelial cell adhesion molecules. Images PMID:1946371

  3. The clinical spectrum of mutations in L1, a neuronal cell adhesion molecule

    SciTech Connect

    Fransen, E.; Vits, L.; Van Camp, G.; Willems, P.J.

    1996-07-12

    Mutations in the gene encoding the neuronal cell adhesion molecule L1 are responsible for several syndromes with clinical overlap, including X-linked hydrocephalus (XLH, HSAS), MASA (mental retardation, aphasia, shuffling gait, adducted thumbs) syndrome, complicated X-linked spastic paraplegia (SP 1), X-linked mental retardation-clasped thumb (MR-CT) syndrome, and some forms of X-linked agenesis of the corpus callosum (ACC). We review 34 L1 mutations in patients with these phenotypes. 22 refs., 3 figs., 4 tabs.

  4. Regulation of platelet biology by platelet endothelial cell adhesion molecule-1.

    PubMed

    Jones, Chris I; Moraes, Leonardo A; Gibbins, Jonathan M

    2012-01-01

    Platelet endothelial cell adhesion molecule-1 (PECAM-1), an immunoreceptor tyrosine-based inhibitory motif containing receptor, plays diverse and apparently contradictory roles in regulating the response of platelets to stimuli; inhibiting platelet response to immunoreceptor tyrosine-based activation motif and G protein-coupled receptor signalling following stimulation with collagen, adenosine diphosphate, and thrombin, as well as enhancing integrin outside-in signalling. These dual, and opposing, roles suggest an important and complex role for PECAM-1 in orchestrating platelet response to vascular damage. Indeed, during thrombus formation, the influence of PECAM-1 on the multiple signalling pathways combines leading to a relatively large inhibitory effect on thrombus formation. PMID:22035359

  5. The role of the cell adhesion molecules (integrins/cadherins) in prostate cancer.

    PubMed

    Drivalos, Alexandros; Papatsoris, Athanasios G; Chrisofos, Michael; Efstathiou, Eleni; Dimopoulos, Meletios A

    2011-01-01

    During prostate carcinogenesis the cellular adhesion molecules, i.e.; integrins and cadherins mediate aberrant interactions between glandular epithelial cells and the extracellular matrix. Several integrin α subunits are downregulated, while β subunits are up-regulated. The expression of several cadherins and catenins has specific prognostic value. There is an association between the expression of the E-cadherin/catenin complex and high grade prostate cancer. Clinical trials evaluating the efficacy of integrin antagonists are ongoing with promising results. In this article we update the role of integrins and cadherins in prostate carcinogenesis and evaluate the therapeutic potential of their manipulation.

  6. The resilient synapse: insights from genetic interference of synaptic cell adhesion molecules.

    PubMed

    Piechotta, Kerstin; Dudanova, Irina; Missler, Markus

    2006-11-01

    Synaptic cell adhesion molecules (SCAMs) are mostly membrane-anchored molecules with extracellular domains that extend into the synaptic cleft. Prototypical SCAMs interact with homologous or heterologous molecules on the surface of adjacent cells, ensuring the precise apposition of pre- and postsynaptic elements. More recent definitions of SCAMs often include molecules involved in axon pathfinding, cell recognition and synaptic differentiation events, making SCAMs functionally and molecularly a highly diverse group. In this review, we summarize the proposed in vivo functions of a large variety of SCAMs. We mainly focus on results obtained from analyses of genetic model organisms, mostly mouse knockout mutants, lacking expression of the respective candidate genes. In contrast to the substantial effect yielded by some knockouts of molecules involved in synaptic vesicle release, no SCAM mutant has been reported thus far that shows a prominently altered structure of the majority of synapses or even lacks synapses altogether. This surprising resilience of synaptic structure might be explained by a high redundancy between different SCAMs, by the assumption that the crucial molecular players in synapse structure have yet to be discovered or by a grand variability in the mechanisms of synapse formation that underlies the diversity of synapses. Whatever the final answer turns out to be, the genetic dissection of the SCAM superfamilies has led to a much better understanding of the different steps required to form, differentiate and modify a synapse.

  7. Expression and role of adhesion molecule CD18 on bovine neutrophils.

    PubMed

    Nagahata, H; Nochi, H; Tamoto, K; Noda, H; Kociba, G J

    1995-01-01

    Expression of CD18 on bovine neutrophils in response to stimulation by zymosan activated serum (ZAS) and phorbol myristate acetate (PMA) and the effects of monoclonal antibodies (MAB) recognizing CD18 or bovine neutrophil surface antigens (S2G8 and S5F8G10) on adherence, chemotactic responses and phagocytosis of bovine neutrophils were evaluated. CD18 expression of neutrophils was increased after ZAS and PMA treatment by 12.2 and 54.2% respectively, and were significantly (p < 0.05, p < 0.01) different from those of untreated neutrophils. CD18 expression by neutrophils from a Holstein-Friesian heifer affected with leukocyte adhesion deficiency was within negative controls when stimulated by ZAS and PMA. Adherence, chemotactic responses, and phagocytosis were significantly decreased (p < 0.01) in neutrophils continuously treated with anti-CD18 MAB (MHM 23). Adherence was also significantly decreased in anti-CD18 pretreated neutrophils. Significant (p < 0.01) differences of chemotactic responses and phagocytosis of neutrophils were found between neutrophils pretreated and continuously treated with anti-CD18 MAB (MHM 23). Monoclonal antibodies to other surface antigens did not significantly alter neutrophil adherence, chemotaxis or phagocytosis. This study demonstrated that CD18 expression on bovine neutrophils is increased significantly by stimulation with ZAS and PMA and that the adhesion molecule CD18 plays an important role in adhesion-related functions. PMID:7704836

  8. Hyalin is a Cell Adhesion Molecule Involved in Mediating Archenteron - Blastocoel Roof Attachment

    PubMed Central

    Carroll, Edward J.; Hutchins-Carroll, Virginia; Coyle-Thompson, Catherine; Oppenheimer, Steven B.

    2008-01-01

    Summary The U. S. National Institutes of Health has designated the sea urchin embryo as a model organism because about twenty-five discoveries in this system have led to insights into the physiology of higher organisms, including humans. Hyalin is a large glycoprotein in the hyaline layer of sea urchin embryos that functions to maintain general adhesive relationships in the developing embryo. It consists of the hyalin repeat domain that has been identified in organisms as diverse as bacteria, worms, flies, mice, sea urchins and humans. Here we show, using a polyclonal antibody raised against the 11.6 S species of hyalin, that it localizes at the tip of the archenteron and on the roof of the blastocoel exactly where these two structures bond in an adhesive interaction that has been of interest for over a century. In addition, the antibody blocks the interaction between the archenteron tip and blastocoel roof. These results, in addition to other recent findings from this laboratory that will be discussed, suggest that hyalin is involved in mediating this cellular interaction. This is the first demonstration that suggests that hyalin is a specific cell adhesion molecule that may function as such in many organisms, including humans. PMID:18262230

  9. Expression of claudins, occludin, junction adhesion molecule A and zona occludens 1 in canine organs.

    PubMed

    Ahn, Changhwan; Shin, Da-Hye; Lee, Dongoh; Kang, Su-Myung; Seok, Ju-Hyung; Kang, Hee Young; Jeung, Eui-Bae

    2016-10-01

    Tight junctions are the outermost structures of intercellular junctions and are classified as transmembrane proteins. These factors form selective permeability barriers between cells, act as paracellular transporters and regulate structural and functional polarity of cells. Although tight junctions have been previously studied, comparison of the transcriptional‑translational levels of these molecules in canine organs remains to be investigated. In the present study, organ‑specific expression of the tight junction proteins, claudin, occludin, junction adhesion molecule A and zona occludens 1 was examined in the canine duodenum, lung, liver and kidney. Results of immunohistochemistry analysis demonstrated that the tight junctions were localized in intestinal villi and glands of the duodenum, bronchiolar epithelia and alveolar walls of the lung, endometrium and myometrium of the hepatocytes, and the distal tubules and glomeruli of the kidney. These results suggest that tight junctions are differently expressed in organs, and therefore may be involved in organ‑specific functions to maintain physiological homeostasis. PMID:27600198

  10. Diatomic molecules and metallic adhesion, cohesion, and chemisorption - A single binding-energy relation

    NASA Technical Reports Server (NTRS)

    Ferrante, J.; Smith, J. R.; Rose, J. H.

    1983-01-01

    Potential-energy relations involving a few parameters in simple analytic forms have been found to represent well the energetics of a wide variety of diatomic molecules. However, such two-atom potential functions are not appropriate for metals. It is well known that, in the case of metals, there exist strong volume-dependent forces which can never be expressed as pairwise interactions. The present investigation has the objective to show that, in spite of the observation concerning metals, a single binding-energy relation can be found which accurately describes diatomic molecules as well as adhesion, cohesion, and chemisorption on metals. This universality reveals a commonality between the molecular and metallic bond.

  11. Expression of claudins, occludin, junction adhesion molecule A and zona occludens 1 in canine organs

    PubMed Central

    Ahn, Changhwan; Shin, Da-Hye; Lee, Dongoh; Kang, Su-Myung; Seok, Ju-Hyung; Kang, Hee Young; Jeung, Eui-Bae

    2016-01-01

    Tight junctions are the outermost structures of intercellular junctions and are classified as transmembrane proteins. These factors form selective permeability barriers between cells, act as paracellular transporters and regulate structural and functional polarity of cells. Although tight junctions have been previously studied, comparison of the transcriptional-translational levels of these molecules in canine organs remains to be investigated. In the present study, organ-specific expression of the tight junction proteins, claudin, occludin, junction adhesion molecule A and zona occludens 1 was examined in the canine duodenum, lung, liver and kidney. Results of immunohistochemistry analysis demonstrated that the tight junctions were localized in intestinal villi and glands of the duodenum, bronchiolar epithelia and alveolar walls of the lung, endometrium and myometrium of the hepatocytes, and the distal tubules and glomeruli of the kidney. These results suggest that tight junctions are differently expressed in organs, and therefore may be involved in organ-specific functions to maintain physiological homeostasis. PMID:27600198

  12. Structure of Reovirus σ1 in Complex with Its Receptor Junctional Adhesion Molecule-A

    PubMed Central

    Kirchner, Eva; Guglielmi, Kristen M.; Strauss, Holger M.; Dermody, Terence S.; Stehle, Thilo

    2008-01-01

    Viral attachment to specific host receptors is the first step in viral infection and serves an essential function in the selection of target cells. Mammalian reoviruses are highly useful experimental models for studies of viral pathogenesis and show promise as vectors for oncolytics and vaccines. Reoviruses engage cells by binding to carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A exists at the cell surface as a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. We report the crystal structure of reovirus attachment protein σ1 in complex with a soluble form of JAM-A. The σ1 protein disrupts the JAM-A dimer, engaging a single JAM-A molecule via virtually the same interface that is used for JAM-A homodimerization. Thus, reovirus takes advantage of the adhesive nature of an immunoglobulin-superfamily receptor by usurping the ligand-binding site of this molecule to attach to the cell surface. The dissociation constant (KD) of the interaction between σ1 and JAM-A is 1,000-fold lower than that of the homophilic interaction between JAM-A molecules, indicating that JAM-A strongly prefers σ1 as a ligand. Analysis of reovirus mutants engineered by plasmid-based reverse genetics revealed residues in σ1 required for binding to JAM-A and infectivity of cultured cells. These studies define biophysical mechanisms of reovirus cell attachment and provide a platform for manipulating reovirus tropism to enhance vector targeting. PMID:19079583

  13. Ankyrin-binding activity of nervous system cell adhesion molecules expressed in adult brain.

    PubMed

    Davis, J Q; Bennett, V

    1993-01-01

    A family of ankyrin-binding glycoproteins have been identified in adult rat brain that include alternatively spliced products of the same pre-mRNA. A composite sequence of ankyrin-binding glycoprotein (ABGP) shares 72% amino acid sequence identity with chicken neurofascin, a membrane-spanning neural cell adhesion molecule in the Ig super-family expressed in embryonic brain. ABGP polypeptides and ankyrin associate as pure proteins in a 1:1 molar stoichiometry at a site located in the predicted cytoplasmic domain. ABGP polypeptides are expressed late in postnatal development to approximately the same levels as ankyrin, and comprise a significant fraction of brain membrane proteins. Immunofluorescence studies have shown that ABGP polypeptides are co-localized with ankyrinB. Major differences in developmental expression have been reported for neurofascin in embryos compared with the late postnatal expression of ABGP, suggesting that ABGP and neurofascin represent products of gene duplication events that have subsequently evolved in parallel with distinct roles. Predicted cytoplasmic domains of rat ABGP and chicken neurofascin are nearly identical to each other and closely related to a group of nervous system cell adhesion molecules with variable extracellular domains, including L1, Nr-CAM and Ng-CAM of vertebrates, and neuroglian of Drosophila. A hypothesis to be evaluated is that ankyrin-binding activity is shared by all of these proteins.

  14. Effect of Cell Adhesion Molecule 1 Expression on Intracellular Granule Movement in Pancreatic α Cells.

    PubMed

    Yokawa, Satoru; Furuno, Tadahide; Suzuki, Takahiro; Inoh, Yoshikazu; Suzuki, Ryo; Hirashima, Naohide

    2016-09-01

    Although glucagon secreted from pancreatic α cells plays a role in increasing glucose concentrations in serum, the mechanism regulating glucagon secretion from α cells remains unclear. Cell adhesion molecule 1 (CADM1), identified as an adhesion molecule in α cells, has been reported not only to communicate among α cells and between nerve fibers, but also to prevent excessive glucagon secretion from α cells. Here, we investigated the effect of CADM1 expression on the movement of intracellular secretory granules in α cells because the granule transport is an important step in secretion. Spinning disk microscopic analysis showed that granules moved at a mean velocity of 0.236 ± 0.010 μm/s in the mouse α cell line αTC6 that expressed CADM1 endogenously. The mean velocity was significantly decreased in CADM1-knockdown (KD) cells (mean velocity: 0.190 ± 0.016 μm/s). The velocity of granule movement decreased greatly in αTC6 cells treated with the microtubule-depolymerizing reagent nocodazole, but not in αTC6 cells treated with the actin-depolymerizing reagent cytochalasin D. No difference in the mean velocity was observed between αTC6 and CADM1-KD cells treated with nocodazole. These results suggest that intracellular granules in pancreatic α cells move along the microtubule network, and that CADM1 influences their velocity. PMID:27262873

  15. Decreased pulmonary inflammation after ethanol exposure and burn injury in intercellular adhesion molecule-1 knockout mice.

    PubMed

    Bird, Melanie D; Morgan, Michelle O; Ramirez, Luis; Yong, Sherri; Kovacs, Elizabeth J

    2010-01-01

    Clinical and laboratory evidence suggests that alcohol consumption dysregulates immune function. Burn patients who consume alcohol before their injuries demonstrate higher rates of morbidity and mortality, including acute respiratory distress syndrome, than patients without alcohol at the time of injury. Our laboratory observed higher levels of proinflammatory cytokines and leukocyte infiltration in the lungs of mice after ethanol exposure and burn injury than with either insult alone. To understand the mechanism of the increased pulmonary inflammatory response in mice treated with ethanol and burn injury, we investigated the role of intercellular adhesion molecule (ICAM)-1. Wild-type and ICAM-1 knockout (KO) mice were treated with vehicle or ethanol and subsequently given a sham or burn injury. Twenty-four hours postinjury, lungs were harvested and analyzed for indices of inflammation. Higher numbers of neutrophils were observed in the lungs of wild-type mice after burn and burn with ethanol treatment. This increase in pulmonary inflammatory cell accumulation was significantly lower in the KO mice. In addition, levels of KC, interleukin-1beta, and interleukin-6 in the lung were decreased in the ICAM-1 KO mice after ethanol exposure and burn injury. Interestingly, no differences were observed in serum or lung tissue content of soluble ICAM-1 24 hours postinjury. These data suggest that upregulation of adhesion molecules such as ICAM-1 on the vascular endothelium may play a critical role in the excessive inflammation seen after ethanol exposure and burn injury.

  16. The immunohistochemical expression of CD24 and CD171 adhesion molecules in borderline ovarian tumors.

    PubMed

    Moulla, Alexandra; Miliaras, Dimosthenis; Sioga, Antonia; Kaidoglou, Aikaterini; Economou, Louisa

    2013-10-01

    CD24 and CD171 are cell adhesion proteins, which have been shown to be overexpressed in several carcinomas and to be associated with a poor clinical outcome. Our aim was to determine the expression of these two adhesion molecules in ovarian borderline neoplasms. We investigated 50 ovarian borderline tumors (serous, mucinous and endometrioid) as well as 29 benign cystadenomas and 25 carcinomas, which were used as controls. Paraffin sections were stained immunohistochemically for CD24 and CD171, and their expression was recorded in a semi-quantitative manner. In normal epithelium and benign ovarian cystadenomas both the CD24 and CD171 expression was negative to low, while their expression was significantly increased in borderline and malignant ovarian tumors. High-grade carcinomas, and carcinomas with metastases to the omentum presented considerably higher CD24 expression than low-grade carcinomas, and carcinomas without metastases. In addition, a few borderline and many malignant tumors presented cytoplasmic CD24 immunoreactivity, whereas all benign and most borderline tumors showed apical localization of this molecule. In conclusion, borderline tumors and carcinomas of the ovary present increased expression of CD24 and CD171 in relation to their benign counterparts, as is the case in malignant tumors of other organs. Change of staining pattern of CD24 (apical to cytoplasmic) apparently relates to a more aggressive phenotype. PMID:24166603

  17. Neural cell adhesion molecule modulates mesenchymal stromal cell migration via activation of MAPK/ERK signaling.

    PubMed

    Shi, Yu; Xia, Yin-Yan; Wang, Lei; Liu, Rui; Khoo, King-Shung; Feng, Zhi-Wei

    2012-10-15

    Mesenchymal Stromal Cells (MSCs) represent promising tools for cellular therapy owing to their multipotentiality and ability to localize to injured, inflamed sites and tumor. Various approaches to manipulate expression of MSC surface markers, including adhesion molecules and chemokine receptors, have been explored to enhance homing of MSCs. Recently, Neural Cell Adhesion Molecule (NCAM) has been found to be expressed on MSCs yet its function remains largely elusive. Herein, we show that bone marrow-derived MSCs from NCAM deficient mice exhibit defective migratory ability and significantly impaired adipogenic and osteogenic differentiation potential. We further explore the mechanism governing NCAM mediated migration of MSCs by showing the interplay between NCAM and Fibroblast Growth Factor Receptor (FGFR) induces activation of MAPK/ERK signaling, thereby the migration of MSCs. In addition, re-expression of NCAM180, but not NCAM140, could restore the defective MAPK/ERK signaling thereby the migration of NCAM deficient MSCs. Finally, we demonstrate that NCAM180 expression level could be manipulated by pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α treatment. Overall, our data reveal the vital function of NCAM in MSCs migration and differentiation thus raising the possibility of manipulating NCAM expression to enhance homing and therapeutic potential of MSCs in cellular therapy.

  18. Gingipains from Porphyromonas gingivalis W83 induce cell adhesion molecule cleavage and apoptosis in endothelial cells.

    PubMed

    Sheets, Shaun M; Potempa, Jan; Travis, James; Casiano, Carlos A; Fletcher, Hansel M

    2005-03-01

    The presence of Porphyromonas gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. To explore the effects of these proteases on endothelial cells, we exposed bovine coronary artery endothelial cells and human microvascular endothelial cells to gingipain-active extracellular protein preparations and/or purified gingipains from P. gingivalis. Treated cells exhibited a rapid loss of cell adhesion properties that was followed by apoptotic cell death. Cleavage of N- and VE-cadherin and integrin beta1 was observed in immunoblots of cell lysates. There was a direct correlation between the kinetics of cleavage of N- and VE-cadherin and loss of cell adhesion properties. Loss of cell adhesion, as well as N- and VE-cadherin and integrin beta1 cleavage, could be inhibited or significantly delayed by preincubation of P. gingivalis W83 gingipain-active extracellular extracts with the cysteine protease inhibitor Nalpha-p-tosyl-l-lysine chloromethylketone. Furthermore, purified gingipains also induced endothelial cell detachment and apoptosis. Apoptosis-associated events, including annexin V positivity, caspase-3 activation, and cleavage of the caspase substrates poly(ADP-ribose) polymerase and topoisomerase I (Topo I), were observed in endothelial cells after detachment. All of the effects observed were correlated with the different levels of cysteine-dependent proteolytic activity of the extracts tested. Taken together, these results indicate that gingipains from P. gingivalis can alter cell adhesion molecules and induce endothelial cell death, which could have implications for the pathogenicity of this organism. PMID:15731052

  19. Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction-associated genes

    PubMed Central

    Zhong, Xiaoming; Drgonova, Jana; Li, Chuan-Yun; Uhl, George R.

    2015-01-01

    Human cell adhesion molecules (CAMs) are essential both for a) proper development, modulation and maintenance of interactions between cells and for b) cell-to-cell (and matrix-to-cell) communication about these interactions. CAMs are thus key to proper development and plasticity of organs and tissues that include the brain. Despite recognition of the existence of these dual CAM roles and appreciation of the differential functional significance of these roles, there have been surprisingly few systematic studies that have carefully enumerated the universe of CAMs, identified the preferred roles for specific CAMs in distinct types of cellular connections and communication, or related these issues to specific brain disorders or brain circuits. In this paper, we substantially update and review the set of human genes that are likely to encode CAMs based on searches of databases, literature reviews and annotations. We describe the likely CAMs and the functional CAM subclasses into which they fall. These include “iCAMs”, whose contacts largely mediate cell to cell communication, those involved in focal adhesions, CAM genes whose products are preferentially involved with stereotyped and morphologically-identifiable connections between cells (adherens junctions, gap junctions) and smaller numbers of genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing binding partners of these iCAMs. CAM data from genetic and genomic studies of addiction in humans and mouse models provide examples of the ways in which CAM variation is likely to contribute to a specific brain-based disorder. We discuss how differences in CAM splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 could enrich this picture. CAM expression in dopamine neurons provides one of the ways in which variations in cell adhesion

  20. Short-term fenofibrate treatment reduces elevated plasma Lp-PLA2 mass and sVCAM-1 levels in a subcohort of hypertriglyceridemic GOLDN participants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with inflammation, atherosclerosis, and coronary heart disease events. In addition, Lp-PLA(2) has been linked to classical markers of endothelial activation, including soluble vascular cell adhesion molecule-1 (sVCAM...

  1. Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes

    PubMed Central

    1996-01-01

    To ensure self tolerance, immature thymocytes with high binding affinity for self peptides linked to major histocompatibility complex (MHC) molecules are eliminated in situ via apoptosis (negative selection). The roles of two costimulatory molecules, B7-1 and intercellular adhesion molecule-1 (ICAM-1), in negative selection was examined by studying apoptosis of T cell receptor transgenic CD4+8+ thymocytes cultured with specific peptides presented by MHC class I- transfected Drosophila cells. When coexpressed on these cells, B7-1 and ICAM-1 act synergistically and cause strong class 1-restricted negative selection of thymocytes. When expressed separately, however, B7-1 and ICAM-1 display opposite functions: negative selection is augmented by B7-1, but is inhibited by ICAM-1. It is notable that B7-1 is expressed selectively in the thymic medulla, whereas ICAM-1 is expressed throughout the thymus. Because of this distribution, the differing functions of B7-1 and ICAM-1 may dictate the sites of positive and negative selection. Thus, in the cortex, the presence of ICAM-1, but not B7-1, on the cortical epithelium may preclude or reduce negative selection and thereby promote positive selection. Conversely, the combined expression of B7-1 and ICAM-1 may define the medulla as the principal site of negative selection. PMID:8760806

  2. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase.

    PubMed

    Victor, Victor M; Rovira-Llopis, Susana; Bañuls, Celia; Diaz-Morales, Noelia; Martinez de Marañon, Arantxa; Rios-Navarro, Cesar; Alvarez, Angeles; Gomez, Marcelino; Rocha, Milagros; Hernández-Mijares, Antonio

    2016-01-01

    Cardiovascular diseases and oxidative stress are related to polycystic ovary syndrome (PCOS) and insulin resistance (IR). We have evaluated the relationship between myeloperoxidase (MPO) and leukocyte activation in PCOS patients according to homeostatic model assessment of IR (HOMA-IR), and have explored a possible correlation between these factors and endocrine and inflammatory parameters. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 101 PCOS subjects and 105 control subjects. We divided PCOS subjects into PCOS non-IR (HOMA-IR<2.5) and PCOS IR (HOMA-IR>2.5). Metabolic and anthropometric parameters, total and mitochondrial reactive oxygen species (ROS) production, MPO levels, interactions between human umbilical vein endothelial cells and leukocytes, adhesion molecules (E-selectin, ICAM-1 and VCAM-1) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. Oxidative stress was observed in PCOS patients, in whom there was an increase in total and mitochondrial ROS production and MPO levels. Enhanced rolling flux and adhesion, and a decrease in polymorphonuclear cell rolling velocity were also detected in PCOS subjects. Increases in IL-6 and TNF-α and adhesion molecules (E-selectin, ICAM-1 and VCAM-1) were also observed, particularly in the PCOS IR group, providing evidence that inflammation and oxidative stress are related in PCOS patients. HOMA-IR was positively correlated with hsCRP (p<0.001, r = 0.304), ROS production (p<0.01, r = 0.593), leukocyte rolling flux (p<0.05, r = 0.446), E-selectin (p<0.01, r = 0.436) and IL-6 (p<0.001, r = 0.443). The results show an increase in the rate of ROS and MPO levels in PCOS patients in general, and particularly in those with IR. Inflammation in PCOS induces leukocyte-endothelium interactions and a simultaneous increase in IL-6, TNF-α, E-selectin, ICAM-1 and VCAM-1. These conditions are aggravated by the presence of IR.

  3. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase

    PubMed Central

    Victor, Victor M.; Rovira-Llopis, Susana; Bañuls, Celia; Diaz-Morales, Noelia; Martinez de Marañon, Arantxa; Rios-Navarro, Cesar; Alvarez, Angeles; Gomez, Marcelino; Rocha, Milagros; Hernández-Mijares, Antonio

    2016-01-01

    Cardiovascular diseases and oxidative stress are related to polycystic ovary syndrome (PCOS) and insulin resistance (IR). We have evaluated the relationship between myeloperoxidase (MPO) and leukocyte activation in PCOS patients according to homeostatic model assessment of IR (HOMA-IR), and have explored a possible correlation between these factors and endocrine and inflammatory parameters. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 101 PCOS subjects and 105 control subjects. We divided PCOS subjects into PCOS non-IR (HOMA-IR<2.5) and PCOS IR (HOMA-IR>2.5). Metabolic and anthropometric parameters, total and mitochondrial reactive oxygen species (ROS) production, MPO levels, interactions between human umbilical vein endothelial cells and leukocytes, adhesion molecules (E-selectin, ICAM-1 and VCAM-1) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. Oxidative stress was observed in PCOS patients, in whom there was an increase in total and mitochondrial ROS production and MPO levels. Enhanced rolling flux and adhesion, and a decrease in polymorphonuclear cell rolling velocity were also detected in PCOS subjects. Increases in IL-6 and TNF-α and adhesion molecules (E-selectin, ICAM-1 and VCAM-1) were also observed, particularly in the PCOS IR group, providing evidence that inflammation and oxidative stress are related in PCOS patients. HOMA-IR was positively correlated with hsCRP (p<0.001, r = 0.304), ROS production (p<0.01, r = 0.593), leukocyte rolling flux (p<0.05, r = 0.446), E-selectin (p<0.01, r = 0.436) and IL-6 (p<0.001, r = 0.443). The results show an increase in the rate of ROS and MPO levels in PCOS patients in general, and particularly in those with IR. Inflammation in PCOS induces leukocyte-endothelium interactions and a simultaneous increase in IL-6, TNF-α, E-selectin, ICAM-1 and VCAM-1. These conditions are aggravated by the presence of IR. PMID:27007571

  4. Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction-associated genes.

    PubMed

    Zhong, Xiaoming; Drgonova, Jana; Li, Chuan-Yun; Uhl, George R

    2015-09-01

    Human cell adhesion molecules (CAMs) are essential for proper development, modulation, and maintenance of interactions between cells and cell-to-cell (and matrix-to-cell) communication about these interactions. Despite the differential functional significance of these roles, there have been surprisingly few systematic studies to enumerate the universe of CAMs and identify specific CAMs in distinct functions. In this paper, we update and review the set of human genes likely to encode CAMs with searches of databases, literature reviews, and annotations. We describe likely CAMs and functional subclasses, including CAMs that have a primary function in information exchange (iCAMs), CAMs involved in focal adhesions, CAM gene products that are preferentially involved with stereotyped and morphologically identifiable connections between cells (e.g., adherens junctions, gap junctions), and smaller numbers of CAM genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing iCAM binding partners. We also discuss data from genetic and genomic studies of addiction in humans and mouse models to highlight the ways in which CAM variation may contribute to a specific brain-based disorder such as addiction. Specific examples include changes in CAM mRNA splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 and CAM expression in dopamine neurons. PMID:25988664

  5. Neural cell adhesion molecule (NCAM) marks adult myogenic cells committed to differentiation

    SciTech Connect

    Capkovic, Katie L.; Stevenson, Severin; Johnson, Marc C.; Thelen, Jay J.; Cornelison, D.D.W.

    2008-04-15

    Although recent advances in broad-scale gene expression analysis have dramatically increased our knowledge of the repertoire of mRNAs present in multiple cell types, it has become increasingly clear that examination of the expression, localization, and associations of the encoded proteins will be critical for determining their functional significance. In particular, many signaling receptors, transducers, and effectors have been proposed to act in higher-order complexes associated with physically distinct areas of the plasma membrane. Adult muscle stem cells (satellite cells) must, upon injury, respond appropriately to a wide range of extracellular stimuli: the role of such signaling scaffolds is therefore a potentially important area of inquiry. To address this question, we first isolated detergent-resistant membrane fractions from primary satellite cells, then analyzed their component proteins using liquid chromatography-tandem mass spectrometry. Transmembrane and juxtamembrane components of adhesion-mediated signaling pathways made up the largest group of identified proteins; in particular, neural cell adhesion molecule (NCAM), a multifunctional cell-surface protein that has previously been associated with muscle regeneration, was significant. Immunohistochemical analysis revealed that not only is NCAM localized to discrete areas of the plasma membrane, it is also a very early marker of commitment to terminal differentiation. Using flow cytometry, we have sorted physically homogeneous myogenic cultures into proliferating and differentiating fractions based solely upon NCAM expression.

  6. A functional integrin ligand on the surface of platelets: intercellular adhesion molecule-2.

    PubMed Central

    Diacovo, T G; deFougerolles, A R; Bainton, D F; Springer, T A

    1994-01-01

    Activated platelets express P-selectin and release leukocyte chemoattractants; however, they have not been known to express integrin ligands important in the stabilization of leukocyte interactions with the vasculature. We now demonstrate the presence of intercellular adhesion molecular-2 (ICAM-2) (CD102), and lack of expression of other beta 2-integrin ligands, ICAM-1 (CD54) and ICAM-3 (CD50), on the surface of resting and stimulated platelets. ICAM-2 isolated from platelets migrates as a band of 59,000 M(r) in reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Staining of bone marrow aspirates with anti-ICAM-2 mAb demonstrates strong reactivity to megakaryocytes. Using frozen thin sections and immunogold labeling, the antigen was shown to be present on the plasma membrane and surface-connected canalicular system of resting platelets. The average number of ICAM-2 molecules per platelet is 3,000 +/- 230 and does not change after activation. In adhesion assays, resting and stimulated platelets were capable of binding through ICAM-2 to purified leukocyte function-associated antigen-1. Activation of T lymphocytes with PMA stimulated binding to platelets that was Mg2+ dependent and could be specifically inhibited by mAbs to either ICAM-2 or leukocyte function-associated antigen-1. ICAM-2 is the only known beta 2-integrin ligand present on platelets, suggesting that it may play an important role in leukocyte-platelet interactions in inflammation and thrombosis. Images PMID:8083366

  7. N-glycosylation controls the function of junctional adhesion molecule-A

    PubMed Central

    Scott, David W.; Tolbert, Caitlin E.; Graham, David M.; Wittchen, Erika; Bear, James E.; Burridge, Keith

    2015-01-01

    Junctional adhesion molecule-A (JAM-A) is an adherens and tight junction protein expressed by endothelial and epithelial cells. JAM-A serves many roles and contributes to barrier function and cell migration and motility, and it also acts as a ligand for the leukocyte receptor LFA-1. JAM-A is reported to contain N-glycans, but the extent of this modification and its contribution to the protein’s functions are unknown. We show that human JAM-A contains a single N-glycan at N185 and that this residue is conserved across multiple mammalian species. A glycomutant lacking all N-glycans, N185Q, is able to reach the cell surface but exhibits decreased protein half-life compared with the wild- type protein. N-glycosylation of JAM-A is required for the protein’s ability to reinforce barrier function and contributes to Rap1 activity. We further show that glycosylation of N185 is required for JAM-A–mediated reduction of cell migration. Finally, we show that N-glycosylation of JAM-A regulates leukocyte adhesion and LFA-1 binding. These findings identify N-glycosylation as critical for JAM-A’s many functions. PMID:26224316

  8. Lymphocyte adhesion molecules in T cell-mediated lysis of human kidney cells.

    PubMed

    Suranyi, M G; Bishop, G A; Clayberger, C; Krensky, A M; Leenaerts, P; Aversa, G; Hall, B M

    1991-02-01

    The complementary adhesion molecules LFA-1 (CD11a, 18)/ICAM-1 (CD54) and LFA-2 (CD2)/LFA-3 (CD58) have been shown to be important in T cell interaction with lymphoid target cells. The role of these ligand pairs in cytotoxicity against somatic cells is less well established. While LFA-3 is expressed by all cells in the kidney, ICAM-1 expression is low in normal kidneys but is increased in allograft rejection. An in vitro cytotoxicity assay was used to examine the relative importance of the two adhesion ligands in immune damage against kidney cells in rejection. HLA-A2 specific cytotoxic T lymphocyte (CTL) recognition of cultured human kidney cells (HKC), of predominantly renal tubular cell origin, was studied. Immunofluorescence studies showed that both induced and uninduced HKC target cells expressed ICAM-1, MHC class I and LFA-3, but only MHC class I and class II antigens and ICAM-1 were significantly upregulated by cytokine induction. Effector cells expressed LFA-1 and LFA-2 but little or no ICAM-1 and LFA-3. Cytokine induction of ICAM-1 expression on HKC target cells increased their susceptibility to lysis. Monoclonal antibody against ICAM-1 or LFA-1 produced the greatest inhibition of HKC lysis, and their effects were not additive. Antibody against LFA-2 (CD2) or LFA-3 also produced significant inhibition, but to a lesser degree, and no additive effect was found.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1706002

  9. Adhesion molecules on the endothelium and mononuclear cells in human atherosclerotic lesions.

    PubMed Central

    van der Wal, A. C.; Das, P. K.; Tigges, A. J.; Becker, A. E.

    1992-01-01

    Atherosclerotic lesions show features of a cell-mediated immune inflammatory process. From this viewpoint, the potential role of arterial endothelium in the recruitment of mononuclear cells (T lymphocytes and macrophages) was studied. The endothelium of diffuse intimal thickening (DIT) and atheromatous plaques (AP) in human coronary arteries and abdominal aortas was characterized for the expression of adhesion molecules ELAM-1, ICAM-1, and the major histocompatibility complex (MHC) class II antigens HLA-DR/DP. A marked increase in expression of ICAM-1 and ELAM-1, and to a lesser extent HLA-DR/DP was observed on endothelial cells that were adjacent to subendothelial infiltrates of T lymphocytes (CD3+, CD11a+, HLA-DR/DP+) and macrophages (CD14+, CD11a+, CD11c+, HLA-DR/DP+). This contrasted with a lower or absent expression of these activation markers at sites without prominent inflammatory cell infiltrates. These findings could be demonstrated in DIT as well as in AP. The observations suggest that cytokines produced by the subintimal infiltrates may activate the endothelium in a similar way as is observed in the microvasculature at sites of immune inflammation. The expression of these activation markers in the microvasculature is associated with enhanced leukocyte adhesion, permeability for macromolecules, and procoagulant activity, features known to occur also in early experimental atherosclerosis. The findings therefore support the concept that arterial endothelium plays an active role in the recruitment of mononuclear cells in atherosclerotic lesions. Images Figure 1 PMID:1281621

  10. Intracellular transport and cell surface delivery of the neural cell adhesion molecule (NCAM).

    PubMed

    Leshchyns'ka, Iryna; Sytnyk, Vladimir

    2015-01-01

    The neural cell adhesion molecule (NCAM) regulates differentiation and functioning of neurons by accumulating at the cell surface where it mediates the interactions of neurons with the extracellular environment. NCAM also induces a number of intracellular signaling cascades, which coordinate interactions at the cell surface with intracellular processes including changes in gene expression, transport and cytoskeleton remodeling. Since NCAM functions at the cell surface, its transport and delivery to the cell surface play a critical role. Here, we review recent advances in our understanding of the molecular mechanisms of the intracellular transport and cell surface delivery of NCAM. We also discuss the data suggesting a possibility of cross talk between activation of NCAM at the cell surface and the intracellular transport and cell surface delivery of NCAM.

  11. The leucine-rich repeat superfamily of synaptic adhesion molecules: LRRTMs and Slitrks.

    PubMed

    Ko, Jaewon

    2012-10-01

    Synapses are asymmetric intercellular junctions connected by multiple synaptic cell adhesion molecules (CAMs). Synaptic CAMs function in various stages of synaptogenesis - the process of synapse creation - encompassing synapse formation, maturation, refinement, plasticity, and elimination. The list of synaptic CAMs has rapidly grown, although their precise functions of most CAMs at synapses remain incomplete. Members of an emerging class of transmembrane proteins containing leucine-rich repeat (LRR) domains have received considerable recent research attention. In this minireview, I discuss recent findings on LRR-containing synaptic CAMs that impact synapse development and circuit formation, focusing on two families of LRR synaptic CAMs: leucine-rich transmembrane proteins (LRRTMs) and Slit and Trk-like family (Slitrks). Their basic biochemical properties, proposed functions at synapses, physiological significances, and open questions are summarized.

  12. The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions.

    PubMed

    Hortsch, Michael; Nagaraj, Kakanahalli; Mualla, Rula

    2014-01-01

    L1-type proteins are transmembrane cell adhesion molecules with an evolutionary well-conserved protein domain structure of usually six immunoglobulin and five fibronectin type III domains. By engaging in many different protein-protein interactions they are involved in a multitude of molecular functions and are important players during the formation and maintenance of metazoan nervous systems. As a result, mutations in L1-type genes cause a great variety of phenotypes, most of which are neurological in nature. In humans, mutations in the L1CAM gene are responsible for L1 syndrome and other L1-type genes have been implicated in conditions as varied as mental retardation, autism, schizophrenia, multiple sclerosis, and other disorders. Equally, the overexpression of L1-type proteins appears to have deleterious effects in various types of human tumor cells, where they generally contribute to an increase in cell mobility and metastatic potential. PMID:25300138

  13. Identification of DNA Aptamers toward Epithelial Cell Adhesion Molecule via Cell-SELEX

    PubMed Central

    Kim, Ji Won; Kim, Eun Young; Kim, Sun Young; Byun, Sang Kyung; Lee, Dasom; Oh, Kyoung-Jin; Kim, Won Kon; Han, Baek Soo; Chi, Seung-Wook; Lee, Sang Chul; Bae, Kwang-Hee

    2014-01-01

    The epithelial cell adhesion molecule (EpCAM, also known as CD326) is a transmembrane glycoprotein that is specifically detected in most adenocarcinomas and cancer stem cells. In this study, we performed a Cell systematic evolution of ligands by exponential enrichment (SELEX) experiment to isolate the aptamers against EpCAM. After seven round of Cell SELEX, we identified several aptamer candidates. Among the selected aptamers, EP166 specifically binds to cells expressing EpCAM with an equilibrium dissociation constant (Kd) in a micromolar range. On the other hand, it did not bind to negative control cells. Moreover, EP166 binds to J1ES cells, a mouse embryonic stem cell line. Therefore, the isolated aptamers against EpCAM could be used as a stem cell marker or in other applications in both stem cell and cancer studies. PMID:25266702

  14. Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma

    PubMed Central

    Liu, Ju-Fang; Tsao, Ya-Ting; Hou, Chun-Han

    2015-01-01

    Osteosarcoma is a common, high malignant, and metastatic bone cancer. Amphiregulin (AREG) has been associated with cancer cellular activities. However, the effect of AREG on metastasis activity in human osteosarcoma cells has yet to be determined. We determined that AREG increases the expression of intercellular adhesion molecule-1 (ICAM-1) through PI3K/Akt signaling pathway via its interaction with the epidermal growth factor receptor, thus resulting in the enhanced cell migration of osteosarcoma. Furthermore, AREG stimulation increased the association of NF-κB to ICAM-1 promoter which then up-regulated ICAM-1 expression. Finally, we observed that shRNA silencing of AREG decreased osteosarcoma metastasis in vivo. Our findings revealed a relationship between osteosarcoma metastatic potential and AREG expression and the modulating effect of AREG on ICAM-1 expression. PMID:26503469

  15. Neutrophil and monocyte adhesion molecules in bronchopulmonary dysplasia, and effects of corticosteroids

    PubMed Central

    Ballabh, P; Simm, M; Kumari, J; Krauss, A; Jain, A; Califano, C; Lesser, M; Cunningham-Rundle..., S

    2004-01-01

    Aims: To study a longitudinal change in the expression of adhesion molecules CD11b, CD18, and CD62L on neutrophils and monocytes in very low birth weight babies who develop respiratory distress syndrome, to compare these levels between bronchopulmonary dysplasia (BPD) and non-BPD infants, and to assess the effect of corticosteroid treatment on these adhesion molecules. Methods: Of 40 eligible neonates, 11 neonates were oxygen dependent at 36 weeks (BPD 36 weeks), 16 infants were oxygen dependent at 28 days, but not at 36 weeks (BPD d28), and 13 infants did not develop BPD. Seventeen neonates received a six day course of steroid treatment. Expression of CD11b, CD18, and CD62L was measured on neutrophils and monocytes in arterial blood on days 1, 3, 7, 14, 21, and 28, and before and 2–3 days after initiation of dexamethasone treatment by flow cytometry. Results: CD18 expression on neutrophils and monocytes and CD62L on neutrophils, measured as mean fluorescent intensity, was significantly decreased in BPD neonates compared to non-BPD neonates on days 1–28. Dexamethasone treatment significantly decreased CD11b, CD18, and CD62L expression on neutrophils, and CD11b and CD18L expression on monocytes. Conclusions: Decreased CD18 expression on neutrophils and monocytes, and decreased CD62L expression on neutrophils, measured as mean fluorescent intensity during the first four weeks of life in micropremies may be risk factors and early predictors of BPD. Dexamethasone use was associated with decreased expression of CD11b, CD18, and CD62L. PMID:14711863

  16. Characterization of hepatocellular carcinoma cell lines based on cell adhesion molecules.

    PubMed

    Jung, Cheol Woong; Song, Tae-Jin; Lee, Kun-Ok; Choi, Sae Byeol; Kim, Wan Bae; Suh, Sung Ock; Kim, Young Chul; Choi, Sang Yong

    2012-06-01

    Many studies which focus on the molecules and mechanisms related to the characteristics of the cancer have been performed. In particular, cell adhesion molecules (CAMs) are known to play a central role in the adhesion of cancer cells to vascular endothelial cells. In this study, the expression of CAMs in hepatocellular carcinoma (HCC) cell lines was analyzed and correlated with the characteristics of various HCC cell lines. Eight human HCC cell lines were used in this study. We analyzed the expression of ICAM-1, E-selectin and the integrin subunits of HCC cell lines by western blot analysis and ELISA kit. We estimated the expression of integrin-α5 using western blot analysis and RT-PCR to compare the expression at the gene level with the protein level. In addition, we determined the expression of TGF-β1, as one of the markers for the cellular activity compared to the levels of expression with the expression of integrin-α3 and -α5. ICAM-1 was highly expressed in all of the cell lines except SNU398 and Hep3B, which exhibit a more aggressive nature among the studied HCC cell lines. E-selectin and integrin subunits varied in all HCC cell lines. In particular, integrin-β2 was highly expressed on all HCC cell lines. In conclusion, the levels of expression of the CAMs may not affect cellular activity, morphology or tumorigenicity. However, most HCC cell lines show various expressions of CAMs, suggesting that HCC cell lines expressing the major CAMs remain candidates for molecular targeted therapy, which may need to be patient-tailored for therapy according to the molecular profile.

  17. Evaluation of soluble adhesion molecules in the diagnosis of amoebiasis, giardiasis and toxoplasmosis.

    PubMed

    el-Shazly, A M; Soliman, M; el-Kalla, M R; Rezk, H; el-Nemr, H; Handoussa, A E; el-Aaty, H E; Morsy, T A

    2001-12-01

    A total of 47 patients with toxoplasmosis (21 cases) with amoebic liver abscess (14 cases) and with giardiasis (12 cases) as well as 14 healthy control were subjected to thorough history taking, clinical examination, stool & urine analysis, complete blood picture, ESR, C-reactive protein, ASO, widal test, blood cultures, liver function tests, serum creatinine, hepatitis viral markers, rheumatoid factor, auto-antibodies, stool culture, rectal snip, chest X-ray, abdominal sonar, level of serum adhesion molecules (sICAM-1, sELAM-1), ELISA detection of Toxoplasma antibodies in serum, liver biopsy, detection and counting of Giardia cysts. In toxoplasmosis group, highly significant increase in serum levels of sICAM-1 (P<0.01) and significant increase in serum levels of sELAM-1 (P<0.05) in comparison to control. However, only sICAM-1 levels were significantly increased in IgM cases more than in IgG cases. In amoebic liver abscess group, both sICAM-1 and sELAM-1 significantly increased when compared with control. In giardiasis group, highly significant increase of serum levels of sELAM-1 was noticed than in control group (P<0.01), while sICAM-1 showed no significant difference (P>0.05). There was no correlation between sELAM-1 and number of cysts in the stool (intensity of infection). Soluble forms of adhesion molecules especially sICAM-1 have the potentiality as good markers of endothelial damage, severity of disease and to less extend load of infection.

  18. Intercellular Adhesion Molecule 1 and Progression of Percent Emphysema: The MESA Lung Study

    PubMed Central

    Aaron, Carrie P.; Schwartz, Joseph E.; Bielinski, Suzette J.; Hoffman, Eric A.; Austin, John H. M.; Oelsner, Elizabeth C.; Donohue, Kathleen M.; Kalhan, Ravi; Berardi, Cecilia; Kaufman, Joel D.; Jacobs, David R.; Tracy, Russell P.; Barr, R.Graham

    2014-01-01

    Endothelial intercellular adhesion molecule (ICAM) 1 binds neutrophils and facilitates their transmigration into the lung; E-selectin facilitates leukocyte rolling. As neutrophils contribute to tissue destruction in emphysema and chronic obstructive pulmonary disease, we hypothesized that soluble ICAM-1 (sICAM-1) and E-selectin (sE-selectin) would be associated with longitudinal progression of emphysema and lung function decline. The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45-84 years old without clinical cardiovascular disease in 2000-02. The MESA Lung Study assessed percent emphysema (<-950 Hounsfield units) on cardiac (2000-07) and full-lung CT scans (2010-12), and spirometry was assessed twice over five years. sICAM-1 and sE-selectin were measured at baseline. Mixed-effect models adjusted for demographics, anthropometry, smoking, C-reactive protein, sphingomyelin and scanner factors. Among 1,865 MESA Lung participants with measurement of sICAM-1 and percent emphysema the mean log-sICAM-1 was 5.5±0.3 ng/mL and percent emphysema increased 0.73 percentage points (95% CI: 0.34, 1.12; P<0.001) over ten years. A one SD increase in sICAM-1 was associated with an accelerated increase in percent emphysema of 0.23 percentage points over ten years (95% CI: 0.06, 0.39; P=0.007). No significant association was found for sE-selectin, or between any adhesion molecule and lung function. Higher levels of sICAM-1 were independently associated with progression of percent emphysema in a general population sample. PMID:25457724

  19. Osteoblast adhesion to orthopaedic implant alloys: Effects of cell adhesion molecules and diamond-like carbon coating

    SciTech Connect

    Kornu, R.; Kelly, M.A.; Smith, R.L.; Maloney, W.J.

    1996-11-01

    In total joint arthroplasty, long-term outcomes depend in part on the biocompatibility of implant alloys. This study analyzed effects of surface finish and diamond-like carbon coating on osteoblast cell adhesion to polished titanium-aluminum-vanadium and polished or grit-blasted cobalt-chromium-molybdenum alloys. Osteoblast binding was tested in the presence and absence of the cell adhesion proteins fibronectin, laminin, fibrinogen, and vitronectin and was quantified by measurement of DNA content. Although adherence occurred in serum-free medium, maximal osteoblast binding required serum and was similar for titanium and cobalt alloys at 2 and 12 hours. With the grit-blasted cobalt alloy, cell binding was reduced 48% (p < 0.05) by 24 hours. Coating the alloys with diamond-like carbon did not alter osteoblast adhesion, whereas fibronectin pretreatment increased cell binding 2.6-fold (p < 0.05). In contrast, fibrinogen, vitronectin, and laminin did not enhance cell adhesion. These results support the hypothesis that cell adhesion proteins can modify cell binding to orthopaedic alloys. Although osteoblast binding was not affected by the presence of diamond-like carbon, this coating substance may influence other longer term processes, such as bone formation, and deserves further study. 40 refs., 4 figs.

  20. Adhesions

    MedlinePlus

    ... surfaces so they can shift easily as the body moves. Adhesions cause tissues and organs to stick together. They might connect the loops of the intestines to each other, to nearby ... can occur anywhere in the body. But they often form after surgery on the ...

  1. The role of cellular adhesion molecules in virus attachment and entry

    PubMed Central

    Bhella, David

    2015-01-01

    As obligate intracellular parasites, viruses must traverse the host-cell plasma membrane to initiate infection. This presents a formidable barrier, which they have evolved diverse strategies to overcome. Common to all entry pathways, however, is a mechanism of specific attachment to cell-surface macromolecules or ‘receptors’. Receptor usage frequently defines viral tropism, and consequently, the evolutionary changes in receptor specificity can lead to emergence of new strains exhibiting altered pathogenicity or host range. Several classes of molecules are exploited as receptors by diverse groups of viruses, including, for example, sialic acid moieties and integrins. In particular, many cell-adhesion molecules that belong to the immunoglobulin-like superfamily of proteins (IgSF CAMs) have been identified as viral receptors. Structural analysis of the interactions between viruses and IgSF CAM receptors has not shown binding to specific features, implying that the Ig-like fold may not be key. Both proteinaceous and enveloped viruses exploit these proteins, however, suggesting convergent evolution of this trait. Their use is surprising given the usually occluded position of CAMs on the cell surface, such as at tight junctions. Nonetheless, the reason for their widespread involvement in virus entry most probably originates in their functional rather than structural characteristics. PMID:25533093

  2. Inflammation Determines the Pro-Adhesive Properties of High Extracellular D-Glucose in Human Endothelial Cells In Vitro and Rat Microvessels In Vivo

    PubMed Central

    Azcutia, Verónica; Abu-Taha, May; Romacho, Tania; Vázquez-Bella, Marta; Matesanz, Nuria; Luscinskas, Francis W.; Rodríguez-Mañas, Leocadio; Sanz, María Jesús; Sánchez-Ferrer, Carlos F.; Peiró, Concepción

    2010-01-01

    Background Hyperglycemia is acknowledged as an independent risk factor for developing diabetes-associated atherosclerosis. At present, most therapeutic approaches are targeted at a tight glycemic control in diabetic patients, although this fails to prevent macrovascular complications of the disease. Indeed, it remains highly controversial whether or not the mere elevation of extracellular D-glucose can directly promote vascular inflammation, which favors early pro-atherosclerotic events. Methods and Findings In the present work, increasing extracellular D-glucose from 5.5 to 22 mmol/L was neither sufficient to induce intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, analyzed by flow cytometry, nor to promote leukocyte adhesion to human umbilical vein endothelial cells (HUVEC) in vitro, measured by flow chamber assays. Interestingly, the elevation of D-glucose levels potentiated ICAM-1 and VCAM-1 expression and leukocyte adhesion induced by a pro-inflammatory stimulus, such as interleukin (IL)-1β (5 ng/mL). In HUVEC, high D-glucose augmented the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear transcription factor-κB (NF-κB) elicited by IL-1β, measured by Western blot and electromobility shift assay (EMSA), respectively, but had no effect by itself. Both ERK 1/2 and NF-κB were necessary for VCAM-1 expression, but not for ICAM-1 expression. In vivo, leukocyte trafficking was evaluated in the rat mesenteric microcirculation by intravital microscopy. In accordance with the in vitro data, the acute intraperitoneal injection of D-glucose increased leukocyte rolling flux, adhesion and migration, but only when IL-1β was co-administered. Conclusions These results indicate that the elevation of extracellular D-glucose levels is not sufficient to promote vascular inflammation, and they highlight the pivotal role of a pro-inflammatory environment in diabetes, as a critical factor

  3. The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment

    PubMed Central

    Klamer, Sofieke; Voermans, Carlijn

    2014-01-01

    Maintenance of haematopoietic stem cells and differentiation of committed progenitors occurs in highly specialized niches. The interactions of haematopoietic stem and progenitor cells (HSPCs) with cells, growth factors and extracellular matrix (ECM) components of the bone marrow (BM) microenvironment control homeostasis of HSPCs. We only start to understand the complexity of the haematopoietic niche(s) that comprises endosteal, arterial, sinusoidal, mesenchymal and neuronal components. These distinct niches produce a broad range of soluble factors and adhesion molecules that modulate HSPC fate during normal hematopoiesis and BM regeneration. Adhesive interactions between HSPCs and the microenvironment will influence their localization and differentiation potential. In this review we highlight the current understanding of the functional role of ECM- and adhesion (regulating) molecules in the haematopoietic niche during homeostatic and regenerative hematopoiesis. This knowledge may lead to the improvement of current cellular therapies and more efficient development of future cellular products. PMID:25482635

  4. Self-assembled monolayer of designed and synthesized triazinedithiolsilane molecule as interfacial adhesion enhancer for integrated circuit.

    PubMed

    Wang, Fang; Li, Yanni; Wang, Yabin; Cao, Zhuo

    2011-08-03

    Self-assembled monolayer (SAM) with tunable surface chemistry and smooth surface provides an approach to adhesion improvement and suppressing deleterious chemical interactions. Here, we demonstrate the SAM comprising of designed and synthesized 6-(3-triethoxysilylpropyl)amino-1,3,5-triazine-2,4-dithiol molecule, which can enhance interfacial adhesion to inhibit copper diffusion used in device metallization. The formation of the triazinedithiolsilane SAM is confirmed by X-ray photoelectron spectroscopy. The adhesion strength between SAM-coated substrate and electroless deposition copper film was up to 13.8 MPa. The design strategy of triazinedithiolsilane molecule is expected to open up the possibilities for replacing traditional organosilane to be applied in microelectronic industry.

  5. Self-assembled monolayer of designed and synthesized triazinedithiolsilane molecule as interfacial adhesion enhancer for integrated circuit

    PubMed Central

    2011-01-01

    Self-assembled monolayer (SAM) with tunable surface chemistry and smooth surface provides an approach to adhesion improvement and suppressing deleterious chemical interactions. Here, we demonstrate the SAM comprising of designed and synthesized 6-(3-triethoxysilylpropyl)amino-1,3,5-triazine-2,4-dithiol molecule, which can enhance interfacial adhesion to inhibit copper diffusion used in device metallization. The formation of the triazinedithiolsilane SAM is confirmed by X-ray photoelectron spectroscopy. The adhesion strength between SAM-coated substrate and electroless deposition copper film was up to 13.8 MPa. The design strategy of triazinedithiolsilane molecule is expected to open up the possibilities for replacing traditional organosilane to be applied in microelectronic industry. PMID:21812994

  6. Cell adhesion molecules in the pathogenesis of and host defence against microbial infection.

    PubMed Central

    Kerr, J R

    1999-01-01

    Eukaryotic cell adhesion molecules (CAMs) are used by various cells and extracellular molecules in host defence against infection. They are involved in many processes including recognition by circulating phagocytes of a site of inflammation, transmigration through the endothelial barrier, diapedesis through basement membrane and extracellular matrix, and release of effector mechanisms at the infected site. CAMs involved in leucocyte-endothelial cell interaction include the selectins, integrins, and members of the immunoglobulin superfamily. However, CAMs are also used by various microorganisms (protozoa, fungi, bacteria, and viruses) during their pathogenesis. For example, bacteria that utilise CAMs include Mycobacterium tuberculosis, Listeria monocytogenes, Yersinia spp, enteropathogenic Escherichia coli, Shigella spp, Neisseria spp, Bordetella spp, and Borrelia burgdorferi. In addition, CAMs are involved in the pathogenetic effects of the RTX toxins of Pasteurella haemolytica, Actinobacillus actinomycetemcomitans, and the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes. A recurrent and topical theme of potential importance within the bacterial group is the intimate relation between CAMs, bacterial protein receptors, and type III secretion systems. For example, the IpaBCD protein complex is secreted by the type III system of Shigella flexneri and interacts with alpha 5 beta 1 integrin on the eukaryotic cell surface, followed by Rho mediated internalisation; this illustrates the relevance of cellular microbiology. CAMs might prove to be novel therapeutic targets. Comparative genomics has provided the knowledge of shared virulence determinants among diverse bacterial genera, and will continue to deepen our understanding of microbial pathogenesis, particularly in the context of the interaction of prokaryotic and eukaryotic molecules. PMID:10694943

  7. Age-Related Cognitive Impairments in Mice with a Conditional Ablation of the Neural Cell Adhesion Molecule

    ERIC Educational Resources Information Center

    Bisaz, Reto; Boadas-Vaello, Pere; Genoux, David; Sandi, Carmen

    2013-01-01

    Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However,…

  8. A Chinese Herbal Preparation Containing Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum Reduces Circulating Adhesion Molecules

    PubMed Central

    O'Brien, Kylie A.; Ling, Shanhong; Abbas, Estelle; Dai, Aozhi; Zhang, Jiansheng; Wang, Wen Cheng; Bensoussan, Alan; Luo, Ruizhi; Guo, Zhi-Xin; Komesaroff, Paul A.

    2011-01-01

    Circulating adhesion molecules (CAMs), surface proteins expressed in the vascular endothelium, have emerged as risk factors for cardiovascular disease (CVD). CAMs are involved in intercellular communication that are believed to play a role in atherosclerosis. A Chinese medicine, the “Dantonic Pill” (DP) (also known as the “Cardiotonic Pill”), containing three Chinese herbal material medica, Radix Salviae Miltiorrhizae, Radix Notoginseng and Borneolum Syntheticum, has been used in China for the prevention and management of CVD. Previous laboratory and animal studies have suggested that this preparation reduces both atherogenesis and adhesion molecule expression. A parallel double blind randomized placebo-controlled study was conducted to assess the effects of the DP on three species of CAM (intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 and endothelial cell selectin (E-selectin)) in participants with mild-moderate hypercholesterolemia. Secondary endpoints included biochemical and hematological variables and clinical effects. Forty participants were randomized to either treatment or control for 12 weeks. Treatment with DP was associated with a statistically significant decrease in ICAM-1 (9% decrease, P = .03) and E-Selectin (15% decrease, P = .004). There was no significant change in renal function tests, liver function tests, glucose, lipids or C-reactive protein levels and clinical adverse effects did not differ between the active and the control groups. There were no relevant changes in participants receiving placebo. These results suggest that this herbal medicine may contribute to the development of a novel approach to cardiovascular risk reduction. PMID:18955365

  9. Medullary carcinoma is associated with expression of intercellular adhesion molecule-1. Implication to its morphology and its clinical behavior.

    PubMed Central

    Bacus, S. S.; Zelnick, C. R.; Chin, D. M.; Yarden, Y.; Kaminsky, D. B.; Bennington, J.; Wen, D.; Marcus, J. N.; Page, D. L.

    1994-01-01

    The histological hallmarks for the diagnosis of medullary breast cancer are circumscription, syncytial architecture, diffuse inflammatory infiltrate, and highly atypical nuclei. The biological and prognostic implication is a lower propensity to metastasize. We studied 19 medullary carcinomas for expression of the intercellular adhesion molecule-1 and lymphocyte-function-associated antigen-1, Neu differentiation factor, tumor necrosis factor-alpha, and the expression of HER-2/neu, HER-4, and HER-3 receptors. Our study revealed that all of the 19 medullary carcinomas expressed the intercellular adhesion molecule-1 and lymphocyte function associated antigen. Eighteen of 19 cancers expressed Neu differentiation factor and tumor necrosis factor-alpha. All medullary cancers expressed the HER-2/neu receptor, however, in the majority of the cases, the staining was confined to the cytoplasm. Only 4 of 12 cancers expressed HER-4 and none of the eight medullary cancers tested expressed HER-3. By comparison, in a control group of infiltrating ductal carcinomas, expression of intercellular adhesion molecule-1, lymphocyte function associated antigen-1, and Neu differentiation factor was positive in about 25 to 30% of the cases, HER-4 was expressed in 75% and HER-3 in 95% of the cases. Taken together, our observations suggest that the expression of intercellular adhesion molecule-1, lymphocyte function associated antigen, Neu differentiation factor, and tumor necrosis factor-alpha as factors that may affect the special morphology and the biological behavior that characterizes medullary carcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7992839

  10. The Neural Cell Adhesion Molecule-Derived Peptide FGL Facilitates Long-Term Plasticity in the Dentate Gyrus in Vivo

    ERIC Educational Resources Information Center

    Dallerac, Glenn; Zerwas, Meike; Novikova, Tatiana; Callu, Delphine; Leblanc-Veyrac, Pascale; Bock, Elisabeth; Berezin, Vladimir; Rampon, Claire; Doyere, Valerie

    2011-01-01

    The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as…

  11. Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway

    PubMed Central

    Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh; Pan, Dengke; Fu, Yu; Brooke, Elizabeth A.S.; Shah, Halley; Zhen, Wei; Zhu, Hong; Liu, Dongmin; Li, Yunbo; Jia, Zhenquan

    2014-01-01

    Sulforaphane, a naturally-occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 (MCP-1), adhesion molecule sVCAM-1 and sE-Selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced NF-κB transcriptional activity, IκBα degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers’ delicate organization as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway. PMID:24880493

  12. Immunohistochemistry of adhesion molecules, metalloproteinases and NO-synthases in extravillous trophoblast of tubal pregnancy.

    PubMed

    Dubernard, G; Galtier-Fougairolles, M; Cortez, A; Uzan, S; Challier, J C

    2005-12-12

    Trophoblast invasion in uterine pregnancy is fine-tuned for the remodelling of the uterine wall and its vascularization. Tubal pregnancy, which occurs in a limited number of patients, involves a dramatic trophoblast invasion in a context of a poor decidualization. By studying the histology of the extravillous trophoblast (EVC) in the anchoring villi, the Ki67 labelling, the location of several adhesion markers (cytokeratin-7, alpha1, alpha6, alphaV, beta1, beta4 integrin subunits and E-cadherin, V/E-cadherin), metalloproteinases (MMP-2, 9 and11), NOS2 and 3, we aimed to detect the specificity of tubal compared to intrauterine pregnancies. No difference could be observed between meso or anti-salpingial trophoblast proliferation or invasion using Ki67. Cytokeratin-7 allowed detection of spindle-shape EVCs and we identified some decidualized stromal cells. Integrins alpha1, beta1 and alphaV, and V/E-cadherin were expressed mainly in the distal EVC correspondingly to intrauterine pregnancy, with a poor expression of alpha1. Integrins alpha6 and beta4, E-cadherin were detected in the distal EVC in contrast to uterine pregnancy. MMP-2, 9, 11 were also shown in distal EVC. NOS2 and 3 labelled the perivascular EVC and NOS3 the endothelial cells of the tubal vessels. These changed distributions of adhesion molecules and MMP together with that of the basic and inducible NOS expressions could be related to mechanical effects in superficial implantation or to a failure of decidualization in tubal pregnancies.

  13. Dynamics of unbinding of cell adhesion molecules: Transition from catch to slip bonds

    NASA Astrophysics Data System (ADS)

    Barsegov, V.; Thirumalai, D.

    2005-02-01

    The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for the specific P-selectin-P-selectin glycoprotein ligand (sPSGL-1) the average bond lifetime t initially increases (catch bonds) at low (10 pN) constant force, f, and decreases when f > 10 pN (slip bonds). In contrast, for the complex with G1 anti-P-selectin monoclonal antibody t monotonically decreases with f. To quantitatively map the energy landscape of such complexes we use a model that considers the possibility of redistribution of population from one force-free state to another force-stabilized bound state. The excellent agreement between theory and experiments allows us to extract energy landscape parameters by fitting the calculated curves to the lifetime measurements for both sPSGL-1 and G1. Surprisingly, the unbinding transition state for P-selectin-G1 complex is close (0.32 nm) to the bound state, implying that the interaction is brittle, i.e., once deformed, the complex fractures. In contrast, the unbinding transition state of the P-selectin-sPSGL-1 complex is far ( 1.5 nm) from the bound state, indicative of a compliant structure. Constant f energy landscape parameters are used to compute the distributions of unbinding times and unbinding forces as a function of the loading rate, rf. For a given rf, unbinding of sPSGL-1 occurs over a broader range of f with the most probable f being an order of magnitude less than for G1. The theory for cell adhesion complexes can be used to predict the outcomes of unbinding of other protein-protein complexes.

  14. Induction of the neural cell adhesion molecule and neuronal aggregation by osteogenic protein 1.

    PubMed Central

    Perides, G; Safran, R M; Rueger, D C; Charness, M E

    1992-01-01

    The neural cell adhesion molecule (N-CAM) plays a fundamental role in nervous system development and regeneration, yet the regulation of the expression of N-CAM in different brain regions has remained poorly understood. Osteogenic protein 1 (OP-1) is a member of the transforming growth factor beta superfamily that is expressed in the nervous system. Treatment of the neuroblastoma-glioma hybrid cell line NG108-15 for 1-4 days with recombinant human OP-1 (hOP-1) induced alterations in cell shape, formation of epithelioid sheets, and aggregation of cells into multilayered clusters. Immunofluorescence studies and Western blots demonstrated a striking differential induction of the three N-CAM isoforms in hOP-1-treated cells. hOP-1 caused a 6-fold up-regulation of the 140-kDa N-CAM, the isoform showing the highest constitutive expression, and a 29-fold up-regulation of the 180-kDa isoform. The 120-kDa isoform was not detected in control NG108-15 cells but was readily identified in hOP-1-treated cells. Incubation of NG108-15 cells with an antisense N-CAM oligonucleotide reduced the induction of N-CAM by hOP-1 and decreased the formation of multilayered cell aggregates. Anti-N-CAM monoclonal antibodies also diminished the formation of multilayered cell aggregates by hOP-1 and decreased cell-cell adhesion when hOP-1-treated NG108-15 cells were dispersed and replated. Thus, hOP-1 produces morphologic changes in NG108-15 cells, at least in part, by inducing N-CAM. These observations suggest that OP-1 or a homologue may participate in the regulation of N-CAM during nervous system development and regeneration. Images PMID:1438217

  15. Increased neutrophil adherence and adhesion molecule mRNA expression in endothelial cells during selenium deficiency.

    PubMed

    Maddox, J F; Aherne, K M; Reddy, C C; Sordillo, L M

    1999-05-01

    Leukocyte aggregation and activation on endothelial cells (EC) are important preliminary events in leukocyte migration into tissue and subsequent inflammation. Thus, an increase in leukocyte adherence has the potential to affect inflammatory disease outcome. Selenium (Se) is an integral part of the antioxidant enzyme glutathione peroxidase (GSH-Px) and plays an important role in the maintenance of the redox state of a cell. Se supplementation in the bovine has been shown to improve the outcome of acute mastitis caused by coliform bacteria, in part by enhancing the speed of neutrophil migration into the affected mammary gland. However, the mechanisms by which Se modulates neutrophil migration have not been elucidated. Therefore, an in vitro model of Se deficiency in primary bovine mammary artery EC was used to examine the impact of Se status on the adhesive properties of EC. The effect of Se on functional activities was examined by measuring neutrophil adherence to Se-deficient and Se-supplemented EC. Se-deficient EC showed significantly enhanced neutrophil adherence when stimulated with tumor necrosis factor alpha (TNF-alpha) for 4 or 24 h, interleukin-1 for 12 h, or H2O2 for 20 min (P < 0.05). To determine the mechanisms underlying these changes in neutrophil adherence, the expression of EC adhesion molecules, ICAM-1, E-selectin, and P-selectin were examined at the molecular level by a competitive reverse transcription-polymerase chain reaction. Results revealed higher mRNA expression for E-selectin and ICAM-1 in Se-deficient EC stimulated with TNF-alpha for 3 and 6 h, and greater expression of P-selectin mRNA in Se-supplemented EC with 3-h TNF-alpha stimulation. These studies provide new information to establish the role of Se nutrition in the initiation of leukocyte adherence to endothelium. PMID:10331495

  16. Extracts from Brassica oleracea L. convar. acephala var. sabellica inhibit TNF-α stimulated neutrophil adhesion in vitro under flow conditions.

    PubMed

    Kuntz, Sabine; Kunz, Clemens

    2014-06-01

    The beneficial effects of vegetables such as leafy cabbage (Brassica oleracea) on health are attributed to their anti-oxidative and anti-inflammatory potential. Therefore, we investigated whether curly kale extracts affect cytokine induced expression of endothelial cell adhesion molecules as well as the adhesion of leukocytes to endothelial cells depending on their polyphenol content and composition. Curly kale leaves were extracted applying two solvents with different polarities (methanolic extracts (ME) and aqueous water extracts (WE)). The anti-oxidant capacity (TEAC-assay (Trolox Equivalent Antioxidant Capacity)), the polyphenol content and the composition were determined colorimetrically. The anti-inflammatory effects were measured in vitro using human umbilical vein endothelial cells (HUVECs). HUVECs were pre-incubated with extracts for 24 h and thereafter stimulated for 5 h with TNF-α (10 ng mL(-1)). Finally, the expression of cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 was determined by semi-quantitative RT-PCR and leukocyte adhesion was observed using a flow adhesion assay. ME have the highest anti-oxidant activity (ME, 66.5 ± 10.9 vs. WE, 45.5 ± 6.7 mmol L(-1) TEAC), polyphenol (ME, 25.8 ± 2.4. vs. WE, 10.8 ± 1.8 mmol L(-1) GAE), flavonoid (ME, 17.9 ± 1.7 vs. WE, 5.3 ± 2.7 mmol L(-1) RE) and flavonol concentrations (ME, 5.8 ± 0.6 vs. WE, 2.1 ± 0.5 mmol L(-1) RE) in comparison to WE. The TEAC and polyphenol values well-correlated with their effect on cell adhesion. Using 10% ME, reduced adhesion of leukocytes to HUVECs was measured (36 ± 13%), whereas 10% WE reduced cell adhesion to 57 ± 5% of the TNF-α stimulated controls (100%). Concomitant with the reduced leukocyte cell adhesion in the flow assay, ME and WE significantly reduced the TNF-α induced expression of cell adhesion molecules: E-selectin (ME, 51.3 ± 10.7 vs. WE, 76.3 ± 11.9%), ICAM-1 (ME, 74.6 ± 10.2 vs. WE, 81.6 ± 7.9%) and VCAM-1 mRNA expression (ME, 35.0 ± 14.0 vs

  17. Endothelial activation by hydrogen peroxide. Selective increases of intercellular adhesion molecule-1 and major histocompatibility complex class I.

    PubMed Central

    Bradley, J. R.; Johnson, D. R.; Pober, J. S.

    1993-01-01

    Products of activated leukocytes may alter vascular endothelial cell (EC) function. For example, ECs respond to leukocyte-derived cytokines, such as tumor necrosis factor (TNF) or interleukin-1, by reversibly altering levels of expression of specific gene products that promote inflammation. In contrast, hydrogen peroxide, a product of TNF-activated neutrophils, can produce irreversible EC injury and death. In this study, we have investigated the effects of subinjurious concentrations of hydrogen peroxide on EC inflammatory functions. Treatment with 50 to 100 mumol/L hydrogen peroxide selectively increases surface expression of intercellular adhesion molecule-1 and major histocompatibility complex class I, but not endothelial leukocyte adhesion molecule-1 (also known as E-selectin), vascular cell adhesion molecule-1, or gp96, a constitutively expressed EC surface protein. Increased major histocompatibility complex class I and intercellular adhesion molecule-1 surface expression is associated with specifically increased messenger RNA levels, suggesting selective endothelial gene activation. Hydrogen peroxide does not activate the transcription factor Nuclear Factor kappa B, an important mediator of TNF-induced gene expression. Co-treatment with hydrogen peroxide inhibits TNF-induced gene expression at 4 hours, an effect which can be attributed to reversible inhibition of TNF binding to EC surface receptors. Hydrogen peroxide also antagonizes the actions of interleukin-1. At 24 hours, TNF and hydrogen peroxide produce, at most, additive increases in intercellular adhesion molecule-1 and major histocompatibility complex class I. These results suggest that subinjurious concentrations of hydrogen peroxide can activate endothelium and that the effects of hydrogen peroxide on ECs differ from those of inflammatory cytokines. Images Figure 3 Figure 4 Figure 5 PMID:8098585

  18. Differential regulation of leukocyte function-associated antigen-1/ intercellular adhesion molecules-1-dependent adhesion and aggregation in HL-60 cells.

    PubMed

    Katagiri, K; Kinashi, T; Irie, S; Katagiri, T

    1996-05-15

    Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adhesion and aggregation. The interaction of leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecules-1 (ICAM-1) mediates cell adhesion and aggregation, which facilitate leukocyte trafficking to inflamed tissues and augment effector functions. We investigated how LFA-1/ICAM-1-mediated adhesion and aggregation are regulated in HL-60 cells induced to differentiate into neutrophils by retinoic acid (RA). Uninduced HL-60 cells did not bind to ICAM-1 even with stimulation by 12-0-tetradecanoyl phorbol-13-acetate, although they express LFA-1 on the cell surface. When cultured with RA for 24 hours, HL-60 cells were able to adhere to ICAM-1 constitutively. The induction of adhesion did not accompany any change in surface density of LFA-1, indicating that the avidity of LFA-1 was increased. The change in its avidity required de novo synthesis of proteins. Although ICAM-1 was intensely expressed on RA-induced HL-60 cells, these cells did not show any cellular aggregation. The HL-60 cells transfected with the active form of Ras (Val12) exhibited LFA-1/ICAM-1-dependent aggregation by RA stimulation without change in the avidity of LFA-1. In these Ras-transfectants, a cytoskeletal protein, paxillin, was tyrosine-phosphorylated, and the level of F-actin increased. Transforming growth factor (TGF) beta, as well as cytochalasin D, prevented both the tyrosine phosphorylation of paxillin and the aggregation without any effects on the avidity of LFA-1. Thus, an increase in the avidity of LFA-1 was not sufficient for the induction of aggregation, which required activation of Ras and reorganization of cytoskeletal proteins. These results suggest that distinct regulatory mechanisms control LFA-1/ICAM-1-dependent adhesion and aggregation in HL-60 cells differentiating into neutrophils.

  19. AlphaII-spectrin participates in the surface expression of cell adhesion molecule L1 and neurite outgrowth.

    PubMed

    Trinh-Trang-Tan, Marie-Marcelle; Bigot, Sylvain; Picot, Julien; Lecomte, Marie-Christine; Kordeli, Ekaterini

    2014-04-01

    AlphaII-spectrin, a basic component of the spectrin-based scaffold which organizes and stabilizes membrane microdomains in most animal cells, has been recently implicated in cell adherence and actin dynamics. Here we investigated the contribution of αΙΙ-spectrin to neuritogenesis, a highly complex cellular process which requires continuous actin cytoskeleton remodeling and cross-talk between extracellular cues and their cell surface receptors, including cell adhesion molecules. Using RNA interference-mediated gene silencing to down-regulate αΙΙ-spectrin expression in human neuroblastoma SH-SY5Y cells, we observed major changes in neurite morphology and cell shape: (1) reduced mean length and a higher number of neurites per cell; occasional long neurites were thinner and displayed abnormal adhesiveness during cell migration resulting in frequent breaks; similar persisting adhesiveness and breaks were also observed in trailing edges of cell bodies; (2) irregular polygonal cell shape in parallel with loss of cortical F-actin from neuronal cell bodies; (3) reduction in protein levels of αΙ- and βΙ-spectrins, but not βΙΙ-spectrin (4) decreased global expression of adhesion molecule L1 and spectrin-binding adapter ankyrin-B, which links L1 to the plasma membrane. Remarkably, αΙΙ-spectrin depletion affected L1 - but not NCAM - cell surface expression, and L1 clustering at growth cones. This study demonstrates that αΙΙ-spectrin is implicated in normal morphology and adhesive properties of neuron cell bodies and neurites, and in cell surface expression and organization of adhesion molecule L1. PMID:24462599

  20. The adhesion molecule PECAM-1 enhances the TGFβ-mediated inhibition of T cell function

    PubMed Central

    Newman, Debra K.; Fu, Guoping; Adams, Tamara; Cui, Weiguo; Arumugam, Vidhyalakshmi; Bluemn, Theresa; Riese, Matthew J.

    2016-01-01

    Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that inhibits the pro-inflammatory functions of T cells, and it is a major factor in abrogating T cell activity against tumors. Canonical signaling results in the activation of Smad proteins, transcription factors that regulate target gene expression. Here, we found that the cell surface molecule platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitates non-canonical (Smad-independent) TGF-β signaling in T cells. Subcutaneously injected tumor cells dependent on TGF-β-mediated suppression of immunity grew more slowly in PECAM-1−/− mice than in their wild type counterparts. T cells isolated from PECAM-1−/− mice demonstrated relative insensitivity to the TGF-β-dependent inhibition of interferon- γ (IFN-γ) production, granzyme B synthesis and cellular proliferation. Similarly, human T cells lacking PECAM-1 demonstrated decreased sensitivity to TGF-β in a manner that was partially restored by re-expression of PECAM-1. Co-incubation of T cells with TGF-β and a T cell-activating antibody resulted in PECAM-1 phosphorylation on an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the recruitment of the inhibitory Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2). Such stimulatory conditions also induced the co-localization of PECAM-1 with the TGF-β receptor complex as identified by co-immunoprecipitation, confocal microscopy, and proximity ligation assays. These studies indicate a role for PECAM-1 in enhancing the inhibitory functions of TGF-β in T cells and suggest that therapeutic targeting of the PECAM-1-TGF-β inhibitory axis represents a means to overcome TGF-β-dependent immunosuppression within the tumor microenvironment. PMID:26956486

  1. The adhesion molecule PECAM-1 enhances the TGF-β-mediated inhibition of T cell function.

    PubMed

    Newman, Debra K; Fu, Guoping; Adams, Tamara; Cui, Weiguo; Arumugam, Vidhyalakshmi; Bluemn, Theresa; Riese, Matthew J

    2016-03-01

    Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that inhibits the proinflammatory functions of T cells, and it is a major factor in abrogating T cell activity against tumors. Canonical TGF-β signaling results in the activation of Smad proteins, which are transcription factors that regulate target gene expression. We found that the cell surface molecule platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitated noncanonical (Smad-independent) TGF-β signaling in T cells. Subcutaneously injected tumor cells that are dependent on TGF-β-mediated suppression of immunity for growth grew more slowly in PECAM-1(-/-) mice than in their wild-type counterparts. T cells isolated from PECAM-1(-/-) mice demonstrated relative insensitivity to the TGF-β-dependent inhibition of interferon-γ (IFN-γ) production, granzyme B synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1 demonstrated decreased sensitivity to TGF-β in a manner that was partially restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-β and a T cell-activating antibody resulted in PECAM-1 phosphorylation on an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the recruitment of the inhibitory Src homology 2 (SH2) domain-containing tyrosine phosphatase-2 (SHP-2). Such conditions also induced the colocalization of PECAM-1 with the TGF-β receptor complex as identified by coimmunoprecipitation, confocal microscopy, and proximity ligation assays. These studies indicate a role for PECAM-1 in enhancing the inhibitory functions of TGF-β in T cells and suggest that therapeutic targeting of the PECAM-1-TGF-β inhibitory axis represents a means to overcome TGF-β-dependent immunosuppression within the tumor microenvironment. PMID:26956486

  2. TNF-α and IFN-γ promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration.

    PubMed

    Jaczewska, Justyna; Abdulreda, Midhat H; Yau, Chi Y; Schmitt, Martin M; Schubert, Irene; Berggren, Per-Olof; Weber, Christian; Koenen, Rory R; Moy, Vincent T; Wojcikiewicz, Ewa P

    2014-02-01

    Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM-A and PECAM-1 but not ICAM-1 or VCAM-1 toward the apical junctional regions of HUVECs following a 6-h stimulation with TNF-α and IFN-γ. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM-A receptors. Further AFM adhesion mapping of the homophilic JAM-A/JAM-A interaction on the surfaces of HUVECs revealed a greater number of JAM-A receptors available for binding along junctional regions after TNF-α and IFN-γ stimulation. Our data reveal for the first time that adhesion "hot spots" of JAM-A receptors are involved in initiating lymphocyte TEM under inflammatory conditions. PMID:24072879

  3. TNF-α and IFN-γ promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration

    PubMed Central

    Jaczewska, Justyna; Abdulreda, Midhat H.; Yau, Chi Y.; Schmitt, Martin M.; Schubert, Irene; Berggren, Per-Olof; Weber, Christian; Koenen, Rory R.; Moy, Vincent T.; Wojcikiewicz, Ewa P.

    2014-01-01

    Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM-A and PECAM-1 but not ICAM-1 or VCAM-1 toward the apical junctional regions of HUVECs following a 6-h stimulation with TNF-α and IFN-γ. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM-A receptors. Further AFM adhesion mapping of the homophilic JAM-A/JAM-A interaction on the surfaces of HUVECs revealed a greater number of JAM-A receptors available for binding along junctional regions after TNF-α and IFN-γ stimulation. Our data reveal for the first time that adhesion “hot spots” of JAM-A receptors are involved in initiating lymphocyte TEM under inflammatory conditions. PMID:24072879

  4. R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding.

    PubMed

    Yan, Xiaocai; Yan, Mingfei; Guo, Yihe; Singh, Gobind; Chen, Yuhong; Yu, Mei; Wang, Demin; Hillery, Cheryl A; Chan, Andrew M

    2015-01-01

    The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-subfamily of small guanosine-5'-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (Rras-/-). An examination of the lymphoid organs of Rras-/- mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of Rras-/- mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from Rras-/- mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in Rras-/- T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, Rras-/- T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with Rras-/- T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response. PMID:26710069

  5. Genetic polymorphisms of cell adhesion molecules in Behcet’s disease in a Chinese Han population

    PubMed Central

    Zheng, Minming; Zhang, Lijun; Yu, Hongsong; Hu, Jiayue; Cao, Qingfeng; Huang, Guo; Huang, Yang; Yuan, Gangxiang; Kijlstra, Aize; Yang, Peizeng

    2016-01-01

    Cell adhesion molecules (CAMs) are involved in various immune-mediated diseases. This study was conducted to investigate the association of single nucleotide polymorphisms (SNPs) of CAMs with Behçet’s disease (BD) in a Chinese Han population. A two-stage association study was carried out in 1149 BD patients and 2107 normal controls. Genotyping of 43 SNPs was performed using MassARRAY System (Sequenom), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP assays. The expression of CD6 and CD11c was examined by real-time PCR and cytokine production was measured by ELISA. A significantly higher frequency of the CT genotype, and a lower frequency of the CC genotype and C allele of CD6 rs11230563 were observed in BD as compared with controls. Analysis of CD11c rs2929 showed that patients with BD had a significantly higher frequency of the GG genotype and G allele, and a lower frequency of the AG genotype as compared with controls. Functional experiments showed an increased CD11c expression and increased production of TNF-α and IL-1beta by LPS stimulated PBMCs in GG carriers of CD11c rs2929 compared to AA/AG carriers. Our study provides evidence that CD6 and CD11c are involved in the susceptibility to BD in a Chinese Han population. PMID:27108704

  6. Down syndrome cell adhesion molecule 1: testing for a role in insect immunity, behaviour and reproduction.

    PubMed

    Peuß, Robert; Wensing, Kristina U; Woestmann, Luisa; Eggert, Hendrik; Milutinović, Barbara; Sroka, Marlene G U; Scharsack, Jörn P; Kurtz, Joachim; Armitage, Sophie A O

    2016-04-01

    Down syndrome cell adhesion molecule 1 (Dscam1) has wide-reaching and vital neuronal functions although the role it plays in insect and crustacean immunity is less well understood. In this study, we combine different approaches to understand the roles that Dscam1 plays in fitness-related contexts in two model insect species. Contrary to our expectations, we found no short-term modulation of Dscam1 gene expression after haemocoelic or oral bacterial exposure in Tribolium castaneum, or after haemocoelic bacterial exposure in Drosophila melanogaster. Furthermore, RNAi-mediated Dscam1 knockdown and subsequent bacterial exposure did not reduce T. castaneum survival. However, Dscam1 knockdown in larvae resulted in adult locomotion defects, as well as dramatically reduced fecundity in males and females. We suggest that Dscam1 does not always play a straightforward role in immunity, but strongly influences behaviour and fecundity. This study takes a step towards understanding more about the role of this intriguing gene from different phenotypic perspectives. PMID:27152227

  7. L1 CELL ADHESION MOLECULE SIGNALING IS INHIBITED BY ETHANOL IN VIVO

    PubMed Central

    Littner, Yoav; Tang, Ningfeng; He, Min; Bearer, Cynthia F.

    2012-01-01

    Background Fetal alcohol spectrum disorder is an immense public health problem. In vitro studies support the hypothesis that L1 cell adhesion molecule (L1) is a target for ethanol developmental neurotoxicity. L1 is critical for the development of the central nervous system. It functions through signal transduction leading to phosphorylation and dephosphorylation of tyrosines on its cytoplasmic domain. The function of L1 is also dependent on trafficking through lipid rafts. Our hypothesis is that L1 is a target for ethanol neurotoxicity in vivo. Our objective is to demonstrate changes in L1 phosphorylation/dephosphorylation and lipid raft association in vivo. Methods Rat pups on postnatal day 6 are administered 4.5, 5.25 and 6 g/kg of ethanol divided into 2 doses 2 hours apart, then sacrificed. Cerebella are rapidly frozen for assay. Blood is analyzed for blood ethanol concentration. L1 tyrosine phosphorylation is determined by immunoprecipitation and dephosphorylation of tyrosine 1176 determined by immunoblot. Lipid rafts are isolated by sucrose density gradient and the distribution of L1 in lipid rafts is determined. Results Ethanol at all doses reduced the relative amount of Y1176 dephosphorylation as well as the relative amount of L1 phosphorylated on other tyrosines. The proportion of L1 present in lipid rafts is significantly increased in pups who received 6 g/kg ethanol compared to intubated controls. Conclusions L1 is a target for ethanol developmental neurotoxicity in vivo. PMID:23050935

  8. RNA released from necrotic keratinocytes upregulates intercellular adhesion molecule-1 expression in melanocytes.

    PubMed

    Zhang, Shujie; Liu, Shuangchun; Yu, Ning; Xiang, Leihong

    2011-12-01

    Intercellular adhesion molecule-1 (ICAM-1) expression has been detected in melanocytes around active vitiligo patches as well as in surgically transplanted melanocytes. However, it is unclear whether and how skin injury induces the inappropriate expression of ICAM-1 and other proinflammatory genes in melanocytes. We previously reported that human melanocytes expressed TLR3. We hypothesized that the TLR3 expressed in melanocytes may recognize skin injury by binding to the endogenous ligands secreted by the damaged keratinocytes. Here we showed that RNA released from necrotic keratinocytes induced the upregulation of ICAM-1 protein and mRNA, as shown by FACS and real-time RT-PCR. Use of NF-κB inhibitor prevents upregulation of ICAM-1 in melanocytes indicating a direct role of NF-κB in necrotic keratinocyte-mediated upregulation of ICAM-1. Using a shRNA-expressing lentivirus, we demonstrated that in human melanocytes, TLR3 seems to be necessary for the upregulation of ICAM-1. Using oligonucleotide microarray, we demonstrated a dramatic increase in proinflammatory cytokine and chemokine transcripts (CXCL10, CXCL11, TNFSF10, CCL5, CCL4, CCL2, IFNB1, CCL20, IL-8, and CCL11). These observations suggested that RNA released from necrotic keratinocytes might act as an endogenous TLR3 ligand for the stimulation of ICAM-1 and other proinflammatory gene expression in human melanocytes, which might be involved in the pathogenesis of vitiligo following skin physical trauma.

  9. NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease

    PubMed Central

    Azeredo, E L; De Oliveira-Pinto, L M; Zagne, S M; Cerqueira, D I S; Nogueira, R M R; Kubelka, C F

    2006-01-01

    During the innate immune response against infections, Natural Killer (NK) cells are as important effector cells as are Cytotoxic T lymphocytes (CTL) generated after antigenic stimulation in the adaptative response. NK cells increase in numbers, after viral infection or vaccination. We investigated the NK cell and CD8 T lymphocyte status in 55 dengue infected patients. The NK (CD56+CD3−) and CD56+ T cell (CD56+CD3+) rates rise during the acute phase of disease. The majority of NK cells from dengue patients display early markers for activation (CD69, HLA-DR, and CD38) and cell adhesion molecules (CD44, CD11a) during the acute phase of disease. The intracellular cytotoxic granule, TIA-1, is also up-regulated early in NK cells. Most of these markers appear also on CD8+ T lymphocytes but during the late acute phase. Circulating IL-15 is elevated in a significant number of patients during early acute infection and its values were statistically correlated with NK frequencies and cytotoxic markers on NKs. We have therefore shown that dengue virus infection is very likely stimulating a cytotoxic response that may be efficient in controlling the virus in synergism with CD8+ T lymphocytes. Interestingly, the heightened CD56+CD3−, CD56+CD3+, CD56+TIA-1+ and CD56+CD11a+ cell rates are associated with mild dengue clinical manifestations and might indicate a good prognosis of the disease. PMID:16412060

  10. Down syndrome cell adhesion molecule 1: testing for a role in insect immunity, behaviour and reproduction

    PubMed Central

    Wensing, Kristina U.; Eggert, Hendrik; Scharsack, Jörn P.

    2016-01-01

    Down syndrome cell adhesion molecule 1 (Dscam1) has wide-reaching and vital neuronal functions although the role it plays in insect and crustacean immunity is less well understood. In this study, we combine different approaches to understand the roles that Dscam1 plays in fitness-related contexts in two model insect species. Contrary to our expectations, we found no short-term modulation of Dscam1 gene expression after haemocoelic or oral bacterial exposure in Tribolium castaneum, or after haemocoelic bacterial exposure in Drosophila melanogaster. Furthermore, RNAi-mediated Dscam1 knockdown and subsequent bacterial exposure did not reduce T. castaneum survival. However, Dscam1 knockdown in larvae resulted in adult locomotion defects, as well as dramatically reduced fecundity in males and females. We suggest that Dscam1 does not always play a straightforward role in immunity, but strongly influences behaviour and fecundity. This study takes a step towards understanding more about the role of this intriguing gene from different phenotypic perspectives. PMID:27152227

  11. Junctional Adhesion Molecule A Promotes Epithelial Tight Junction Assembly to Augment Lung Barrier Function

    PubMed Central

    Mitchell, Leslie A.; Ward, Christina; Kwon, Mike; Mitchell, Patrick O.; Quintero, David A.; Nusrat, Asma; Parkos, Charles A.; Koval, Michael

    2016-01-01

    Epithelial barrier function is maintained by tight junction proteins that control paracellular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, loss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, loss of JAM-A decreased β1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A−/− mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM-A−/− mice to edema correlated with increased, transient disruption of claudin-18, zonula occludens 1, and zonula occludens 2 localization to lung tight junctions in situ along with a delay in up-regulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key role of JAM-A in promoting tight junction homeostasis and lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton. PMID:25438062

  12. Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Improves Regeneration After Injury.

    PubMed

    Lutz, David; Kataria, Hardeep; Kleene, Ralf; Loers, Gabriele; Chaudhary, Harshita; Guseva, Daria; Wu, Bin; Jakovcevski, Igor; Schachner, Melitta

    2016-07-01

    Myelin basic protein (MBP) is a serine protease that cleaves neural cell adhesion molecule L1 and generates a transmembrane L1 fragment which facilitates L1-dependent functions in vitro, such as neurite outgrowth, neuronal cell migration and survival, myelination by Schwann cells as well as Schwann cell proliferation, migration, and process formation. Ablation and blocking of MBP or disruption of its proteolytic activity by mutation of a proteolytically active serine residue abolish L1-dependent cellular responses. In utero injection of adeno-associated virus encoding proteolytically active MBP into MBP-deficient shiverer mice normalizes differentiation, myelination, and synaptogenesis in the developing postnatal spinal cord, in contrast to proteolytically inactive MBP. Application of active MBP to the injured wild-type spinal cord and femoral nerve augments levels of a transmembrane L1 fragment, promotes remyelination, and improves functional recovery after injury. Application of MBP antibody impairs recovery. Virus-mediated expression of active MBP in the lesion site after spinal cord injury results in improved functional recovery, whereas injection of virus encoding proteolytically inactive MBP fails to do so. The present study provides evidence for a novel L1-mediated function of MBP in the developing spinal cord and in the injured adult mammalian nervous system that leads to enhanced recovery after acute trauma.

  13. Annexin A2 Acts as an Adhesion Molecule on the Endometrial Epithelium during Implantation in Mice

    PubMed Central

    Lee, Kai-Fai; Chiu, Philip C. N.; Pang, Ronald T. K.; Ng, Ernest H. Y.; Yeung, William S. B.

    2015-01-01

    To determine the function of Annexin A2 (Axna2) in mouse embryo implantation in vivo, experimental manipulation of Axna2 activities was performed in mouse endometrial tissue in vivo and in vitro. Histological examination of endometrial tissues was performed throughout the reproduction cycle and after steroid treatment. Embryo implantation was determined after blockage of the Axna2 activities by siRNA or anti-Axna2 antibody. The expression of Axna2 immunoreactivies in the endometrial luminal epithelium changed cyclically in the estrus cycle and was upregulated by estrogen. After nidatory estrogen surge, there was a concentration of Axna2 immunoreactivities at the interface between the implanting embryo and the luminal epithelium. The phenomenon was likely to be induced by the implanting embryos as no such concentration of signal was observed in the inter-implantation sites and in pseudopregnancy. Knockdown of Axna2 by siRNA reduced attachment of mouse blastocysts onto endometrial tissues in vitro. Consistently, the number of implantation sites was significantly reduced after infusion of anti-Axna2 antibody into the uterine cavity. Steroids and embryos modulate the expression of Axna2 in the endometrial epithelium. Axna2 may function as an adhesion molecule during embryo implantation in mice. PMID:26444699

  14. Annexin A2 Acts as an Adhesion Molecule on the Endometrial Epithelium during Implantation in Mice.

    PubMed

    Wang, Bing; Ye, Tian-Min; Lee, Kai-Fai; Chiu, Philip C N; Pang, Ronald T K; Ng, Ernest H Y; Yeung, William S B

    2015-01-01

    To determine the function of Annexin A2 (Axna2) in mouse embryo implantation in vivo, experimental manipulation of Axna2 activities was performed in mouse endometrial tissue in vivo and in vitro. Histological examination of endometrial tissues was performed throughout the reproduction cycle and after steroid treatment. Embryo implantation was determined after blockage of the Axna2 activities by siRNA or anti-Axna2 antibody. The expression of Axna2 immunoreactivies in the endometrial luminal epithelium changed cyclically in the estrus cycle and was upregulated by estrogen. After nidatory estrogen surge, there was a concentration of Axna2 immunoreactivities at the interface between the implanting embryo and the luminal epithelium. The phenomenon was likely to be induced by the implanting embryos as no such concentration of signal was observed in the inter-implantation sites and in pseudopregnancy. Knockdown of Axna2 by siRNA reduced attachment of mouse blastocysts onto endometrial tissues in vitro. Consistently, the number of implantation sites was significantly reduced after infusion of anti-Axna2 antibody into the uterine cavity. Steroids and embryos modulate the expression of Axna2 in the endometrial epithelium. Axna2 may function as an adhesion molecule during embryo implantation in mice.

  15. The Prion Protein Controls Polysialylation of Neural Cell Adhesion Molecule 1 during Cellular Morphogenesis

    PubMed Central

    Mehrabian, Mohadeseh; Brethour, Dylan; Wang, Hansen; Xi, Zhengrui; Rogaeva, Ekaterina; Schmitt-Ulms, Gerold

    2015-01-01

    Despite its multi-faceted role in neurodegenerative diseases, the physiological function of the prion protein (PrP) has remained elusive. On the basis of its evolutionary relationship to ZIP metal ion transporters, we considered that PrP may contribute to the morphogenetic reprogramming of cells underlying epithelial-to-mesenchymal transitions (EMT). Consistent with this hypothesis, PrP transcription increased more than tenfold during EMT, and stable PrP-deficient cells failed to complete EMT in a mammalian cell model. A global comparative proteomics analysis identified the neural cell adhesion molecule 1 (NCAM1) as a candidate mediator of this impairment, which led to the observation that PrP-deficient cells fail to undergo NCAM1 polysialylation during EMT. Surprisingly, this defect was caused by a perturbed transcription of the polysialyltransferase ST8SIA2 gene. Proteomics data pointed toward β-catenin as a transcriptional regulator affected in PrP-deficient cells. Indeed, pharmacological blockade or siRNA-based knockdown of β-catenin mimicked PrP-deficiency in regards to NCAM1 polysialylation. Our data established the existence of a PrP-ST8SIA2-NCAM signaling loop, merged two mature fields of investigation and offer a simple model for explaining phenotypes linked to PrP. PMID:26288071

  16. Myelin basic protein cleaves cell adhesion molecule L1 and promotes neuritogenesis and cell survival.

    PubMed

    Lutz, David; Loers, Gabriele; Kleene, Ralf; Oezen, Iris; Kataria, Hardeep; Katagihallimath, Nainesh; Braren, Ingke; Harauz, George; Schachner, Melitta

    2014-05-01

    The cell adhesion molecule L1 is a Lewis(x)-carrying glycoprotein that plays important roles in the developing and adult nervous system. Here we show that myelin basic protein (MBP) binds to L1 in a Lewis(x)-dependent manner. Furthermore, we demonstrate that MBP is released by murine cerebellar neurons as a sumoylated dynamin-containing protein upon L1 stimulation and that this MBP cleaves L1 as a serine protease in the L1 extracellular domain at Arg(687) yielding a transmembrane fragment that promotes neurite outgrowth and neuronal survival in cell culture. L1-induced neurite outgrowth and neuronal survival are reduced in MBP-deficient cerebellar neurons and in wild-type cerebellar neurons in the presence of an MBP antibody or L1 peptide containing the MBP cleavage site. Genetic ablation of MBP in shiverer mice and mutagenesis of the proteolytically active site in MBP or of the MBP cleavage site within L1 as well as serine protease inhibitors and an L1 peptide containing the MBP cleavage site abolish generation of the L1 fragment. Our findings provide evidence for novel functions of MBP in the nervous system. PMID:24671420

  17. Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Improves Regeneration After Injury.

    PubMed

    Lutz, David; Kataria, Hardeep; Kleene, Ralf; Loers, Gabriele; Chaudhary, Harshita; Guseva, Daria; Wu, Bin; Jakovcevski, Igor; Schachner, Melitta

    2016-07-01

    Myelin basic protein (MBP) is a serine protease that cleaves neural cell adhesion molecule L1 and generates a transmembrane L1 fragment which facilitates L1-dependent functions in vitro, such as neurite outgrowth, neuronal cell migration and survival, myelination by Schwann cells as well as Schwann cell proliferation, migration, and process formation. Ablation and blocking of MBP or disruption of its proteolytic activity by mutation of a proteolytically active serine residue abolish L1-dependent cellular responses. In utero injection of adeno-associated virus encoding proteolytically active MBP into MBP-deficient shiverer mice normalizes differentiation, myelination, and synaptogenesis in the developing postnatal spinal cord, in contrast to proteolytically inactive MBP. Application of active MBP to the injured wild-type spinal cord and femoral nerve augments levels of a transmembrane L1 fragment, promotes remyelination, and improves functional recovery after injury. Application of MBP antibody impairs recovery. Virus-mediated expression of active MBP in the lesion site after spinal cord injury results in improved functional recovery, whereas injection of virus encoding proteolytically inactive MBP fails to do so. The present study provides evidence for a novel L1-mediated function of MBP in the developing spinal cord and in the injured adult mammalian nervous system that leads to enhanced recovery after acute trauma. PMID:26081148

  18. The Prion Protein Controls Polysialylation of Neural Cell Adhesion Molecule 1 during Cellular Morphogenesis.

    PubMed

    Mehrabian, Mohadeseh; Brethour, Dylan; Wang, Hansen; Xi, Zhengrui; Rogaeva, Ekaterina; Schmitt-Ulms, Gerold

    2015-01-01

    Despite its multi-faceted role in neurodegenerative diseases, the physiological function of the prion protein (PrP) has remained elusive. On the basis of its evolutionary relationship to ZIP metal ion transporters, we considered that PrP may contribute to the morphogenetic reprogramming of cells underlying epithelial-to-mesenchymal transitions (EMT). Consistent with this hypothesis, PrP transcription increased more than tenfold during EMT, and stable PrP-deficient cells failed to complete EMT in a mammalian cell model. A global comparative proteomics analysis identified the neural cell adhesion molecule 1 (NCAM1) as a candidate mediator of this impairment, which led to the observation that PrP-deficient cells fail to undergo NCAM1 polysialylation during EMT. Surprisingly, this defect was caused by a perturbed transcription of the polysialyltransferase ST8SIA2 gene. Proteomics data pointed toward β-catenin as a transcriptional regulator affected in PrP-deficient cells. Indeed, pharmacological blockade or siRNA-based knockdown of β-catenin mimicked PrP-deficiency in regards to NCAM1 polysialylation. Our data established the existence of a PrP-ST8SIA2-NCAM signaling loop, merged two mature fields of investigation and offer a simple model for explaining phenotypes linked to PrP. PMID:26288071

  19. Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions

    PubMed Central

    Seidenfaden, Ralph; Krauter, Andrea; Schertzinger, Frank; Gerardy-Schahn, Rita; Hildebrandt, Herbert

    2003-01-01

    Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), promotes neural plasticity and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression profiles were initiated by enzymatic removal of PSA and by ectopic expression of NCAM or PSA-NCAM. Removal of PSA from the cell surface led to reduced proliferation and activated extracellular signal-regulated kinase (ERK), inducing enhanced survival and neuronal differentiation of neuroblastoma cells. Blocking with an NCAM-specific peptide prevented these effects. Combinatorial transinteraction studies with cells and membranes with different PSA and NCAM phenotypes revealed that heterophilic NCAM binding mimics the cellular responses to PSA removal. In conclusion, our data demonstrate that PSA masks heterophilic NCAM signals, having a direct impact on tumor cell growth. This provides a mechanism for how PSA may promote the genesis and progression of highly aggressive PSA-NCAM-positive tumors. PMID:12897159

  20. Functional studies of truncated soluble intercellular adhesion molecule 1 expressed in Escherichia coli.

    PubMed Central

    Martin, S; Martin, A; Staunton, D E; Springer, T A

    1993-01-01

    We have expressed in Escherichia coli the two N-terminal immunoglobulin (Ig)-like domains of the intercellular adhesion molecule 1 (ICAM-1). The first 188 residues of ICAM-1 were expressed with an N-terminal methionine (MP188) or as a maltose-binding fusion protein which was cleaved with factor Xa (XP188). After refolding, both MP188 and XP188 were active in binding to the leukocyte integrin lymphocyte function-associated antigen 1, which has previously been shown to bind to the N-terminal Ig domain of ICAM-1. The major group of rhinoviruses and malaria-infected erythrocytes bind to distinct sites within the first Ig-like domain of ICAM-1. Both MP188 and XP188 bound to malaria-infected erythrocytes; however, only XP188 inhibited human rhinovirus plaque formation. A product (MdQ1P188) with the initiation methionine fused to residue 2, i.e., with glutamine 1 deleted, inhibited plaque formation. MdQ1P188 was able to induce a conformational change of the virus capsid as shown by conversion of 149S particles to 85S particles, whereas MP188 had no effect. These results show that functionally active fragments of ICAM-1 can be produced in E. coli, that glycosylation is not required for ligand binding, and that the N-terminal residue of ICAM-1 is proximal to or part of the human rhinovirus-binding site. Images PMID:8101071

  1. Biosynthesis of the neural cell adhesion molecule: characterization of polypeptide C

    PubMed Central

    1985-01-01

    The biosynthesis of the neural cell adhesion molecule (N-CAM) was studied in primary cultures of rat cerebral glial cells, cerebellar granule neurons, and skeletal muscle cells. The three cell types produced different N-CAM polypeptide patterns. Glial cells synthesized a 135,000 Mr polypeptide B and a 115,000 Mr polypeptide C, whereas neurons expressed a 200,000 Mr polypeptide A as well as polypeptide B. Skeletal muscle cells produced polypeptide B. The polypeptides synthesized by the three cell types were immunochemically identical. The membrane association of polypeptide C was investigated with methods that distinguish peripheral and integral membrane proteins. Polypeptide C was found to be a peripheral membrane protein, whereas polypeptides A and B were integral membrane proteins with cytoplasmic domains of approximately 50,000 and approximately 25,000 Mr, respectively. The affinity of the membrane binding of polypeptide C increased during postnatal development. The posttranslational modifications of polypeptide C were investigated in glial cell cultures, and it was found to be N-linked glycosylated and sulfated. PMID:4066759

  2. Role of Intercellular Adhesion Molecule-1 in Radiation-Induced Brain Injury

    SciTech Connect

    Wu, K.-L.; Tu Ba; Li Yuqing; Wong, C. Shun

    2010-01-15

    Purpose: To determine the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of brain injury after irradiation (IR). Methods and Materials: We assessed the expression of ICAM-1 in mouse brain after cranial IR and determined the histopathologic and behavioral changes in mice that were either wildtype (+/+) or knockout (-/-) of the ICAM-1 gene after IR. Results: There was an early dose-dependent increase in ICAM-1 mRNA and protein expression after IR. Increased ICAM-1 immunoreactivity was observed in endothelia and glia of ICAM-1+/+ mice up to 8 months after IR. ICAM-1-/- mice showed no expression. ICAM-1+/+ and ICAM-1-/- mice showed similar vascular abnormalities at 2 months after 10-17 Gy, and there was evidence for demyelination and inhibition of hippocampal neurogenesis at 8 months after 10 Gy. After 10 Gy, irradiated ICAM-1+/+ and ICAM-1-/- mice showed similar behavioral changes at 2-6 months in open field, light-dark chamber, and T-maze compared with age-matched genotype controls. Conclusion: There is early and late upregulation of ICAM-1 in the vasculature and glia of mouse brain after IR. ICAM-1, however, does not have a causative role in the histopathologic injury and behavioral dysfunction after moderate single doses of cranial IR.

  3. CHLORHEXIDINE INHIBITS L1 CELL ADHESION MOLECULE MEDIATED NEURITE OUTGROWTH IN VITRO

    PubMed Central

    Milstone, Aaron M.; Bamford, Penny; Aucott, Susan W.; Tang, Ningfeng; White, Kimberly R.; Bearer, Cynthia F.

    2013-01-01

    Background Chlorhexidine is a skin disinfectant that reduces skin and mucous membrane bacterial colonization and inhibits organism growth. Despite numerous studies assessing chlorhexidine safety in term infants, residual concerns have limited its use in hospitalized neonates, especially low birth weight preterm infants. The aim of this study was to assess the potential neurotoxicity of chlorhexidine on the developing central nervous system using a well-established in vitro model of neurite outgrowth that includes laminin and L1 cell adhesion molecule (L1) as neurite outgrowth promoting substrates. Methods Cerebellar granule neurons are plated on either poly L-lysine, L1 or laminin. Chlorhexidine, hexachlorophene or their excipients are added to the media. Neurons are grown for 24 h, then fixed and neurite length measured. Results Chlorhexidine significantly reduced the length of neurites grown on L1 but not laminin. Chlorhexidine concentrations as low as 125 ng/ml statistically significantly reduced neurite length on L1. Hexachlorophene did not affect neurite length. Conclusion Chlorhexidine at concentrations detected in the blood following topical applications in preterm infants specifically inhibited L1 mediated neurite outgrowth of cerebellar granule neurons. It is now vital to determine whether the blood brain barrier is permeable to chlorhexidine in preterm infants. PMID:24126818

  4. Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.

    PubMed Central

    Gotley, D. C.; Fawcett, J.; Walsh, M. D.; Reeder, J. A.; Simmons, D. L.; Antalis, T. M.

    1996-01-01

    Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression. Images Figure 2 Figure 3 Figure 5 Figure 6 PMID:8695347

  5. Polymorphisms in the intercellular adhesion molecule 1 gene and cancer risk: a meta-analysis

    PubMed Central

    Tang, Weifeng; Wang, Yafeng; Chen, Yuanmei; Gu, Haiyong; Chen, Shuchen; Kang, Mingqiang

    2015-01-01

    Objectives: The correlation between intercellular adhesion molecule 1 (ICAM-1) common polymorphisms (rs5498 A>G and rs3093030 C>T) and cancer susceptibility has been explored in various ethnic groups and different cancer types; however, these investigations have yielded contradictory results. To address the relationship more precisely, we performed this meta-analysis. Design and methods: EmBase, PubMed and China National Knowledge Infrastructure (CNKI) databases were searched by two authors independently for eligible publications before April 8, 2015. Random-effects or fixed-effects model was harnessed to calculate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) when appropriate. Results: The result suggested that the ICAM-1 rs5498 A>G polymorphism is not associated with cancer susceptibility in overall cancer. In a stratified analysis by ethnicity, a significant increased cancer risk was identified among Asians, but the inverse association was found among Caucasians. In a stratified analysis by cancer type, ICAM-1 rs5498 A>G polymorphism was associated with a significantly increased risk of oral cancer, but with protection from colorectal cancer and melanoma. ICAM-1 rs3093030 C>T polymorphism is not correlated with cancer susceptibility. Conclusions: In summary, this meta-analysis highlights that the ICAM-1 rs5498 A>G polymorphism probably contributes to decreased susceptibility to cancer, especially in Caucasians, in melanoma and colorectal cancer subgroup, but it may be a risk factor for oral cancer and Asians. PMID:26550112

  6. Origin of metazoan adhesion molecules and adhesion receptors as deduced from cDNA analyses in the marine sponge Geodia cydonium: a review.

    PubMed

    Müller, W E

    1997-09-01

    The phylogenetic relationships of the kingdom Animalia (Metazoa) have long been questioned. Whether the lowest eukaryotic multicellular organisms, the metazoan phylum Porifera (sponges), independently evolved multicellularity from a separate protist lineage (polyphyly of animals) or whether they were derived from the same protist group as the other animal phyla (monophyly) remains unclear. Analyses of the genes that are typical for multicellularity, e.g. those coding for adhesion molecules (galectin) and adhesion receptors (receptor tyrosine kinase, integrin receptor, receptors featuring scavenger receptor cysteine-rich domains) or elements involved in signal transduction pathways (G-proteins, Ser/Thr protein kinases), especially from the marine sponge Geodia cydonium, indicate that all animals, including sponges, are of monophyletic origin. PMID:9232818

  7. Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells

    PubMed Central

    Zhang, Wei-Wei; Zhan, Shu-Hui; Geng, Chang-Xin; Sun, Xin; Erkan, Mert; Kleeff, Jörg; Xie, Xiang-Jun

    2016-01-01

    Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues. Subsequently, reverse transcription-quantitative polymerase chain reaction and immunoblotting were applied to assess the expression of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, as well as in PSCs. An enzyme-linked immunosorbent assay was used to measure ALCAM levels in cell culture medium stimulated by hypoxia, tumor necrosis factor (TNF)-α and transforming growth factor-β. Silencing of ALCAM was performed using ALCAM small interfering (si)RNA and immunocytochemistry was used to analyze the inhibition efficiency. An invasion assay and a cell interaction assay were performed to assess the invasive ability and co-cultured adhesive potential of Panc-1 and T3M4 cells, as well as PSCs. Histologically, ALCAM expression was generally weak or absent in pancreatic cancer cells, but was markedly upregulated in PSCs in pancreatic cancer tissues. ALCAM was highly expressed in PSCs from CP tissues and PSCs surrounding pancreatic intraepithelial neoplasias, as well as in pancreatic cancer cells. ALCAM mRNA was highly expressed in PSCs, with a low to moderate expression in T3M4 and Panc-1 cells. Similar to the mRNA expression, immunoblotting demonstrated that ALCAM protein levels were high in PSCs and T3M4 cells, but low in Panc-1 cells. The expression of TNF-α increased, while hypoxia decreased the secretion of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, and also in

  8. Proper migration and axon outgrowth of zebrafish cranial motoneuron subpopulations require the cell adhesion molecule MDGA2A

    PubMed Central

    Ingold, Esther; vom Berg-Maurer, Colette M.; Burckhardt, Christoph J.; Lehnherr, André; Rieder, Philip; Keller, Philip J.; Stelzer, Ernst H.; Greber, Urs F.; Neuhauss, Stephan C. F.; Gesemann, Matthias

    2015-01-01

    ABSTRACT The formation of functional neuronal circuits relies on accurate migration and proper axonal outgrowth of neuronal precursors. On the route to their targets migrating cells and growing axons depend on both, directional information from neurotropic cues and adhesive interactions mediated via extracellular matrix molecules or neighbouring cells. The inactivation of guidance cues or the interference with cell adhesion can cause severe defects in neuronal migration and axon guidance. In this study we have analyzed the function of the MAM domain containing glycosylphosphatidylinositol anchor 2A (MDGA2A) protein in zebrafish cranial motoneuron development. MDGA2A is prominently expressed in distinct clusters of cranial motoneurons, especially in the ones of the trigeminal and facial nerves. Analyses of MDGA2A knockdown embryos by light sheet and confocal microscopy revealed impaired migration and aberrant axonal outgrowth of these neurons; suggesting that adhesive interactions mediated by MDGA2A are required for the proper arrangement and outgrowth of cranial motoneuron subtypes. PMID:25572423

  9. Extracellular Matrix can Recover the Downregulation of Adhesion Molecules after Cell Detachment and Enhance Endothelial Cell Engraftment.

    PubMed

    He, Ningning; Xu, Yang; Du, Wei; Qi, Xin; Liang, Lu; Wang, Yuebing; Feng, Guowei; Fan, Yan; Han, Zhongchao; Kong, Deling; Cheng, Zhen; Wu, Joseph C; He, Zuoxiang; Li, Zongjin

    2015-01-01

    The low cell engraftment after transplantation limits the successful application of stem cell therapy and the exact pathway leading to acute donor cell death following transplantation is still unknown. Here we investigated if processes involved in cell preparation could initiate downregulation of adhesion-related survival signals, and further affect cell engraftment after transplantation. Human embryonic stem cell-derived endothelial cells (hESC-ECs) were suspended in PBS or Matrigel and kept at 4 °C. Quantitative RT-PCR analysis was used to test the adhesion and apoptosis genes' expression of hESC-ECs. We demonstrated that cell detachment can cause downregulation of cell adhesion and extracellular matrix (ECM) molecules, but no obvious cell anoikis, a form of apoptosis after cell detachment, was observed. The downregulation of adhesion and ECM molecules could be regained in the presence of Matrigel. Finally, we transplanted hESC-ECs into a mouse myocardial ischemia model. When transplanted with Matrigel, the long-term engraftment of hESC-ECs was increased through promoting angiogenesis and inhibiting apoptosis, and this was confirmed by bioluminescence imaging. In conclusion, ECM could rescue the functional genes expression after cell detached from culture dish, and this finding highlights the importance of increasing stem cell engraftment by mimicking stem cell niches through ECM application.

  10. Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference

    PubMed Central

    Choi, Su-Yeon; Han, Kihoon; Cutforth, Tyler; Chung, Woosuk; Park, Haram; Lee, Dongsoo; Kim, Ryunhee; Kim, Myeong-Heui; Choi, Yeeun; Shen, Kang; Kim, Eunjoon

    2015-01-01

    Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report mice lacking Neph2 (Neph2-/- mice) display moderate hyperactivity in a familiar, but not novel, environment and defective novel object recognition with normal performances in Morris water maze spatial learning and memory, contextual fear conditioning and extinction, and pattern separation tests. These mice also show normal levels of anxiety-like behaviors, social interaction, and repetitive behaviors. At the synapse level, Neph2-/- dentate gyrus granule cells exhibit unaltered dendritic spine density and spontaneous excitatory synaptic transmission. These results suggest that Neph2 is important for normal locomotor activity and object recognition memory. PMID:26283919

  11. Nitric oxide pretreatment enhances atheroma component highlighting in vivo with intercellular adhesion molecule-1-targeted echogenic liposomes.

    PubMed

    Kee, Patrick H; Kim, Hyunggun; Huang, Shaoling; Laing, Susan T; Moody, Melanie R; Vela, Deborah; Klegerman, Melvin E; McPherson, David D

    2014-06-01

    We present an ultrasound technique for the detection of inflammatory changes in developing atheromas. We used contrast-enhanced ultrasound imaging with (i) microbubbles targeted to intercellular adhesion molecule-1 (ICAM-1), a molecule of adhesion involved in inflammatory processes in lesions of atheromas in New Zealand White rabbits, and (ii) pretreatment with nitric oxide-loaded microbubbles and ultrasound activation at the site of the endothelium to enhance the permeability of the arterial wall and the penetration of ICAM-1-targeted microbubbles. This procedure increases acoustic enhancement 1.2-fold. Pretreatment with nitric oxide-loaded echogenic liposomes and ultrasound activation can potentially facilitate the subsequent penetration of targeted echogenic liposomes into the arterial wall, thus allowing improved detection of inflammatory changes in developing atheromas.

  12. Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes

    PubMed Central

    Mori, S; Takahashi, HK; Liu, K; Wake, H; Zhang, J; Liu, R; Yoshino, T; Nishibori, M

    2010-01-01

    BACKGROUND AND PURPOSE Advanced glycation end products (AGEs) subtypes, proteins or lipids that become glycated after exposure to sugars, can induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) are involved in inflammation in diabetic patients; monocytes are activated by these AGEs. Ciprofloxacin (CIP), a fluorinated 4-quinolone, is often used clinically to treat infections associated with diabetis due to its antibacterial properties. It also modulates immune responses in human peripheral blood mononuclear cells (PBMC) therefore we investigated the involvement of AGEs in these effects. EXPERIMENTAL APPROACH Expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 was examined by flow cytometry. The production of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, prostaglandin E2 (PGE2) and cAMP were determined by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 expression was determined by Western blot analysis. Lymphocyte proliferation was determined by [3H]-thymidine uptake. KEY RESULTS CIP induced PGE2 production in monocytes, irrespective of the presence of AGE-2 and AGE-3, by enhancing COX-2 expression; this led to an elevation of intracellular cAMP in monocytes. Non-selective and selective COX-2 inhibitors, indomethacin and NS398, inhibited CIP-induced PGE2 and cAMP production. In addition, CIP inhibited AGE-2- and AGE-3-induced expressions of ICAM-1, B7.1, B7.2 and CD40 in monocytes, the production of TNF-α and IFN-γ and lymphocyte proliferation in PBMC. Indomethacin, NS398 and a protein kinase A inhibitor, H89, inhibited the actions of CIP. CONCLUSIONS AND IMPLICATIONS CIP exerts immunomodulatory activity via PGE2, implying therapeutic potential of CIP for the treatment of AGE-2- and AGE-3-induced inflammatory responses. PMID:20718752

  13. Perinodular ductular reaction/epithelial cell adhesion molecule loss in small hepatic nodules

    PubMed Central

    Zhang, Qin; Zhang, Chuan-Shan; Xin, Qi; Ma, Zhe; Liu, Gui-Qiu; Liu, Bing-Bing; Wang, Feng-Mei; Gao, Ying-Tang; Du, Zhi

    2014-01-01

    AIM: To investigate if loss of epithelial cell adhesion molecule (EpCAM) is associated with microinvasion in hepatocellular carcinomas (HCCs) in the presence of chronic hepatitis B. METHODS: The expression of EpCAM, cytokeratin 7 (CK7) and CK19 in 112 hepatic nodules was studied, including 20 HCCs with nodules ≤ 3 cm, 26 HCCs with nodules > 3 cm, 20 high-grade dysplastic nodules, 26 cirrhotic, large regenerative nodules and 20 cases of cirrhosis. RESULTS: Membranes of ductular reaction (DR) hepatobiliary cells, interlobular bile duct and some hepatic cells were positive for EpCAM expression. Active expression of DR/EpCAM was observed in the majority of noninvasive nodules (50/66, 75.76%); however, expression was absent in the major area of invasion in HCCs (42/46, 91.30%). DR/EpCAM loss in HCCs ≤ 3 cm was higher than in high-grade dysplastic nodules (HGDNs) (P < 0.05), cirrhotic, large regenerative nodules and cirrhosis (P < 0.01). Furthermore, patients (20 HCCs ≤ 3 cm, 26 HCCs > 3 cm, 20 HGDNs) with DR/EpCAM expression had a higher overall survival rate (P < 0.01) and lower early recurrence rate (P < 0.01). DR/EpCAM expression showed a close relationship with DR/CK7 and DR/CK19 expression (P < 0.01). The area under the receiver operating characteristic (ROC) curve of DR/EpCAM was similar to that of DR/CK7 and DR/CK19 (P > 0.05). The diagnostic specificity and diagnostic accuracy were both increased when DR/EpCAM, DR/CK7 and DR/CK19 were combined (P < 0.01). CONCLUSION: DR/EpCAM loss may be a useful marker for determining microinvasion in HCCs ≤ 3 cm, but also for predicting prognosis. PMID:25152593

  14. Neural Cell Adhesion Molecule NrCAM Regulates Semaphorin 3F-Induced Dendritic Spine Remodeling

    PubMed Central

    Demyanenko, Galina P.; Mohan, Vishwa; Zhang, Xuying; Brennaman, Leann H.; Dharbal, Katherine E.S.; Tran, Tracy S.; Manis, Paul B.

    2014-01-01

    Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits. PMID:25143608

  15. Differential up-regulation of circulating soluble and endothelial cell intercellular adhesion molecule-1 in mice.

    PubMed Central

    Komatsu, S.; Flores, S.; Gerritsen, M. E.; Anderson, D. C.; Granger, D. N.

    1997-01-01

    Although circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) are frequently used as an indicator of the severity of different immune, inflammatory, or neoplastic diseases, little is known about the factors that govern plasma sICAM-1 concentration and its relationship to the membranous form of ICAM-1 (mICAM-1) expressed on vascular endothelial cells. Plasma sICAM-1 concentration (measured by enzyme-linked immunosorbent assay) and mICAM-1 expression (measured using the dual radiolabeled monoclonal antibody technique) in different vascular beds (eg, lung, small intestine, and spleen) were monitored in wild-type (C57BL) and ICAM-1-deficient mice, before and after administration of tumor necrosis factor (TNF)-alpha. In wild-type mice, TNF-alpha elicited time-dependent increases in lung and intestine mICAM-1 (plateau achieved at 12 hours), with a corresponding increase in plasma sICAM-1 (peaked at 5 hours and then declined). The initial increases in mICAM-1 and pulmonary leukocyte sequestration (measured as lung myeloperoxidase activity) induced by TNF-alpha preceded any detectable elevation in sICAM-1. In ICAM-1-deficient mice, plasma sICAM-1 was reduced by approximately 70%, with > 95% reductions of mICAM-1 in lung and intestine, and > 75% reduction in splenic accumulation of anti-ICAM-1 antibody. Although TNF-alpha doubled plasma sICAM-1 in ICAM-1-deficient mice, mICAM-1 was unaffected in all tissues. Either splenectomy or pretreatment with cycloheximide resulted in an attenuated TNF-induced increase in sICAM-1, without affecting mICAM-1 expression. These findings indicate that plasma sICAM-1 concentration does not accurately reflect the level of ICAM-1 expression on endothelial cells in different vascular beds. PMID:9212746

  16. R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding

    PubMed Central

    Yan, Xiaocai; Yan, Mingfei; Guo, Yihe; Singh, Gobind; Chen, Yuhong; Yu, Mei; Wang, Demin; Hillery, Cheryl A.; Chan, Andrew M.

    2015-01-01

    The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-subfamily of small guanosine-5’-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (Rras−/−). An examination of the lymphoid organs of Rras−/− mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of Rras−/− mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from Rras−/− mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in Rras−/− T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, Rras−/− T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with Rras−/− T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response. PMID:26710069

  17. Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells

    PubMed Central

    Arabzadeh, Azadeh; Dupaul-Chicoine, Jeremy; Breton, Valérie; Haftchenary, Sina; Yumeen, Sara; Turbide, Claire; Saleh, Maya; McGregor, Kevin; Greenwood, Celia M T; Akavia, Uri David; Blumberg, Richard S; Gunning, Patrick T; Beauchemin, Nicole

    2015-01-01

    Objective Nearly 20%–29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis. Design Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC. Results MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival. Conclusions CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas. PMID:25666195

  18. Cyclic AMP pathway modifies memory through neural cell adhesion molecule alterations in the rat hippocampus.

    PubMed

    Razmi, Ali; Sahebgharani, Mousa; Khani, Mohammad Hossein; Paylakhi, Seyed Hassan; Faizi, Mehrdad; Zarrindast, Mohammad-Reza

    2014-01-01

    Neural Cell Adhesion Molecules (NCAMs) are known to influence memory by affecting neural cell-cell and cell-extracellular matrix junctions. This study investigated the possible role of cAMP pathway in the expression of hippocampal NCAM and its polysialylated derivative (PSA-NCAM). The following pharmacological tools were employed for manipulation of cAMP pathway: a) forskolin; the activator of adenylyl cyclase (AC), b) 8-Br-cAMP; a protein kinase A (PKA) agonist, c) 8-pCPT-2'-O-Me-cAMP; a selective enhancer of exchange protein activated by cAMP (Epac) and d) Rp-cAMP; a PKA inhibitor. Memory acquisition was tested by passive avoidance paradigm after injecting the above compounds for three consecutive days into the CA1 region of dorsal hippocampus of rats. Forskolin and 8-Br-cAMP enhanced memory retrieval while Rp-cAMP significantly reduced memory and NCAM levels. 8-pCPT-2'-O-Me-cAMP failed to alter memory performance or NCAM levels as compared to vehicle. We observed no significant changes in PSA-NCAM, however the expression of St8sia4 and St8sia2 (the polysialyltransferase isoforms) were altered. The mRNA levels of St8sia4 was down-regulated by 8-Br-cAMP, Rp-cAMP and 8-pCPT while forskolin led to almost 3 and 5 fold increase in mRNAs of St8sia2 and St8sia4, respectively. The current insight might endorse the predominant role of PKA as compared to Epac in cAMP pathway in expression of NCAM and memory function. PMID:24901853

  19. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule.

    PubMed

    Yoshida, Tomoyuki; Shiroshima, Tomoko; Lee, Sung-Jin; Yasumura, Misato; Uemura, Takeshi; Chen, Xigui; Iwakura, Yoichiro; Mishina, Masayoshi

    2012-02-22

    Interleukin-1 receptor accessory protein (IL-1RAcP) is the essential component of receptor complexes mediating immune responses to interleukin-1 family cytokines. IL-1RAcP in the brain exists in two isoforms, IL-1RAcP and IL-1RAcPb, differing only in the C-terminal region. Here, we found robust synaptogenic activities of IL-1RAcP in cultured cortical neurons. Knockdown of IL-1RAcP isoforms in cultured cortical neurons suppressed synapse formation as indicated by decreases of active zone protein Bassoon puncta and dendritic protrusions. IL-1RAcP recovered the accumulation of presynaptic Bassoon puncta, while IL-1RAcPb rescued both Bassoon puncta and dendritic protrusions. Consistently, the expression of IL-1RAcP in cortical neurons enhances the accumulation of Bassoon puncta and that of IL-1RAcPb stimulated both Bassoon puncta accumulation and spinogenesis. IL-1RAcP interacted with protein tyrosine phosphatase (PTP) δ through the extracellular domain. Mini-exon peptides in the Ig-like domains of PTPδ splice variants were critical for their efficient binding to IL-1RAcP. The synaptogenic activities of IL-1RAcP isoforms were diminished in cortical neurons from PTPδ knock-out mice. Correspondingly, PTPδ required IL-1RAcPb to induce postsynaptic differentiation. Thus, IL-1RAcPb bidirectionally regulated synapse formation of cortical neurons. Furthermore, the spine densities of cortical and hippocampal pyramidal neurons were reduced in IL-1RAcP knock-out mice lacking both isoforms. These results suggest that IL-1RAcP isoforms function as trans-synaptic cell adhesion molecules in the brain and organize synapse formation. Thus, IL-1RAcP represents an interesting molecular link between immune systems and synapse formation in the brain.

  20. Expression and Localization of Neural Cell Adhesion Molecule and Polysialic Acid during Chick Corneal Development

    PubMed Central

    Schwend, Tyler; Conrad, Gary W.

    2012-01-01

    Purpose. To assay for expression and localization of neural cell adhesion molecule (NCAM) and polysialic acid (polySia) in the chick cornea during embryonic and postnatal development. Methods. Real time quantitative PCR and Western blot analyses were used to determine NCAM expression and polysiaylation in embryonic, hatchling, and adult chick corneas. Immunofluorescence staining for NCAM and polySia was conducted on cryosections of embryonic and adult corneas, whole embryonic corneas, and trigeminal neurons. Results. NCAM and ST8SiaII mRNA transcripts peaked by embryonic day (E)9, remained steady between E10 and E14 and slowly decreased thereafter during embryonic development. Both gene transcripts showed > 190-fold decline in the adult chick cornea compared with E9. In contrast, ST8SiaIV expression gradually decreased 26.5-fold from E6 to E19, increased thereafter, and rose to the early embryonic level in the adult cornea. Western blot analysis revealed NCAM was polysialylated and its expression developmentally changed. Other polysiaylated proteins aside from NCAM were also detected by Western blot analysis. Five NCAM isoforms including NCAM-120, NCAM-180 and three soluble NCAM isoforms with low molecular weights (87–96 kDa) were present in chick corneas, with NCAM-120 being the predominate isoform. NCAM was localized to the epithelium, stroma, and stromal extracellular matrix (ECM) of the embryonic cornea. In stroma, NCAM expression shifted from anterior to posterior stroma during embryonic development and eventually became undetectable in 20-week-old adult cornea. Additionally, both NCAM and polySia were detected on embryonic corneal and pericorneal nerves. Conclusions. NCAM and polySia are expressed and developmentally regulated in chick corneas. Both membrane-associated and soluble NCAM isoforms are expressed in chick corneas. The distributions of NCAM and polySia in cornea and on corneal nerves suggest their potential functions in corneal innervation. PMID

  1. High expression of epithelial cellular adhesion molecule in peritoneal metastasis of gastric cancer.

    PubMed

    Imano, Motohiro; Itoh, Tatsuki; Satou, Takao; Yasuda, Atsushi; Nishiki, Kohei; Kato, Hiroaki; Shiraishi, Osamu; Peng, Ying-Feng; Shinkai, Masayuki; Tsubaki, Masahiro; Yasuda, Takushi; Imamoto, Haruhiko; Nishida, Shozo; Takeyama, Yoshifumi; Furkawa, Hiroshi; Okuno, Kiyokata; Shiozaki, Hitoshi

    2013-12-01

    Intraperitoneally administrated epithelial cellular adhesion molecule (EpCAM) monoclonal antibody is a therapeutic agent in patients with malignant effusion in several types of carcinoma. However, the role of EpCAM in peritoneal metastasis (PM) lesions and primary lesions of gastric cancer (GC) is still unclear. Therefore, in this study, we investigated EpCAM expression in GC patients with PM. We investigated the expression of EpCAM in 35PM lesions and 104 biopsy samples as primary lesions. Immunohistochemical staining was performed using the Ventana Benchmark XT (Roche Diagnostics) system. EpCAM expression was evaluated by calculating the total immunostaining score, which is the product of the proportion score and the intensity score. Overexpression was defined as a total score greater than 4. All PM specimens showed overexpression of EpCAM, and GC cells in both the surface layer and the deep layer of the PM showed a high expression of EpCAM. Meanwhile, in the biopsy sample, the expression of EpCAM ranged from none to strong. The EpCAM score results for PM specimens and biopsy samples were 11.0 ± 2.0 and 6.9 ± 3.9, respectively. The difference between the scores was statistically significant (P < 0.05). The intraperitoneally administrated EpCAM antibody might have a anti-cancer effect in PM lesions of GC. Additionally, it can be assumed that only GC cells which express a high level of EpCAM might metastasize to the peritoneum.

  2. Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression

    PubMed Central

    DeLisser, Horace; Liu, Yong; Desprez, Pierre-Yves; Thor, Ann; Briasouli, Paraskevei; Handumrongkul, Chakrapong; Wilfong, Jonathon; Yount, Garret; Nosrati, Mehdi; Fong, Sylvia; Shtivelman, Emma; Fehrenbach, Melane; Cao, Gaoyuan; Moore, Dan H.; Nayak, Shruti; Liggitt, Denny; Kashani-Sabet, Mohammed; Debs, Robert

    2010-01-01

    Most patients who die from cancer succumb to treatment-refractory advanced metastatic progression. Although the early stages of tumor metastasis result in the formation of clinically silent micrometastatic foci, its later stages primarily reflect the progressive, organ-destructive growth of already advanced metastases. Early-stage metastasis is regulated by multiple factors within tumor cells as well as by the tumor microenvironment (TME). In contrast, the molecular determinants that control advanced metastatic progression remain essentially uncharacterized, precluding the development of therapies targeted against it. Here we show that the TME, functioning in part through platelet endothelial cell adhesion molecule 1 (PECAM-1), drives advanced metastatic progression and is essential for progression through its preterminal end stage. PECAM-1–KO and chimeric mice revealed that its metastasis-promoting effects are mediated specifically through vascular endothelial cell (VEC) PECAM-1. Anti–PECAM-1 mAb therapy suppresses both end-stage metastatic progression and tumor-induced cachexia in tumor-bearing mice. It reduces proliferation, but not angiogenesis or apoptosis, within advanced tumor metastases. Because its antimetastatic effects are mediated by binding to VEC rather than to tumor cells, anti–PECAM-1 mAb appears to act independently of tumor type. A modified 3D coculture assay showed that anti–PECAM-1 mAb inhibits the proliferation of PECAM-1–negative tumor cells by altering the concentrations of secreted factors. Our studies indicate that a complex interplay between elements of the TME and advanced tumor metastases directs end-stage metastatic progression. They also suggest that some therapeutic interventions may target late-stage metastases specifically. mAb-based targeting of PECAM-1 represents a TME-targeted therapeutic approach that suppresses the end stages of metastatic progression, until now a refractory clinical entity. PMID:20926749

  3. Dihydromunduletone Is a Small-Molecule Selective Adhesion G Protein-Coupled Receptor Antagonist.

    PubMed

    Stoveken, Hannah M; Bahr, Laura L; Anders, M W; Wojtovich, Andrew P; Smrcka, Alan V; Tall, Gregory G

    2016-09-01

    Adhesion G protein-coupled receptors (aGPCRs) have emerging roles in development and tissue maintenance and is the most prevalent GPCR subclass mutated in human cancers, but to date, no drugs have been developed to target them in any disease. aGPCR extracellular domains contain a conserved subdomain that mediates self-cleavage proximal to the start of the 7-transmembrane domain (7TM). The two receptor protomers, extracellular domain and amino terminal fragment (NTF), and the 7TM or C-terminal fragment remain noncovalently bound at the plasma membrane in a low-activity state. We recently demonstrated that NTF dissociation liberates the 7TM N-terminal stalk, which acts as a tethered-peptide agonist permitting receptor-dependent heterotrimeric G protein activation. In many cases, natural aGPCR ligands are extracellular matrix proteins that dissociate the NTF to reveal the tethered agonist. Given the perceived difficulty in modifying extracellular matrix proteins to create aGPCR probes, we developed a serum response element (SRE)-luciferase-based screening approach to identify GPR56/ADGRG1 small-molecule inhibitors. A 2000-compound library comprising known drugs and natural products was screened for GPR56-dependent SRE activation inhibitors that did not inhibit constitutively active Gα13-dependent SRE activation. Dihydromunduletone (DHM), a rotenoid derivative, was validated using cell-free aGPCR/heterotrimeric G protein guanosine 5'-3-O-(thio)triphosphate binding reconstitution assays. DHM inhibited GPR56 and GPR114/ADGRG5, which have similar tethered agonists, but not the aGPCR GPR110/ADGRF1, M3 muscarinic acetylcholine, or β2 adrenergic GPCRs. DHM inhibited tethered peptide agonist-stimulated and synthetic peptide agonist-stimulated GPR56 but did not inhibit basal activity, demonstrating that it antagonizes the peptide agonist. DHM is a novel aGPCR antagonist and potentially useful chemical probe that may be developed as a future aGPCR therapeutic. PMID:27338081

  4. Loss of cell adhesion molecule CHL1 improves homeostatic adaptation and survival in hypoxic stress.

    PubMed

    Huang, X; Sun, J; Rong, W; Zhao, T; Li, D H; Ding, X; Wu, L Y; Wu, K; Schachner, M; Xiao, Z C; Zhu, L L; Fan, M

    2013-01-01

    Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1(-/-)) mice. We found that, compared with wild-type littermates, CHL1(-/-) mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1(-/-) mice appeared to be increased compared with CHL1(+/+) mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1(-/-) mice compared with CHL1(+/+) mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1(-/-) mice were also significantly higher than those of CHL1(+/+) mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH. PMID:23949217

  5. Expression of intercellular adhesive molecule-1 in liver cancer tissues andliver cancer metastasis

    PubMed Central

    Sun, Jing-Jing; Zhou, Xin-Da; Zhou, Ge; Liu, Yin-Kun

    1998-01-01

    AIM: To study the relationship between intercellular adhesive molecule-1 (ICAM-1) and liver cancer metastasis and to search for factors to predict metastasis of liver cancer. METHODS: ICAM-1 expression in fresh tissues of normal liver and hepatocellular cancer (HCC) was examined by immunoperoxidase staining. The expression of ICAM-1 in human hepatoma, tumor surrounding tissues and normal livers were semiquantitatively analyzed by Dot immuno blot. Tissue ICAM-1 expression at mRNA level was detected by Northern blot. RESULTS: All 6 cases of normal liver samples were negative in anti-ICAM-1 immunohistochemical staining, 80.0% (36/45) of HCC presented various ICAM-1 expression. The number of positive cells was a little higher in large tumors, tumors with intact capsule and metastasis, but there was no significant difference. Two cases with cancer embolus also had high ICAM-1 expression. ICAM-1 concentration in HCC (13.43 ± 0.09) was higher than that in tumor surrounding tissues (5.89 ± 0.17, P < 0.01) and normal livers (4.27 ± 0.21, P < 0.01). It was also higher in metastasis group (20.24 ± 0.30) than in nonmetastasis group (10.23 ± 0.12, P < 0.05). Northern blot analysis revealed that ICAM-1 expression at mRNA level was also higher in HCC and cancer embolus than that in tumor surrounding tissues and normal livers. CONCLUSION: Tissue ICAM-1 could indicate the growth and metastasis of HCC, and may be an index that can predict liver cancer metastasis. PMID:11819275

  6. Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells

    PubMed Central

    1993-01-01

    Attachment of circulating tumor cells to endothelial cell adhesion molecules restricted to select vascular compartments is thought to be responsible for site-specific metastasis. Lung-metastatic rat R3230AC- MET breast and RPC-2 prostate carcinoma cells bound outside-out endothelial cell membrane vesicles, prepared by perfusion of the rat lung vasculature with a low-strength formaldehyde solution, in significantly higher numbers than their nonmetastatic counterparts R3230AC-LR and RPC-LR. In contrast, vesicles derived from the vasculature of a nonmetastasized organ (e.g., hind leg muscle) showed no binding preference for either of the four tumor cell lines. Lung- derived endothelial vesicles were used here to generate mAbs against lung endothelial cell adhesion molecules. The first group of mice were actively immunized against lung endothelial vesicles, whereas the second group was injected with syngeneic mouse antiserum against leg endothelial vesicles before active immunization with lung endothelial vesicles. 17 hybridoma supernatants obtained from the two fusions bound lung vesicles with at least a 10-fold higher affinity than leg vesicles. Seven (four obtained by a passive/active immunization protocol) stained rat capillary endothelia. One mAb, mAb 8.6A3, inhibited specific adhesion of lung-derived vesicles to lung-metastatic breast and prostate carcinoma cells. Purification of the antigen (endothelial cell adhesion molecule) from rat lung extracts revealed a protein with a 110-kD mol wt. NH2-terminal sequencing established identity with dipeptidyl peptidase IV which had been reported to serve as a fibronectin-binding protein. These results indicate that vesicles obtained from in situ perfused organs are a convenient immunogen for the production of antibodies to compartment-specific endothelial cell surface molecules, and reinforce the concept that endothelial cell surface components are selectively recognized by circulating cancer cells during metastasis

  7. [Pathogenetic and clinical significance of the adhesion molecule expression on T cells of the lung in sarcoid alveolitis].

    PubMed

    Gerli, R; Galandrini, R; Agea, E; Bini, P; Tognellini, R

    1990-01-01

    A double immunofluorescence analysis of CD4+ cell population from bronchoalveolar lavage (BAL) fluid samples of patients with active pulmonary sarcoidosis was carried out. The results showed that, unlike BAL and peripheral blood CD4+ cells of healthy subjects, almost all BAL CD4+ cells of the patients highly express, besides CDw29 antigen, LFA-1 and ICAM-1 adhesion molecules. The co-expression of these molecules on BAL CD4+ cells during high intensity sarcoid alveolitis could represent a marker of immunological memory. The relevant pathogenetic and clinical implications of this observation are discussed. PMID:2199744

  8. Drosophila chaoptin, a member of the leucine-rich repeat family, is a photoreceptor cell-specific adhesion molecule.

    PubMed Central

    Krantz, D E; Zipursky, S L

    1990-01-01

    Drosophila chaoptin, required for photoreceptor cell morphogenesis, is a member of the leucine-rich repeat family of proteins. On the basis of biochemical and genetic analyses we previously proposed that chaoptin might function as a cell adhesion molecule. To test this hypothesis, chaoptin cDNA driven by the hsp 70 promoter was transfected into non-self-adherent Drosophila Schneider line 2 (S2) cells. Following heat shock induction of chaoptin expression, the transfected S2 cells formed multicellular aggregates. Mixing experiments of chaoptin expressing and non-expressing cells suggest that chaoptin expressing cells adhere homotypically. Previously it was shown that chaoptin is exclusively localized to photoreceptor cells. Thus, chaoptin is a cell-type-specific adhesion molecule. Biochemical analyses presented in this paper demonstrate that chaoptin is linked to the extracellular surface of the plasma membrane by covalent attachment to glycosyl-phosphatidylinositol. We propose that chaoptin and several other members of the leucine-rich repeat family of proteins define a new class of cell adhesion molecules. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 8. PMID:2189727

  9. Heterotypic binding between neuronal membrane vesicles and glial cells is mediated by a specific cell adhesion molecule

    PubMed Central

    1984-01-01

    By means of a multistage quantitative assay, we have identified a new kind of cell adhesion molecule (CAM) on neuronal cells of the chick embryo that is involved in their adhesion to glial cells. The assay used to identify the binding component (which we name neuron-glia CAM or Ng-CAM) was designed to distinguish between homotypic binding (e.g., neuron to neuron) and heterotypic binding (e.g., neuron to glia). This distinction was essential because a single neuron might simultaneously carry different CAMs separately mediating each of these interactions. The adhesion of neuronal cells to glial cells in vitro was previously found to be inhibited by Fab' fragments prepared from antisera against neuronal membranes but not by Fab' fragments against N-CAM, the neural cell adhesion molecule. This suggested that neuron-glia adhesion is mediated by specific cell surface molecules different from previously isolated CAMs . To verify that this was the case, neuronal membrane vesicles were labeled internally with 6-carboxyfluorescein and externally with 125I-labeled antibodies to N-CAM to block their homotypic binding. Labeled vesicles bound to glial cells but not to fibroblasts during a 30-min incubation period. The specific binding of the neuronal vesicles to glial cells was measured by fluorescence microscopy and gamma spectroscopy of the 125I label. Binding increased with increasing concentrations of both glial cells and neuronal vesicles. Fab' fragments prepared from anti-neuronal membrane sera that inhibited binding between neurons and glial cells were also found to inhibit neuronal vesicle binding to glial cells. The inhibitory activity of the Fab' fragments was depleted by preincubation with neuronal cells but not with glial cells. Trypsin treatment of neuronal membrane vesicles released material that neutralized Fab' fragment inhibition; after chromatography, neutralizing activity was enriched 50- fold. This fraction was injected into mice to produce monoclonal

  10. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion

    PubMed Central

    Oberoi, Raghav; Schuett, Jutta; Schuett, Harald; Koch, Ann-Kathrin; Luchtefeld, Maren

    2016-01-01

    Objective It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab–which is approved for several inflammatory disorders–on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. Methods and Results Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. Conclusion Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID:27467817

  11. Different cytokeratin and neuronal cell adhesion molecule staining patterns in focal nodular hyperplasia and hepatic adenoma and their significance

    PubMed Central

    Iyer, Anita; Robert, Marie E.; Bifulco, Carlo B.; Salem, Ronald R.; Jain, Dhanpat

    2013-01-01

    Summary Differentiating focal nodular hyperplasia from hepatic adenoma can be challenging. Cytokeratin 7, neuronal cell adhesion molecule, and cytokeratin 19 are differentially expressed in hepatocytes, biliary epithelium, and possibly hepatic progenitor/stem cells. CD34 is known to have altered expression patterns in the hepatic endothelium in conditions associated with abnormal perfusion and in hepatocellular carcinoma. The purpose of this study was to examine the expression pattern of these markers in focal nodular hyperplasia and hepatic adenoma and assess their diagnostic use. Ten resection specimens each of hepatic adenoma and focal nodular hyperplasia (including a case of telangiectatic focal nodular hyperplasia) were selected for the study. Immunohistochemical analysis was performed using antibodies against cytokeratin 7, cytokeratin 19, neuronal cell adhesion molecule, and CD34 on formalin-fixed, paraffin-embedded sections from each case. The staining patterns and intensity for each marker were analyzed. In hepatic adenoma, the cytokeratin 7 stain revealed strong positivity in hepatocytes in patches, with a gradual decrease in the staining intensity as the cells differentiated towards mature hepatocytes. Although bile ducts were typically absent in hepatic adenoma, occasional ductules could be identified with cytokeratin 7 stain. In focal nodular hyperplasia, cytokeratin 7 showed strong staining of the biliary epithelium within the fibrous septa and staining of the peripheral hepatocytes of most lobules that was focal and weaker than hepatic adenoma. Cytokeratin 19 and neuronal cell adhesion molecule showed patchy and moderate staining in the biliary epithelium of the ductules in focal nodular hyperplasia. While in the hepatic adenoma, cytokeratin 19 showed only rare positivity in occasional cells within ductules, and neuronal cell adhesion molecule marked occasional isolated cells in the lesion. CD34 showed staining of sinusoids in the inflow areas

  12. Secreted adhesion molecules of Strongyloides venezuelensis are produced by oesophageal glands and are components of the wall of tunnels constructed by adult worms in the host intestinal mucosa.

    PubMed

    Maruyama, H; El-Malky, M; Kumagai, T; Ohta, N

    2003-02-01

    The parasitic female of Strongyloides venezuelensis keeps invading the epithelial layer of the host intestinal mucosa. Upon invasion, it adheres to the surface of the intestinal epithelial cells with adhesion molecules secreted from the mouth. It has been demonstrated that S. venezuelensis are expelled from the intestine because mucosal mast cells inhibit the attachment of adult worms to the mucosal surface. In the present study, we generated specific antibodies against secreted adhesion molecules to investigate their function in vivo, because these molecules have been demonstrated only in vitro in spite of the importance in the infection processes. A mouse monoclonal antibody specific to S. venezuelensis adhesion molecules inhibited the attachment of adult worms to plastic dishes and the binding of adhesion molecules to rat intestinal epithelial cells. Immunohistochemical study revealed that adhesion molecules were produced by oesophageal glands and were continuously secreted in vivo to line the wall of the tunnels formed by adult worms in the intestinal mucosa. Our findings indicate that adhesion molecules play essential roles in the infection processes of S. venezuelensis in the host intestine. PMID:12636354

  13. Expression of intercellular adhesion molecule-1 on macrophages in vitro as a marker of activation.

    PubMed

    Bernatchez, S F; Atkinson, M R; Parks, P J

    1997-10-01

    Macrophage activation is a major component of wound healing. It also determines the extent of inflammatory reactions and the response of the body to implanted materials. We have previously shown, using an in vitro model, that the extent of spreading of macrophages on different materials is a marker of activation, and that a soluble inducer has a dose-response effect on the secretion of cytokines in the culture medium. This work investigates the expression of three different cell surface markers [macrophages MAC-1, MAC-3 and intercellular adhesion molecule-1 (ICAM-1)] on macrophages in vitro using confocal microscopy and shows that ICAM-1 is also a marker of macrophage activation in this model. We observed increased amounts of ICAM-1 on activated macrophages compared to unactivated macrophages, whereas MAC-1 and MAC-3 were either expressed constitutively or demonstrated no quantitative change in expression after activation under the same experimental conditions. We also tested the expression of ICAM-1 with various concentrations of soluble inducers (lipopolysaccharide, 0.001, 0.01, 0.1, 1 and 10 micrograms ml-1. S-27609, 0.1, 0.25, 0.5, 1, 2 and 3 micrograms ml-1 and on a sheet of polylactic acid alone or in combination with soluble inducers. All doses of soluble inducers induced the expression of ICAM-1 on cells grown in glass chamber slides. The induction was not dose related but seemed to work rather in an on-off manner. There was no effect of material on ICAM-1 expression on the cell surface when no soluble inducer was added. This was similar to cytokine secretion, which was not induced by our material alone. When either lipopolysaccharide or S-27609 was used in combination with the material, there was an increase in the average measured intensity of ICAM-1. In this in vitro model, ICAM-1 staining as measured by confocal microscopy is a marker for macrophage activation. Our results suggest that the extent of macrophage activation as measured by ICAM-1 and by

  14. The Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) Genes among Clinical Isolates of Staphylococcus aureus from Hospitalized Children

    PubMed Central

    Ghasemian, Abdolmajid; Najar Peerayeh, Shahin; Bakhshi, Bita; Mirzaee, Mohsen

    2015-01-01

    Background: Isolates of Staphylococcus aureus express a myriad of adhesive surface proteins that play important role in colonization of the bacteria on nasal and skin surfaces, beginning the process of pathogenesis. The aim of this study was to screen several of the Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) genes among the isolate of S. aureus from hospitalized children. Methods: A total of 22 S. aureus isolates were collected from hospitalized children in Tehran from 2012 to 2013. Detection of the mecA and several adhesive surface proteins genes including clfA, B (encoding clumping factors A, B); fnbA, B (encoding finronectin binding proteins A, B); fib (encoding fibrinogen binding protein); eno (encoding laminin binding protein); cna (encoding collagen binding protein); ebps (encoding elastin binding protein) and bbp (encoding bone sialo-protein binding protein), was performed by PCR. Results: The clfAB genes were detected among all the isolates. The prevalence of fnbA, fnbB, fib, eno, cna, ebps and bbp was 63%, 6%, 50%, 59%, 82%, 63%, 9% and 0%, respectively. Conclusion: The high prevalence of these genes is important for future plans in vaccine designation. MRSA and MSSA isolates similarly can produce adhesive surface proteins for colonization. PMID:26351495

  15. Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation

    SciTech Connect

    Lee, Gloria; Lo, Annie; Short, Sarah A.; Mankelow, Tosti J.; Spring, Frances; Parsons, Stephen F.; Mohandas, Narla; Anstee, David J.; Chasis, Joel Anne

    2006-02-15

    Erythroid progenitors differentiate in erythroblastic islands, bone marrow niches composed of erythroblasts surrounding a central macrophage. Evidence suggests that within islands adhesive interactions regulate erythropoiesis and apoptosis. We are exploring whether erythroid intercellular adhesion molecule-4 (ICAM-4), animmunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counter receptors. Since macrophages express alpha V, ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knockout mice and developed quantitative, live cell techniques for harvesting intact islands and for reforming islands in vitro. We observed a 47 percent decrease in islands reconstituted from ICAM-4 null marrow compared to wild type. We also found a striking decrease in islands formed in vivo in knockout mice. Further, peptides that block ICAM-4 alpha V adhesion produced a 53-57 percent decrease in reconstituted islands, strongly suggesting that ICAM-4 binding to macrophage alpha V functions in island integrity. Importantly, we documented that alpha V integrin is expressed in macrophages isolated from erythro blastic islands. Collectively, these data provide convincing evidence that ICAM-4 is critical in erythroblastic island formation via ICAM-4/alpha V adhesion and also demonstrate that the novel experimental strategies we developed will be valuable in exploring molecular mechanisms of erythroblastic island formation and their functional role in regulating erythropoiesis.

  16. Obstructive jaundice causes reduced expression of polymorphonuclear leucocyte adhesion molecules and a depressed response to bacterial wall products in vitro.

    PubMed Central

    Plusa, S; Webster, N; Primrose, J

    1996-01-01

    BACKGROUND--Obstructive jaundice is associated with an increased incidence of infection and endotoxaemia, which may result from impaired host immunity. Neutrophil adhesion to vascular endothelium is a key part of the inflammatory response. AIMS--To investigate neutrophil adhesion molecule expression and activation in obstructive jaundice. PATIENTS--Nine adult patients with obstructive jaundice and 11 control subjects. METHODS--The expression of the neutrophil adhesion receptors L-selectin, CD11a, CD11b, CD11c, and CD15 was determined using flow cytometry. CD11b expression in response to stimulation with fMLP and endotoxin was measured. RESULTS--The basal expression of L-selectin, CD11a, and CD15 was significantly decreased in jaundiced patients (p < 0.05) and the expression of CD11b in response to stimulation with fMLP and endotoxin was significantly impaired in the jaundiced group. Endotoxin stimulation without plasma did not reverse the impaired response showing that it is not caused by endotoxin inactivation by plasma proteins. CONCLUSIONS--Neutrophils from patients with obstructive jaundice show decreased adhesion receptor expression and an impaired response to stimulation with bacterial products. This cellular dysfunction may be responsible for the high incidence of septic complications in these patients. PMID:8707129

  17. Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-κB in endothelial cells.

    PubMed

    Tang, Norina; Sun, Bing; Gupta, Archana; Rempel, Hans; Pulliam, Lynn

    2016-09-01

    HIV-infected individuals have activated monocytes with an IFNα phenotype and elevated levels of circulating LPS. These individuals also have a risk of premature cardiovascular disease. The effect of activated monocyte exosomes (Exos) on endothelial cells is unknown. To determine whether Exos from immune-activated monocytes could alter endothelial cell expression and contribute to monocyte/macrophage transmigration and adhesion, we isolated Exos from monocytes stimulated with IFNα, LPS, or both (I/L). We show that monocyte Exos contain different inflammatory microRNA cargo depending on stimulation. When LPS Exos or I/L Exos were added to HUVECs, we found a significant increase in adhesion molecule ICAM-1, chemokine ligand (CCL)-2, and cytokine IL-6 mRNAs and proteins compared with cells treated with IFNα Exos or Exos derived from unstimulated monocytes. Inhibition of transcription factor NF-κB, a common inflammatory cytokine pathway, prevented induction of CCL2, IL6, and ICAM1 Inhibition of TLR4 resulted in differential blockage of the targets. Our results demonstrate for the first time that primary human monocyte Exos enter endothelial cells and cause dysfunction via the TLR4 and NF-κB pathways, which may contribute to heart disease in HIV infection and other diseases involving chronic immune activation.-Tang, N., Sun, B., Gupta, A., Rempel, H., Pulliam, L. Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-κB in endothelial cells. PMID:27226520

  18. Epidermal Expression of Intercellular Adhesion Molecule 1 is Not a Primary Inducer of Cutaneous Inflammation in Transgenic Mice

    NASA Astrophysics Data System (ADS)

    Williams, Ifor R.; Kupper, Thomas S.

    1994-10-01

    Keratinocytes at sites of cutaneous inflammation have increased expression of intercellular adhesion molecule 1 (ICAM-1), a cytokine-inducible adhesion molecule which binds the leukocyte integrins LFA-1 and Mac-1. Transgenic mice were prepared in which the expression of mouse ICAM-1 was targeted to basal keratinocytes by using the human K14 keratin promoter. The level of constitutive expression attained in the transgenic mice exceeded the peak level of ICAM-1 expression induced on nontransgenic mouse keratinocytes in vitro by optimal combinations of interferon γ and tumor necrosis factor α or in vivo by proinflammatory stimuli such as phorbol 12-myristate 13-acetate. In vitro adhesion assays demonstrated that cultured transgenic keratinocytes were superior to normal keratinocytes as a substrate for the LFA-1-dependent binding of mouse T cells, confirming that the transgene-encoded ICAM-1 was expressed in a functional form. However, the high level of constitutive ICAM-1 expression achieved on keratinocytes in vivo in these transgenic mice did not result in additional recruitment of CD45^+ leukocytes into transgenic epidermis, nor did it elicit dermal inflammation. Keratinocyte ICAM-1 expression also did not potentiate contact-hypersensitivity reactions to epicutaneous application of haptens. The absence of a spontaneous phenotype in these transgenic mice was not the result of increased levels of soluble ICAM-1, since serum levels of soluble ICAM-1 were equal in transgenic mice and controls. We conclude that elevated ICAM-1 expression on keratinocytes cannot act independently to influence leukocyte trafficking and elicit cutaneous inflammation.

  19. Ligation of MHC class I and class II molecules can lead to heterologous desensitization of signal transduction pathways that regulate homotypic adhesion in human lymphocytes.

    PubMed

    Wagner, N; Engel, P; Vega, M; Tedder, T F

    1994-06-01

    Engagement of lymphocyte MHC class I and class II Ags activates an array of intracellular signal transduction pathways that up-regulates the activity of cell-surface adhesion receptors, resulting in homotypic cell-cell aggregation. In this study, engagement of MHC class I and class II molecules with specific mAbs was shown to also inhibit lymphocyte homotypic adhesion. Two mAbs reactive with class II Ag, homotypic adhesion blocking mAb (HAB)-2, and HAB-3, and one mAb reactive with class I Ag, HAB-4, were generated that inhibited homotypic adhesion of activated lymphocytes and B and T cell lines at concentrations as low as 0.1 microgram/ml. Binding of these mAbs resulted in heterologous desensitization of other surface signal transduction molecules as homotypic adhesion induced through class I, class II, CD19, CD20, CD39, CD40, Leu-13, and PMA was also inhibited. The spontaneous adhesion exhibited by some cell lines was also abrogated by binding of these mAbs. Abs that either induced, blocked, or had no effect on adhesion bound to distinct epitopes on class I, whereas the anti-class II mAbs recognized either distinct or overlapping epitopes. Thus, engagement of distinct epitopes on MHC molecules can result in homologous or heterologous desensitization of cell-surface signaling molecules. The induction or inhibition of homotypic adhesion through class I molecules did not require the presence of the cytoplasmic domain, as deletion of this portion of the class I molecule had no effect. In contrast, the transmembrane region was essential for signal transduction as the mAbs binding to a chimeric molecule in which the transmembrane and cytoplasmic domains of class I were exchanged with those of the HB15 molecule did not induce or inhibit homotypic adhesion. Although this report is the first demonstration that homotypic adhesion can be influenced in a negative manner through MHC molecules, these findings demonstrate a considerable level of cross-talk between MHC molecules

  20. S fimbriae of uropathogenic Escherichia coli bind to primary human renal proximal tubular epithelial cells but do not induce expression of intercellular adhesion molecule 1.

    PubMed Central

    Kreft, B; Placzek, M; Doehn, C; Hacker, J; Schmidt, G; Wasenauer, G; Daha, M R; van der Woude, F J; Sack, K

    1995-01-01

    We have recently reported an increase of expression of the intercellular adhesion molecule 1 by renal carcinoma cells in response to S fimbriae of Escherichia coli. Now we demonstrate that E. coli expressing S and P fimbriae strongly binds to human proximal tubular epithelial cells. However, in primary and simian virus 40-transfected renal tubular epithelial cells S fimbriae do not enhance the expression of intercellular adhesion molecule 1. PMID:7622256

  1. Effect of Cell Adhesion Molecules on the Neurite Outgrowth of Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons.

    PubMed

    Peng, Su-Ping; Schachner, Melitta; Boddeke, Erik; Copray, Sjef

    2016-04-01

    Intrastriatal transplantation of dopaminergic neurons has been shown to be a potentially very effective therapeutic approach for the treatment of Parkinson's disease (PD). With the detection of induced pluripotent stem cells (iPSCs), an unlimited source of autologous dopaminergic (DA) neurons became available. Although the iPSC-derived dopaminergic neurons exhibited most of the fundamental dopaminergic characteristics, detailed analysis and comparison with primary DA neurons have shown some aberrations in the expression of genes involved in neuronal development and neurite outgrowth. The limited outgrowth of the iPSC-derived DA neurons may hamper their potential application in cell transplantation therapy for PD. In the present study, we examined whether the forced expression of L1 cell adhesion molecule (L1CAM) and polysialylated neuronal cell adhesion molecule (PSA-NCAM), via gene transduction, can promote the neurite formation and outgrowth of iPSC-derived DA neurons. In cultures on astrocyte layers, both adhesion factors significantly increased neurite formation of the adhesion factor overexpressing iPSC-derived DA neurons in comparison to control iPSC-derived DA neurons. The same tendency was observed when the DA neurons were plated on postnatal organotypic striatal slices; however, this effect did not reach statistical significance. Next, we examined the neurite outgrowth of the L1CAM- or PSA-NCAM-overexpressing iPSC-derived DA neurons after implantation in the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats, the animal model for PD. Like the outgrowth on the organotypic striatal slices, no significant L1CAM- and PSA-NCAM-enforced neurite outgrowth of the implanted DA neurons was observed. Apparently, induced expression of L1CAM or PSA-NCAM in the iPSC-derived DA neurons cannot completely restore the neurite outgrowth potential that was reduced in these DA neurons as a consequence of epigenetic aberrations resulting from the i

  2. Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway

    SciTech Connect

    Oesterling, Elizabeth; Toborek, Michal; Hennig, Bernhard

    2008-10-15

    Toxicologic and epidemiologic studies have linked benzo[a]pyrene (B[a]P) exposure with cardiovascular diseases such as atherosclerosis. The mechanisms of action leading to these diseases have not been fully understood. One key step in the development of atherosclerosis is vascular endothelial dysfunction, which is characterized by increased adhesiveness. To determine if B[a]P could lead to increased endothelial adhesiveness, the effects of B[a]P on human endothelial cell intercellular adhesion molecule-1 (ICAM-1) expression was investigated. B[a]P was able to increase ICAM-1 protein only after pretreatment with the aryl hydrocarbon receptor (AhR) agonist {beta}-naphthoflavone ({beta}-NF). Knockdown of AhR by siRNA or treatment with AhR antagonist {alpha}-naphthoflavone ({alpha}-NF) eliminated the induction of ICAM-1 from B[a]P, confirming the necessity of AhR in this process. Likewise, B[a]P only increased monocyte adhesion to the vascular endothelium when cells were pretreated with {beta}-NF. Experiments were done to define a signaling mechanism. B[a]P increased phosphorylation of MEK and p38-MAPK, and inhibitors to these proteins blunted the ICAM-1 induction. B[a]P was also able to increase AP-1 DNA binding and phosphorylation of cJun. Phosphorylation of cJun was disrupted by MEK and p38-MAPK inhibitors linking the signaling cascade. Finally, the importance of membrane microdomains, caveolae, was demonstrated by knockdown of the structural protein caveolin-1. Disruption of caveolae eliminated the B[a]P-induced ICAM-1 expression. These data suggest a possible pro-inflammatory mechanism of action of B[a]P involving caveolae, leading to increased vascular endothelial adhesiveness, and this inflammation may be a critical step in the development of B[a]P-induced atherosclerosis.

  3. MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

    PubMed Central

    Lu, Cecilia S.; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

    2014-01-01

    Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins. PMID:25135978

  4. Polysialic acid-neural cell adhesion molecule in brain plasticity: from synapses to integration of new neurons.

    PubMed

    Gascon, Eduardo; Vutskits, Laszlo; Kiss, Jozsef Zoltan

    2007-11-01

    Isoforms of the neuronal cell adhesion molecule (NCAM) carrying the linear homopolymer of alpha 2,8-linked sialic acid (polysialic acid, PSA) have emerged as particularly attractive candidates for promoting plasticity in the nervous system. The large negatively charged PSA chain of NCAM is postulated to be a spacer that reduces adhesion forces between cells allowing dynamic changes in membrane contacts. Accumulating evidence also suggests that PSA-NCAM-mediated interactions lead to activation of intracellular signaling cascades that are fundamental to the biological functions of the molecule. An important role of PSA-NCAM appears to be during development, when its expression level is high and where it contributes to the regulation of cell shape, growth or migration. However, PSA-NCAM does persist in adult brain structures such as the hippocampus that display a high degree of plasticity where it is involved in activity-induced synaptic plasticity. Recent advances in the field of PSA-NCAM research have not only consolidated the importance of this molecule in plasticity processes but also suggest a role for PSA-NCAM in the regulation of higher cognitive functions and psychiatric disorders. In this review, we discuss the role and mode of actions of PSA-NCAM in structural plasticity as well as its potential link to cognitive processes.

  5. Biogenesis and fate of the cell-cell adhesion molecule, agglutinin, during gametogenesis and fertilization of Chlamydomonas reinhardtii

    SciTech Connect

    Hunnicutt, G.R.

    1989-01-01

    Fertilization in Chlamydomonas begins with the species-specific recognition and adhesion between gametes of opposite mating types via agglutinin molecules on the flagellar surface. This adhesion generates a cAMP-mediated sexual signal that initiates the subsequent events of call wall release, mating structure activation, and cell fusion. Although flagella of paired gametes remain attached to each other until the zygote forms, the process is dynamic. Engaged agglutinins rapidly become inactivated and turnover, requiring the constant supply of new agglutinins to replace the lost molecules. A population of cell body associated agglutinins has been postulated to the pool of agglutinins recruited during this turnover. Cell body agglutinins, therefore were identified, purified, localized within the cells and compared to flagellar agglutinins. The relationship between these two agglutinin populations was also examined. Cell body agglutinins were biochemically indistinguishable from the flagellar form with respect to their M{sub r}, sedimentation coefficient, and hydrophobicity elution properties. Functionally, however, these molecules were inactive in situ. The calculated surface density of agglutinins in the cell body and flagellar domains was similar and thus could not explain their functional difference, but two domains contiguous and yet distinctive suggested they may be separated by a functional barrier. To test this, a method was developed, using a monoclonal antibody and cycloheximide, that removed the flagellar agglutinins so movement between the domains could be monitored. Mobilization of agglutinins onto the flagella did not occur unless sexual signaling was induced with cAMP and papaverine.

  6. MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.

    PubMed

    Lu, Cecilia S; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

    2014-09-26

    Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

  7. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors.

    PubMed

    Rao, Chandra G; Chianese, David; Doyle, Gerald V; Miller, M Craig; Russell, Thomas; Sanders, Renouard A; Terstappen, Leon W M M

    2005-07-01

    The epithelial cell adhesion molecule (EpCAM) is involved in homophilic cell-cell adhesion in normal epithelia and is frequently overexpressed in primary and metastatic adenocarcinomas. It has been postulated that during detachment and dissemination of tumor cells, EpCAM may be down-regulated. Circulating tumor cells (CTC) may demonstrate this phenomenon as they have successfully escaped their local microenvironment and entered the circulation. EpCAM expression of CTC was compared to tumor cells in paraffin-embedded tissue arrays containing various benign diseases and carcinomas. EpCAM expression on CTC was determined by flow cytometry (FCM) and by immunohistochemistry (IHC) in paraffin-embedded tissue. To permit comparison of FCM results to those derived by IHC, EpCAM was quantified on cancer cell lines by FCM and then paraffin-embedded cell-blocks of these lines were used as staining guides for IHC analysis of tissue arrays. By IHC, 97% (384/397) of solid tissues analyzed had detectable EpCAM, with 72% of tissues showing antigen expression levels of > or =400,000 EpCAM molecules per cell. FCM analysis of CTC from 100 metastatic carcinoma patients with > or =2 CTC/90 microl blood showed EpCAM expression ranging from 9,900 to 246,000 (mean 49,700) antigens per cell. EpCAM expression was approximately 10-fold lower on CTC as compared to primary and metastatic tissues, suggesting that EpCAM expression is transient and dependent upon the local micro-environment. This supports the hypothesis that this adhesion molecule is down-regulated on carcinoma cells in the circulation.

  8. Chronic Restraint Stress Induces an Isoform-Specific Regulation on the Neural Cell Adhesion Molecule in the Hippocampus

    PubMed Central

    Touyarot, K.; Sandi, C.

    2002-01-01

    Existing evidence indicates that 21-days exposure of rats to restraint stress induces dendritic atrophy in pyramidal cells of the hippocampus. This phenomenon has been related to altered performance in hippocampal-dependent learning tasks. Prior studies have shown that hippocampal expression of cell adhesion molecules is modified by such stress treatment, with the neural cell adhesion molecule (NCAM) decreasing and L1 increasing, their expression, at both the mRNA and protein levels. Given that NCAM comprises several isoforms, we investigated here whether chronic stress might differentially affect the expression of the three major isoforms (NCAM-120, NCAM-140, NCAM-180) in the hippocampus. In addition, as glucocorticoids have been implicated in the deleterious effects induced by chronic stress, we also evaluated plasma corticosterone levels and the hippocampal expression of the corticosteroid mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The results showed that the protein concentration of the NCAM-140 isoform decreased in the hippoampus of stressed rats. This effect was isoform-specific, because NCAM-120 and NCAM-180 levels were not significantly modified. In addition, whereas basal levels of plasma corticosterone tended to be increased, MR and GR concentrations were not significantly altered. Although possible changes in NCAM-120, NCAM-180 and corticosteroid receptors at earlier time points of the stress period cannot be ignored; this study suggests that a down-regulation of NCAM-140 might be implicated in the structural alterations consistently shown to be induced in the hippocampus by chronic stress exposure. As NCAM-140 is involved in cell-cell adhesion and neurite outgrowth, these findings suggest that this molecule might be one of the molecular mechanisms involved in the complex interactions among neurodegeneration-related events. PMID:12757368

  9. Adhesion through L-selectin requires a threshold hydrodynamic shear

    NASA Astrophysics Data System (ADS)

    Finger, Erik B.; Purl, Kamal D.; Alon, Ronen; Lawrence, Michael B.; von Andrian, Ulrich H.; Springer, Timothy A.

    1996-01-01

    SELECTINS are cell adhesion molecules that bind carbohydrate ligands and promote interaction between leukocytes and the vessel wall in vascular shear flow1,2. Selectin-ligand bonds have high mechanical strength, allowing initial tethering to the vessel wall through one or few bonds, and have fast on and off rates, permitting rolling in response to hydrodynamic drag3. The L-selectin molecule on leukocytes binds to peripheral node addressin on high endothelial venules of lymph nodes to mediate leukocyte rolling4,5 and binds to a ligand on neutrophils to mediate rolling of leukocytes over one another6. Here we describe a surprising mechanism for regulation of these interactions, both in vitro and in vivo. Shear above a critical threshold is required to promote and maintain rolling interactions through L-selectin, but not through E-selectin, P-selectin or VCAM-1. The shear threshold requirement for L-selectin may be physiologically important in low shear to prevent inappropriate aggregation of leukocytes and interaction with the vessel wall.

  10. Unraveling the Secrets of Bacterial Adhesion Organelles Using Single-Molecule Force Spectroscopy

    NASA Astrophysics Data System (ADS)

    Axner, Ove; Björnham, Oscar; Castelain, Mickaël; Koutris, Efstratios; Schedin, Staffan; Fällman, Erik; Andersson, Magnus

    Many types of bacterium express micrometer-long attachment organelles (so-called pili) whose role is to mediate adhesion to host tissue. Until recently, little was known about their function in the adhesion process. Force-measuring optical tweezers (FMOT) have since then been used to unravel the biomechanical properties of various types of pili, primarily those from uropathogenic E. coli, in particular their force-vs.-elongation response, but lately also some properties of the adhesin are situated at the distal end of the pilus. This knowledge provides an understanding of how piliated bacteria can sustain external shear forces caused by rinsing processes, e.g., urine flow. It has been found that many types of pilus exhibit unique and complex force-vs.-elongation responses. It has been conjectured that their dissimilar properties impose significant differences in their ability to sustain external forces and that different types of pilus therefore have dissimilar predisposition to withstand different types of rinsing conditions. An understanding of these properties is of high importance since it can serve as a basis for finding new means to combat bacterial adhesion, including that caused by antibiotic-resistance bacteria. This work presents a review of the current status of the assessment of biophysical properties of individual pili on single bacteria exposed to strain/stress, primarily by the FMOT technique. It also addresses, for the first time, how the elongation and retraction properties of the rod couple to the adhesive properties of the tip adhesin.

  11. Promotion of cell migration by neural cell adhesion molecule (NCAM) is enhanced by PSA in a polysialyltransferase-specific manner.

    PubMed

    Guan, Feng; Wang, Xin; He, Fa

    2015-01-01

    Neural cell adhesion molecule 140 (NCAM-140) is a glycoprotein and always highly polysialylated in cancer. Functions of polysialic acid (PSA) that binds to N-glycan termini on NCAM remain unclear. ldlD-14 cells, a CHO cell mutant deficient in UDP-Gal 4-epimerase, are useful for structural and functional studies of Gal-containing glycoproteins because their abnormal glycosylation can be converted to normal status by exogenous addition of galactose (Gal). We cloned the genes for NCAM-140 and for polysialyltransferases STX and PST (responsible for PSA synthesis) from normal murine mammary gland epithelial (NMuMG) cells and transfected them into ldlD-14 and human breast cancer cells MCF-7. The effect of PSA on NCAM-mediated cell proliferation, motility, migration and adhesion was studied. We found that NCAM-140 significantly promoted cell proliferation, motility and migration, while polysialylation of NCAM-140 catalyzed by STX, but not by PST, enhanced NCAM-mediated cell migration, but not cell proliferation or motility. In addition, PSA catalyzed by different polysialyltransferases affected the adhesion of NCAM to different extracellular matrix (ECM) components. PMID:25885924

  12. In vitro characterization of multivalent adhesion molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel.

    PubMed

    Krachler, Anne Marie; Mende, Katrin; Murray, Clinton; Orth, Kim

    2012-07-01

    Treatment of wounded military personnel at military medical centers is often complicated by colonization and infection of wounds with pathogenic bacteria. These include nosocomially transmitted, often multidrug-resistant pathogens such as Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa and extended spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. We analyzed the efficacy of multivalent adhesion molecule (MAM) 7-based anti-adhesion treatment of host cells against aforementioned pathogens in a tissue culture infection model. Herein, we observed that a correlation between two important hallmarks of virulence, attachment and cytotoxicity, could serve as a useful predictor for the success of MAM7-based inhibition against bacterial infections. Initially, we characterized 20 patient isolates (five from each pathogen mentioned above) in terms of genotypic diversity, antimicrobial susceptibility and important hallmarks of pathogenicity (biofilm formation, attachment to and cytotoxicity toward cultured host cells). All isolates displayed a high degree of genotypic diversity, which was also reflected by large strain-to-strain variability in terms of biofilm formation, attachment and cytotoxicity within each group of pathogen. Using non-pathogenic bacteria expressing MAM7 or latex beads coated with recombinant MAM7 for anti-adhesion treatment, we showed a decrease in cytotoxicity, indicating that MAM7 has potential as a prophylactic agent to attenuate infection by multidrug-resistant bacterial pathogens.

  13. Interleukin 3 stimulates proliferation and triggers endothelial-leukocyte adhesion molecule 1 gene activation of human endothelial cells.

    PubMed

    Brizzi, M F; Garbarino, G; Rossi, P R; Pagliardi, G L; Arduino, C; Avanzi, G C; Pegoraro, L

    1993-06-01

    Proliferation and functional activation of endothelial cells within a tissue site of inflammation are regulated by humoral factors released by cells, such as T lymphocytes and monocytes, infiltrating the perivascular space. In the present study we investigated the effects of interleukin 3 (IL-3), an activated T lymphocyte-derived cytokine, on cultured human umbilical vein endothelial cells (HUVEC). Proliferative activity, evaluated both by estimation of the fraction of cells in the S phase and by direct cell count demonstrated that IL-3, at the dose of 25 ng/ml, enhances more than threefold both DNA synthesis and cell proliferation above baseline control conditions. Binding studies with radioiodinated ligand demonstrated that HUVEC constitutively express a smaller number of IL-3 binding sites (approximately 99 binding sites per cell, with an apparent Kd of 149 pM). Accordingly, molecular analysis showed the presence of transcripts for both alpha and beta subunits of the IL-3 receptor. Functional activation of endothelial cells was evaluated by the expression of the endothelial-leukocyte adhesion molecule 1 (ELAM-1) transcript and by leukocyte adhesion. The ELAM-1 gene transcript was clearly detectable 4 h after IL-3 addition and started to decrease after 12 h. Moreover, IL-3-induced ELAM-1 transcription was followed by enhanced adhesion of neutrophils and CD4+ T cells to HUVEC. The findings that IL-3 can stimulate both proliferation and functional activation of endothelial cells suggest that this cytokine can be involved in sustaining the process of chronic inflammation.

  14. Drosophila Furrowed/Selectin is a homophilic cell adhesion molecule stabilizing Frizzled and intercellular interactions during PCP establishment

    PubMed Central

    Chin, Mei-Ling; Mlodzik, Marek

    2013-01-01

    Summary Establishment of planar cell polarity (PCP) in a tissue requires coordination of directional signals from cell to cell. It is thought that this is mediated by the core PCP factors, which include cell adhesion molecules. Here, we demonstrate that furrowed, the Drosophila Selectin, is required for PCP generation. Disruption of PCP in furrowed-deficient flies results from a primary defect in Fz levels and cell adhesion. Furrowed localizes at/near apical junctions, largely co-localizing with Frizzled and Flamingo (Fmi). It physically interacts with and stabilizes Frizzled, and further, it mediates intercellular Frizzled-Van Gogh (Vang)/Strabismus interactions, similarly to Fmi. Furrowed does so through a homophilic cell adhesion role that is distinct from its known carbohydrate-binding function described during vertebrate blood-cell/endothelial cell interactions. Importantly, the carbohydrate function is dispensable for PCP establishment. In vivo studies suggest that Furrowed functions partially redundantly with Fmi, mediating intercellular Frizzled-Vang interactions between neighboring cells. PMID:23973164

  15. New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

    SciTech Connect

    Jouet, M.; Kenwick, S.; Moncla, A.

    1995-06-01

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function. 39 refs., 5 figs., 3 tabs.

  16. Assessment expression of the adhesion molecules, CD134 and CD137, in patients with colorectal cancer by flow cytometry.

    PubMed

    Cepowicz, D; Stasiak-Barmuta, A; Zalewski, B; Piotrowski, Z

    2004-01-01

    The aim of the study was to assess the expression of adhesion molecules, CD134 and CD137, in the peripheral blood in correlation with clinical advancement, the histological grade, the size and type of tumour growth, tissue infiltration, and lymph node and metastases to lymph nodes and liver. The study involved 28 patients with primary colorectal cancer. The expression of both molecules was investigated on the day of the surgery, before the procedure and ten days after the operation by means of flow cytometry. The expression of CD134 was markedly higher, compared to CD137, both on the day of the surgery and ten days after the operation. A significant increase was observed in CD134 expression ten days after the surgery. CD137 expression increased with the higher stage of clinical advancement, but decreased with the enhancement of colon wall infiltration. CD134 showed a similar expression for all the stages of tumour clinical advancement.

  17. Macrophage function in alloxan diabetic mice: expression of adhesion molecules, generation of monokines and oxygen and NO radicals

    PubMed Central

    Ptak, W; Klimek, M; Bryniarski, K; Ptak, M; Majcher, P

    1998-01-01

    The increased incidence of bacterial and mycotic infections in poorly controlled diabetic patients or animals is frequently attributed to impaired activities of professional phagocytes (granulocytes, macrophages) in hypoinsulinaemic milieu. We measured production of monokines (IL-6 and tumour necrosis factor-alpha (TNF-α)), active NO and reactive oxygen intermediates (ROIs), as well as expression of several cell surface adhesion molecules (Mac-1, -2 and -3, intercellular adhesion molecule-1 (ICAM-1) and FcγRII), by thioglycollate medium-induced peritoneal macrophages of normoglycaemic and alloxan diabetic CBA/J mice (blood glucose level in the range 300 or 500 mg/dl). Macrophages of animals with moderate diabetes (300 mg/dl) produced significantly more IL-6 and TNF-α and ROIs than cells of control mice and showed an increased expression of all cell surface molecules, except Mac-3. NO/NO2 production was not affected. Administration of insulin restored enhanced values to normal levels, except for the production of ROIs which remained unusually high. We conclude that two separate mechanisms influence macrophage physiology in diabetes—lack of saturation of insulin receptors on macrophages and an indirect effect due to formation of advanced glycosylation endproducts (AGE) on their surfaces. The latter is possibly responsible for increased generation of ROIs, since it cannot be down-regulated by prolonged insulin treatment. How the increased activity of macrophages of moderately diabetic mice (enhanced production of proinflammatory monokines and oxygen radicals as well as expression of molecules) is related to their ability to kill bacteria is now under investigation. PMID:9764597

  18. Effect of a diet and exercise intervention on oxidative stress, inflammation and monocyte adhesion in diabetic men.

    PubMed

    Roberts, Christian K; Won, Dean; Pruthi, Sandeep; Lin, San San; Barnard, R James

    2006-09-01

    Diabetes increases the risk of coronary artery disease. We examined the effects of lifestyle modification on key contributing factors to atherogenesis, including oxidative stress, inflammation and cell adhesion. Diabetic men (N=13) were placed on a high-fiber, low-fat diet in a 3-week residential program where food was provided ad libitum and daily aerobic exercise was performed. In each subject, pre- and post-intervention fasting blood was drawn for circulating levels of serum lipids, glucose and insulin, oxidative stress marker 8-isoprostaglandin F2alpha (8-iso-PGF2alpha), the inflammatory protein C-reactive protein (CRP), and soluble intracellular adhesion molecule (sICAM)-1 and sE-selectin as indicators of endothelial activation. Using subject sera and human aortic endothelial cell (HAEC) culture systems, serum-induced monocyte adhesion, ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) and cell surface abundance, and monocyte chemotactic protein-1 (MCP-1) production were determined. Nitric oxide (NO), superoxide, and hydrogen peroxide production were measured in vitro by fluorometric detection. After 3 weeks, significant reductions (p<0.05) in BMI, all serum lipids including total cholesterol (pre: 188.9+/-10.1 mg/dL versus post: 146.3+/-3.8 mg/dL) and low-density lipoprotein (103.1+/-10.2 mg/dL versus 76.4+/-4.3 mg/dL), fasting serum glucose (157.5+/-10.1 mg/dL versus 126.7+/-8.7 mg/dL), insulin (33.8+/-4.0 microU/ml versus 23.8+/-3.4 microU/ml), homeostasis model assessment for insulin resistance, 8-iso-PGF2alpha, CRP, sICAM-1, and sE-selectin were noted. In vitro, serum-stimulated monocyte adhesion, cellular ICAM-1 and VCAM-1 expression (p<0.05), and fluorometric detection of superoxide and hydrogen peroxide production decreased, while a concomitant increase in NO production was noted (all p<0.01). A combination of diet and exercise ameliorates oxidative stress, inflammation, and monocyte-endothelial interaction. Intensive lifestyle modification may

  19. Applications of traction force microscopy in measuring adhesion molecule dependent cell contractility

    NASA Astrophysics Data System (ADS)

    Mann, Cynthia Marie

    This work describes the use of polyacrylamide hydrogels as controlled elastic modulus substrates for single cell traction force microscopy studies. The first section describes the use of EDC/NHS chemistry to convalently link microbeads to the hydrogel matrix for the purpose of performing long-term traction force studies (7 days). The final study uses the C2C12 cell line to demonstrate that integrin-mediated adhesion to soft substrates causes different cell behavior than N-cahderin-mediated adhesion to soft substrates. Cells plated on laminin-coated hydrogels exhibited stiffness dependent increases in cell spreading, whereas cells plated on N-cadherin-coated substrates. Similarly, cells plated on laminin-coated substrates exhibited substrate stiffness dependent increases in normalized net contractile moment, however the same cells plated on N-cadherin-coated substrates were unable to deform any but the softest hydrogels.

  20. Semi-microdroplet assay for cell adhesion molecules. M.S. Thesis

    NASA Technical Reports Server (NTRS)

    Tawa, Lawrence Shinzo

    1988-01-01

    A new cell-to-cell adhesion assay was devised. Using dissociated embryos of the sea urchin, this procedure involves rotating a 0.100 ml suspension of single cells with 0.100 ml of the solution to be tested in the bulb portion of a transfer pipet with the tip removed. After 1 hour of rotation at 60 rpm at 15 C, the contents of each bulb were transferred into individual wells of a 96 well flat bottom plate. After the plate was incubated for 1 hour at 15 C, black and white photographs were taken with a 35 mm camera attached to an inverted photomicroscope. Examining a proof sheet of the negatives directly allowed a rapid evaluation of suspected cell adhesion promoting factors. A ranking system was used to evaluate all samples. The assay was tested by examining the effect of specific solutions on the aggregation of single cells obtained from dissociated 23 hour embryos.

  1. Polyclonal neural cell adhesion molecule antibody prolongs the effective duration time of botulinum toxin in decreasing muscle strength.

    PubMed

    Guo, Yan; Pan, Lizhen; Liu, Wuchao; Pan, Yougui; Nie, Zhiyu; Jin, Lingjing

    2015-11-01

    This study aimed to investigate if the effective duration time of botulinum toxin A (Btx-A) could be prolonged by polyclonal neural cell adhesion molecule antibody (P-NCAM-Ab). 175 male SD rats were randomly divided into three major groups: control group (n = 25), Btx-A group (n = 25), and P-NCAM-Ab groups. P-NCAM-Ab groups were composed of five sub-groups, with 25 rats each in the dose-response study. Muscle strength of rat lower limbs was determined using a survey system. The expressions of muscle-specific receptor tyrosine kinase (MuSK) and neural cell adhesion molecule (NCAM) were determined by real-time polymerase chain reactions (RT-PCR) and western blotting (WB). The muscle strength was significantly decreased by Btx-A in Btx-A/P-NCAM-Ab groups compared with normal control group. Besides, the muscle strength of P-NCAM-Ab group was significantly decreased compared with the Btx-A group. The recovery time of muscle strength in P-NCAM-Ab group was significantly longer compared with Btx-A group. RT-PCR and WB assay showed that PNCAM-Ab delayed the increase of MuSK and NCAM after Btx-A injection. P-NCAM-Ab prolongs the effective duration time of Btx-A in decreasing muscle strength, which could provide a novel enhancement in clinical application.

  2. The adherence of endothelial cells to Dacron induces the expression of the intercellular adhesion molecule (ICAM-1).

    PubMed Central

    Margiotta, M S; Robertson, F S; Greco, R S

    1992-01-01

    The intercellular adhesion molecule (ICAM-1) is a glycoprotein expressed by endothelial cells activated by cytokines. The lymphocyte-function-associated antigen (LFA-1) is an integrin expressed by activated white blood cells. Together, this receptor-ligand pair is responsible, in part, for the localization of neutrophils at sites of inflammation. Using an in vitro model, the authors studied the binding of antibodies against ICAM-1 by human saphenous vein endothelial cells (HSVEC) adherent to Dacron and control cultureware. After adherence to Dacron pretreated with fibronectin, 24% more HSVEC-bound antibody against ICAM-1 compared with HSVEC on controls. In contrast, 90% more HSVEC adherent to Dacron incubated with whole blood bound anti-ICAM-1 antibodies. These cells bound 17.7-fold greater amounts of antibody compared with HSVEC on controls. Pretreating Dacron with plasma resulted in no increase in antibody binding compared with control. Our studies suggest that the cellular components of blood in contact with Dacron create a microenvironment that activates HSVEC and enhances ICAM-1 expression. Induction of this adhesion molecule may play a pivotal role in the migration and localization of leukocytes at the site of the vascular prosthesis. PMID:1359845

  3. Expression of cell adhesion molecule E-cadherin in Xenopus embryos begins at gastrulation and predominates in the ectoderm

    PubMed Central

    1989-01-01

    The expression of the Ca2+-dependent epithelial cell adhesion molecule E-cadherin (also known as uvomorulin and L-CAM) in the early stages of embryonic development of Xenopus laevis was examined. E-Cadherin was identified in the Xenopus A6 epithelial cell line by antibody cross- reactivity and several biochemical characteristics. Four independent mAbs were generated against purified Xenopus E-cadherin. All four mAbs recognized the same polypeptides in A6 cells, adult epithelial tissues, and embryos. These mAbs inhibited the formation of cell contacts between A6 cells and stained the basolateral plasma membranes of A6 cells, hepatocytes, and alveolar epithelial cells. The time of E- cadherin expression in early Xenopus embryos was determined by immunoblotting. Unlike its expression in early mouse embryos, E- cadherin was not present in the eggs or early blastula of Xenopus laevis. These findings indicate that a different Ca2+-dependent cell adhesion molecule, perhaps another member of the cadherin gene family, is responsible for the Ca2+-dependent adhesion between cleavage stage Xenopus blastomeres. Detectable accumulation of E-cadherin started just before gastrulation at stage 9 1/2 and increased rapidly up to the end of gastrulation at stage 15. In stage 15 embryos, specific immunofluorescence staining of E-cadherin was discernible only in ectoderm, but not in mesoderm and endoderm. The ectoderm at this stage consists of two cell layers. The outer cell layer of ectoderm was stained intensely, and staining was localized to the basolateral plasma membrane of these cells. Lower levels of staining were observed in the inner cell layer of ectoderm. The coincidence of E-cadherin expression with the process of gastrulation and its restriction to the ectoderm indicate that it may play a role in the morphogenetic movements of gastrulation and resulting segregation of embryonic germ layers. PMID:2472408

  4. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro.

    PubMed

    Ayuk, Sandra M; Abrahamse, Heidi; Houreld, Nicolette N

    2016-08-01

    Cell adhesion molecules (CAMs) are cell surface glycoproteins that facilitate cell-cell contacts and adhesion with the extracellular matrix (ECM). Cellular adhesion is affected by various disease conditions, such as diabetes mellitus (DM) and inflammation. Photobiomodulation (PBM) stimulates biological processes and expression of these cellular molecules. The aim of this experimental work was to demonstrate the role of PBM at 830nm on CAMs in diabetic wounded fibroblast cells. Isolated human skin fibroblast cells were used. Normal (N-) and diabetic wounded (DW-) cells were irradiated with a continuous wave diode laser at 830nm with an energy density of 5J/cm(2). Real time reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine the relative gene expression of 39 CAMs 48h post-irradiation. Normalized expression levels from irradiated cells were calculated relative to non-irradiated control cells according to the 2^(-ΔΔCt) method. Thirty-one genes were significantly regulated in N-cells (28 were genes up-regulated and three genes down-regulated), and 22 genes in DW-cells (five genes were up-regulated and 17 genes down-regulated). PBM induced a stimulatory effect on various CAMs namely cadherins, integrins, selectins and immunoglobulins, and hence may be used as a complementary therapy in advancing treatment of non-healing diabetic ulcers. The regulation of CAMs as well as evaluating the role of PBM on the molecular effects of these genes may expand knowledge and prompt further research into the cellular mechanisms in diabetic wound healing that may lead to valuable clinical outcomes. PMID:27295416

  5. Engagement of major histocompatibility complex class I and class II molecules up-regulates intercellular adhesion of human B cells via a CD11/CD18-independent mechanism.

    PubMed

    Alcover, A; Juillard, V; Acuto, O

    1992-02-01

    We have studied the role of major histocompatibility complex (MHC) molecules in the regulation of intercellular adhesion of human B cells. We found that molecules able to bind to MHC class II molecules, such as monoclonal antibodies or staphylococcal enterotoxins, induced rapid and sustained homotypic adhesion of Epstein-Barr virus