Endothelial cell expression of adhesion molecules is induced by fetal plasma from pregnancies with umbilical placental vascular disease.

PubMed

Wang, Xin; Athayde, Neil; Trudinger, Brian

2002-07-01

To test the hypothesis that local production with spill into the fetal circulation of factor(s) injurious to endothelium is responsible for the vascular pathology present when the umbilical artery Doppler study is abnormal. Expression of adhesion molecules is a feature of endothelial cell activation. Case-control study. University teaching hospital. Fetal plasma was collected from 27 normal pregnancies, 39 pregnancies with umbilical placental vascular disease defined by abnormal umbilical artery Doppler and 11 pregnancies with pre-eclampsia and normal umbilical artery Doppler. Isolated and cultured human umbilical vein endothelial cells from normal pregnancies were incubated with fetal plasma from three study groups. mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) were assessed by reverse transcription-polymerase chain reaction. To confirm the occurrence of this in vivo, we measured the levels of soluble fractions of sICAM-1, sVCAM-1 and sPECAM-1 in the fetal circulation in the fetal plasma used for endothelial cell incubation. The mRNA expression of ICAM-1 [median 1.1 (interquartile range 0.5-1.9) vs 0.7 (0.3-1.2), P < 0.05] and PECAM-1 [2.1 (1.2-3.0) vs 1.5 (0.7-2.1), P < 0.05] was significantly higher following incubation with fetal plasma from umbilical placental vascular disease compared with the normal group. There was no difference in the expression of VCAM-1 [1.2 (0.9-1.8) vs 1.1 (0.8-1.6), ns]. The group with maternal pre-eclampsia and normal umbilical artery Doppler did not differ from the normal group. In the umbilical placental vascular disease group, the results were similar in the presence or absence of pre-eclampsia. For soluble fractions of the adhesion molecules released into the fetal circulation, we found the levels (ng/mL) of sICAM- I [median 248.5 (interquartile range 197.3-315.7) vs 174.2 (144.5-212.9), P < 0.05] and sPECAM

Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38.

PubMed

Russell-Puleri, Sparkle; Dela Paz, Nathaniel G; Adams, Diana; Chattopadhyay, Mitali; Cancel, Limary; Ebong, Eno; Orr, A Wayne; Frangos, John A; Tarbell, John M

2017-03-01

Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I 2 (PGI 2 ) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI 2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm 2 for 5 h to examine shear stress-induced induction of COX-2/PGI 2 Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI 2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of α 5 β 1 -integrin, upregulation of COX-2, and release of PGI 2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002) substantially inhibited FSS activation of α 5 β 1 -integrin, upregulation of COX-2 gene and protein expression, and release of PGI 2 in BAECs. Inhibition of integrin-associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear-induced upregulation of COX-2. Finally, a PECAM-1 -/- mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI 2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI 2 release compared with wild-type animals. NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates

Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38

PubMed Central

Russell-Puleri, Sparkle; dela Paz, Nathaniel G.; Adams, Diana; Chattopadhyay, Mitali; Cancel, Limary; Ebong, Eno; Orr, A. Wayne; Frangos, John A.

2017-01-01

Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I2 (PGI2) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm2 for 5 h to examine shear stress-induced induction of COX-2/PGI2. Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of α5β1-integrin, upregulation of COX-2, and release of PGI2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002) substantially inhibited FSS activation of α5β1-integrin, upregulation of COX-2 gene and protein expression, and release of PGI2 in BAECs. Inhibition of integrin-associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear-induced upregulation of COX-2. Finally, a PECAM-1−/− mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI2 release compared with wild-type animals. NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2

Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy.

PubMed

Papasavvas, Emmanouil; Azzoni, Livio; Pistilli, Maxwell; Hancock, Aidan; Reynolds, Griffin; Gallo, Cecile; Ondercin, Joe; Kostman, Jay R; Mounzer, Karam; Shull, Jane; Montaner, Luis J

2008-06-19

We investigated the effect of short viremic episodes on soluble markers associated with endothelial stress and cardiovascular disease risk in chronically HIV-1-infected patients followed during continuous antiretroviral therapy, antiretroviral therapy interruption and antiretroviral therapy resumption. We assessed changes in plasma levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 by enzyme-linked immunosorbent assay, as well as T-cell activation (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+) by flow cytometry, in 36 chronically HIV-1-infected patients participating in a randomized study. Patients were divided into the following three groups: a, on continuous antiretroviral therapy; b, on a 6-week antiretroviral therapy interruption; or c, on antiretroviral therapy interruption extended to the achievement of viral set point. Although all measurements remained stable over a 40-week follow-up on antiretroviral therapy, plasma levels of soluble vascular cell adhesion molecule-1 (P < 0.0001) and soluble intercellular adhesion molecule-1 (P = 0.003) increased during treatment interruption in correlation with viral rebound and T-cell activation. No significant changes in von Willebrand factor were observed in any of the groups. After resuming antiretroviral therapy, soluble vascular cell adhesion molecule-1 levels remained elevated even after achievement of viral suppression to less than 50 copies/ml. The prompt rise in plasma soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1 upon viral rebound suggests an acute increase in endothelial stress upon treatment interruption, which may persists after viral resuppression of virus. Thus, viral replication during short-term treatment interruption may increase the overall cardiovascular risk during and beyond treatment interruption.

Expression of adhesion molecules is specific and time-dependent in cytokine-stimulated endothelial cells in culture.

PubMed

Scholz, D; Devaux, B; Hirche, A; Pötzsch, B; Kropp, B; Schaper, W; Schaper, J

1996-06-01

The time course of expression of the adhesion molecules E-selectin, VCAM-1, ICAM-1 and PECAM-1 was studied in interleukin-1 beta-stimulated human umbilical vein cells (HUVEC) and the subcellular sites of synthesis were determined by means of fluorescence immunohistochemistry. The maximal number of cells labelled for E-selectin was observed at 2-4 h, for VCAM-1 at 4-8 h and ICAM-1 at 6-72 h. At 8 h, E-selectin and VCAM-1 started to disappear, but ICAM-1-positive cells persisted. PECAM-1 was constitutively expressed. De novo synthesis for E-selectin started at 1 h and for both, VCAM-1 and ICAM-1 at 1.5-2 h. Maximal synthetic activity was observed at 2.5-4 h for E-selectin and at 4-6 h for VCAM-1 and ICAM-1; thereafter, synthesis slowly decreased. Transport granules occurred at 1.5 h for E-selectin and 4 h for VCAM-1; they were absent for ICAM-1. Diffuse cellular and membrane labelling indicative of the functional activity of the adhesion molecules began at 2-4 h for E-selectin, and 4 h for VCAM, but was constitutively present for ICAM-1. In conclusion, each adhesion molecule shows a specific time-dependent course of appearance and disappearance in interleukin-1 beta-stimulated HUVECs in accordance with their physiological role in vivo. These morphological results confirm data obtained by flow cytometry and Western blotting, but they provide new information about the behaviour of individual cells with regard to the sites of synthesis and cellular localization of the adhesion molecules.

Circulating vascular cell adhesion molecule-1 in pre-eclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-eclampsia.

PubMed

Higgins, J R; Papayianni, A; Brady, H R; Darling, M R; Walshe, J J

1998-08-01

Our purpose was to investigate circulating levels of vascular cell adhesion molecule-1 in the peripheral and uteroplacental circulations during normotensive and hypertensive pregnancies. This prospective observational study involved 2 patient groups. Group 1 consisted of 22 women with pre-eclampsia and 30 normotensive women followed up longitudinally through pregnancy and post partum. There were an additional 13 women with established gestational hypertension. Group 2 consisted of 20 women with established pre-eclampsia and 19 normotensive control subjects undergoing cesarean delivery. Plasma levels of vascular cell adhesion molecule-1 were measured in blood drawn from the antecubital vein (group 1) and from both the antecubital and uterine veins (group 2). Data were analyzed by analysis of variance. In group 1 vascular cell adhesion molecule-1 levels did not change significantly throughout normal pregnancy and post partum. Women with established pre-eclampsia had increased vascular cell adhesion molecule-1 levels compared with the normotensive pregnancy group (P = .01). Vascular cell adhesion molecule-1 levels were not elevated in women with established gestational hypertension. In group 2 significantly higher levels of vascular cell adhesion molecule-1 were detected in the uteroplacental (P < .0001) and peripheral (P < .0001) circulations of pre-eclamptic women by comparison with normotensive women. In the pre-eclamptic group there was a tendency toward higher vascular cell adhesion molecule-1 levels in the peripheral circulation than in the uteroplacental circulation (P = .06). In contrast to vascular cell adhesion molecule-1, circulating levels of E-selectin and intercellular adhesion molecule-1, other major leukocyte adhesion molecules expressed by the endothelium, were not different in pre-eclamptic and normotensive pregnancies. Established pre-eclampsia is characterized by selective dysregulation of vascular cell adhesion molecule-1 homeostasis. This event

Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion.

PubMed

Lacal, Pedro Miguel; Petrillo, Maria Grazia; Ruffini, Federica; Muzi, Alessia; Bianchini, Rodolfo; Ronchetti, Simona; Migliorati, Graziella; Riccardi, Carlo; Graziani, Grazia; Nocentini, Giuseppe

2013-10-01

The interaction of glucocorticoid-induced tumor necrosis factor receptor-family related (GITR) protein with its ligand (GITRL) modulates different functions, including immune/inflammatory response. These effects are consequent to intracellular signals activated by both GITR and GITRL. Previous results have suggested that lack of GITR expression in GITR(-/-) mice decreases the number of leukocytes within inflamed tissues. We performed experiments to analyze whether the GITRL/GITR system modulates leukocyte adhesion and extravasation. For that purpose, we first evaluated the capability of murine splenocytes to adhere to endothelial cells (EC). Our results indicated that adhesion of GITR(-/-) splenocytes to EC was reduced as compared with wild-type cells, suggesting that GITR plays a role in adhesion and that this effect may be due to GITRL-GITR interaction. Moreover, adhesion was increased when EC were pretreated with an agonist GITR-Fc fusion protein, thus indicating that triggering of GITRL plays a role in adhesion by EC regulation. In a human in vitro model, the adhesion to human EC of HL-60 cells differentiated toward the monocytic lineage was increased by EC pretreatment with agonist GITR-Fc. Conversely, antagonistic anti-GITR and anti-GITRL Ab decreased adhesion, thus further indicating that GITRL triggering increases the EC capability to support leukocyte adhesion. EC treatment with GITR-Fc favored extravasation, as demonstrated by a transmigration assay. Notably, GITRL triggering increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and anti-ICAM-1 and anti-VCAM-1 Abs reversed GITR-Fc effects. Our study demonstrates that GITRL triggering in EC increases leukocyte adhesion and transmigration, suggesting new anti-inflammatory therapeutic approaches based on inhibition of GITRL-GITR interaction.

Monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in exudative age-related macular degeneration.

PubMed

Jonas, Jost B; Tao, Yong; Neumaier, Michael; Findeisen, Peter

2010-10-01

To examine intraocular concentrations of monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and vascular endothelial growth factor (VEGF) in eyes with exudative age-related macular degeneration (AMD). The investigation included a study group of 28 patients (28 eyes) with exudative AMD and a control group of 25 patients (25 eyes) with cataract. The concentrations of MCP-1, sICAM-1, sVCAM-1, and VEGF in aqueous humor samples obtained during surgery were measured using a solid-phase chemiluminescence immunoassay. The study group as compared with the control group had higher aqueous concentrations of sICAM-1 (mean [SD], 844 [2073] vs 246 [206] pg/mL, respectively; P < .001), sVCAM-1 (mean [SD], 7978 [7120] vs 2999 [1426] pg/mL, respectively; P < .001), and MCP-1 (mean [SD], 587 [338] vs 435 [221] pg/mL, respectively; P = .07). The concentration of VEGF did not vary significantly between the groups (P = .76). The MCP-1 concentration was significantly associated with macular thickness (r = 0.40; P = .004). It decreased significantly with the type of subfoveal neovascular membrane (classic membrane type, occult membrane, retinal pigment epithelium detachment) (P = .009). The concentrations of sICAM-1, sVCAM-1, and VEGF were not significantly associated with membrane type and macular thickness (P ≥ .18). Concentrations of MCP-1, sICAM-1, and sVCAM-1 are significantly associated with exudative AMD, even in the presence of normal VEGF concentrations. Intraocular MCP-1 concentrations are correlated with the subfoveal neovascular membrane type and the amount of macular edema. One may infer that MCP-1, sICAM-1, and sVCAM-1 could potentially be additional target molecules in therapy for exudative AMD.

Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1.

PubMed Central

Johnson-Tidey, R. R.; McGregor, J. L.; Taylor, P. R.; Poston, R. N.

1994-01-01

P-selectin (GMP-140) is an adhesion molecule present within endothelial cells that is rapidly translocated to the cell membrane upon activation, where it mediates endothelial-leukocyte interactions. Immunohistochemical analysis of human atherosclerotic plaques has shown strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques. P-selectin is not, however, detected in normal arterial endothelium or in endothelium overlying inactive fibrous plaques. Color image analysis was used to quantitate the degree of P-selectin expression in the endothelium and demonstrates a statistically significant increase in P-selectin expression by atherosclerotic endothelial cells. Double immunofluorescence shows that some of this P-selectin is expressed on the luminal surface of the endothelial cells. Previous work has demonstrated a significant up-regulation in the expression of the intercellular adhesion molecule-1 in atherosclerotic endothelium and a study on the expression of intercellular adhesion molecule-1 and P-selectin in atherosclerosis shows a highly positive correlation. These results suggest that the selective and cooperative expression of P-selectin and intercellular adhesion molecule-1 may be involved in the recruitment of monocytes into sites of atherosclerosis. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:7513951

Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)-mediated Inhibitory Signaling is Regulated by Sequential Phosphorylation Mediated by Distinct Nonreceptor Tyrosine Kinases: A Case Study Involving PECAM-1

PubMed Central

Tourdot, Benjamin E.; Brenner, Michelle K.; Keough, Kathleen C.; Holyst, Trudy; Newman, Peter J.; Newman, Debra K.

2013-01-01

The activation state of many blood and vascular cells is tightly controlled by a delicate balance between receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs) and those that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Precisely how the timing of cellular activation by ITAM-coupled receptors is regulated by ITIM-containing receptors is, however, poorly understood. Using platelet endothelial cell adhesion molecule 1 (PECAM-1) as a prototypical ITIM-bearing receptor, we demonstrate that initiation of inhibitory signaling occurs via a novel, sequential process in which Src family kinases phosphorylate the C-terminal ITIM, thereby enabling phosphorylation of the N-terminal ITIM of PECAM-1 by other Src homology 2 domain-containing non-receptor tyrosine kinases (NRTKs). NRTKs capable of mediating the second phosphorylation event include C-terminal Src kinase (Csk) and Bruton’s tyrosine kinase (Btk). Btk and Csk function downstream of phosphatidylinositol 3-kinase (PI3K) activation during ITAM-dependent platelet activation. In ITAM-activated platelets that were treated with a PI3K inhibitor, PECAM-1 was phosphorylated but did not bind the tandem SH2 domain-containing tyrosine phosphatase SHP-2, indicating that it was not phosphorylated on its N-terminal ITIM. Csk bound to and phosphorylated PECAM-1 more efficiently than did Btk, and required its SH2 domain to perform these functions. Additionally, the phosphorylation of the N-terminal ITIM of Siglec-9 by Csk is enhanced by the prior phosphorylation of its C-terminal ITIM, providing evidence that the ITIMs of other dual ITIM-containing receptors are also sequentially phosphorylated. On the basis of these findings, we propose that sequential ITIM phosphorylation provides a general mechanism for precise temporal control over the recruitment and activation of tandem SH2 domain-containing tyrosine phosphatases that dampen ITAM-dependent signals. PMID:23418871

Hydrodynamic shear shows distinct roles for LFA-1 and Mac-1 in neutrophil adhesion to intercellular adhesion molecule-1.

PubMed

Neelamegham, S; Taylor, A D; Burns, A R; Smith, C W; Simon, S I

1998-09-01

The binding of neutrophil beta2 integrin to intercellular adhesion molecule-1 (ICAM-1) expressed on the inflamed endothelium is critical for neutrophil arrest at sites of tissue inflammation. To quantify the strength and kinetics of this interaction, we measured the adhesion between chemotactically stimulated neutrophils and ICAM-1-transfected mouse cells (E3-ICAM) in suspension in a cone-plate viscometer at shear rates typical of venular blood flow (100 s-1 to 500 s-1). The kinetics of aggregation were fit with a mathematical model based on two-body collision theory. This enabled estimation of adhesion efficiency, defined as the probability with which collisions between cells resulted in firm adhesion. The efficiency of beta2-integrin-dependent adhesion was highest ( approximately 0.2) at 100 s-1 and it decreased to approximately zero at 400 s-1. Both LFA-1 and Mac-1 contributed equally to adhesion efficiency over the initial 30 seconds of stimulation, but adhesion was entirely Mac-1-dependent by 120 seconds. Two hydrodynamic parameters were observed to influence integrin-dependent adhesion efficiency: the level of shear stress and the intercellular contact duration. Below a critical shear stress (<2 dyn/cm2), contact duration predominantly limited adhesion efficiency. The estimated minimum contact duration for beta2-integrin binding was approximately 6.5 ms. Above the critical shear stress (>2 dyn/cm2), the efficiency of neutrophil adhesion to E3-ICAM was limited by both the contact duration and the tensile stress. We conclude that at low shear, neutrophil adhesion is modulated independently through either LFA-1 or Mac-1, which initially contribute with equal efficiency, but differ over the duration of chemotactic stimulation. Copyright 1998 by The American Society of Hematology.

Intercellular adhesion molecule-1 augments myoblast adhesion and fusion through homophilic trans-interactions.

PubMed

Pizza, Francis X; Martin, Ryan A; Springer, Evan M; Leffler, Maxwell S; Woelmer, Bryce R; Recker, Isaac J; Leaman, Douglas W

2017-07-11

The overall objective of the study was to identify mechanisms through which intercellular adhesion molecule-1 (ICAM-1) augments the adhesive and fusogenic properties of myogenic cells. Hypotheses were tested using cultured myoblasts and fibroblasts, which do not constitutively express ICAM-1, and myoblasts and fibroblasts forced to express full length ICAM-1 or a truncated form lacking the cytoplasmic domain of ICAM-1. ICAM-1 mediated myoblast adhesion and fusion were quantified using novel assays and cell mixing experiments. We report that ICAM-1 augments myoblast adhesion to myoblasts and myotubes through homophilic trans-interactions. Such adhesive interactions enhanced levels of active Rac in adherent and fusing myoblasts, as well as triggered lamellipodia, spreading, and fusion of myoblasts through the signaling function of the cytoplasmic domain of ICAM-1. Rac inhibition negated ICAM-1 mediated lamellipodia, spreading, and fusion of myoblasts. The fusogenic property of ICAM-1-ICAM-1 interactions was restricted to myogenic cells, as forced expression of ICAM-1 by fibroblasts did not augment their fusion to ICAM-1+ myoblasts/myotubes. We conclude that ICAM-1 augments myoblast adhesion and fusion through its ability to self-associate and initiate Rac-mediated remodeling of the actin cytoskeleton.

Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1

NASA Astrophysics Data System (ADS)

Koch, Alisa E.; Halloran, Margaret M.; Haskell, Catherine J.; Shah, Manisha R.; Polverini, Peter J.

1995-08-01

ENDOTHELIAL adhesion molecules facilitate the entry of leukocytes into inflamed tissues. This in turn promotes neovascularization, a process central to the progression of rheumatoid arthritis, tumour growth and wound repair1. Here we test the hypothesis that soluble endothelial adhesion molecules promote angiogenesis2á¤-4. Human recombinant soluble E-selectin and soluble vascular cell adhesion molecule-1 induced chemotaxis of human endothelial cells in vitro and were angiogenic in rat cornea. Soluble E-selectin acted on endothelial cells in part through a sialyl Lewis-X-dependent mechanism, while soluble vascular cell adhesion molecule-1 acted on endothelial cells in part through a very late antigen (VLA)-4 dependent mechanism. The chemotactic activity of rheumatoid synovial fluid for endothelial cells, and also its angiogenic activity, were blocked by antibodies to either soluble E-selectin or soluble vascular cell adhesion molecule-1. These results suggest a novel function for soluble endothelial adhesion molecules as mediators of angiogenesis.

Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis.

PubMed

Imamaki, Rie; Ogawa, Kazuko; Kizuka, Yasuhiko; Komi, Yusuke; Kojima, Soichi; Kotani, Norihiro; Honke, Koichi; Honda, Takashi; Taniguchi, Naoyuki; Kitazume, Shinobu

2018-05-02

Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation-dependent regulatory mechanism for tumor angiogenesis. St6gal1 -/- mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1 -/- endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that cooperative functionality of PECAM-VEGFR2-integrin β3 was disturbed in St6gal1 -/- mice. First, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that the absence of α2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-β3, indicating that the reduction of cell surface integrin-β3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of α2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that α2,6-sialylation is critically involved in endothelial survival by controlling the cell surface stability and signal transduction of angiogenic molecules, and could be a novel target for anti-angiogenesis therapy.

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

Pirfenidone induces intercellular adhesion molecule-1 (ICAM-1) down-regulation on cultured human synovial fibroblasts

PubMed Central

Kaneko, M; Inoue, H; Nakazawa, R; Azuma, N; Suzuki, M; Yamauchi, S; Margolin, S B; Tsubota, K; Saito, I

1998-01-01

Pirfenidone has been shown to modify some cytokine regulatory actions and inhibit fibroblast biochemical reactions resulting in inhibition of proliferation and collagen matrix synthesis by fibroblast. We have investigated the effect of pirfenidone on the expression of cell adhesion molecules. The synovial fibroblasts were treated with IL-1α in the presence or absence of pirfenidone (range 0–1000 μm), and assayed for the expression of adhesion molecules such as ICAM-1 and endothelial-leucocyte adhesion molecule-1 (E-selectin) by cell ELISA. Pirfenidone significantly down-regulated the expression of ICAM-1 on cultured synovial fibroblasts in a dose-dependent manner. In contrast, expression of E-selectin was not affected. Furthermore, we examined whether pirfenidone affects the cellular binding between cultured lymphocytes and IL-1α-stimulated synovial fibroblasts by in vitro binding assay and found their mutual binding was significantly suppressed in a dose-dependent manner by pirfenidone. It is speculated that down-regulation of ICAM-1 might be one of the novel mechanisms of action of pirfenidone. These data indicate a novel mechanism of action for pirfenidone to reduce the activation of synovial fibroblasts. PMID:9697986

Associations of combined polymorphisms of the platelet membrane glycoproteins Ia and IIIa and the platelet-endothelial cell adhesion molecule-1 and P-Selectin genes with IVF implantation failures.

PubMed

Vlachadis, Nikolaos; Tsamadias, Vasileios; Vrachnis, Nikolaos; Kaparos, Georgios; Vitoratos, Nikolaos; Kouskouni, Evaggelia; Economou, Emmanuel

2017-04-01

The aim of the study was to investigate the combined impact of the genetic heterogeneity of the glycoproteins Ia (GpIa) and IIIa (GpIIIa) and the platelet-endothelial cell adhesion molecule-1 (PECAM-1) and P-Selectin genes on IVF embryo transfer implantation failures (IVF-ET failures). Sixty nulligravida women with previous IVF-ET failures and 60 fertile controls were genotyped for the GpIa-C807T, GpIIIa-PlA1/PA2, PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms by pyrosequencing. Compared with wild-type combined homozygotes, carriers of combinations of risk alleles in two gene loci were at significantly increased risk for IVF-ET failure, whereas carriers of the combination of GpIa-807T, GpIIIa-PlA2 and PECAM-1-373G alleles had OR = 52.50 (95%CI: 4.05-680.95, p < .001). The area under the receiver-operating characteristic curve (AUC) based on the number of polymorphisms and the number of risk alleles per subject was 75.4% (95%CI: 66.7%-82.8%, p < .001) and 72.5% (95%CI: 63.6%-80.3%, p < .001), respectively. The OR per polymorphism and risk allele increase was 4.26 (95%CI: 2.15-8.41, p < .001) and 2.85 (95%CI: 1.71-4.76, p < .001), respectively. The above associations were more robust among younger women. The combined analysis of these polymorphisms revealed strong association of combined carriers with IVF-ET failures especially for younger women and provided a genetic risk score with good diagnostic accuracy in the prediction of IVF-ET failures.

The Drosophila cell adhesion molecule Neuroglian regulates Lissencephaly-1 localisation in circulating immunosurveillance cells.

PubMed

Williams, Michael J

2009-03-25

When the parasitoid wasp Leptopilina boulardi lays its eggs in Drosophila larvae phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. This requires these circulating immunosurveillance cells (haemocytes) to change from a non-adhesive to an adhesive state enabling them to bind to the invader. Interestingly, attachment of leukocytes, platelets, and insect haemocytes requires the same adhesion complexes as epithelial and neuronal cells. Here evidence is presented showing that the Drosophila L1-type cell adhesion molecule Neuroglian (Nrg) is required for haemocytes to encapsulate L. boulardi wasp eggs. The amino acid sequence FIGQY containing a conserved phosphorylated tyrosine is found in the intracellular domain of all L1-type cell adhesion molecules. This conserved tyrosine is phosphorylated at the cell periphery of plasmatocytes and lamellocytes prior to parasitisation, but dephosphorylated after immune activation. Intriguingly, another pool of Nrg located near the nucleus of plasmatocytes remains phosphorylated after parasitisation. In mammalian neuronal cells phosphorylated neurofascin, another L1-type cell adhesion molecule interacts with a nucleokinesis complex containing the microtubule binding protein lissencephaly-1 (Lis1) 1. Interestingly in plasmatocytes from Nrg mutants the nucleokinesis regulating protein Lissencephaly-1 (Lis1) fails to localise properly around the nucleus and is instead found diffuse throughout the cytoplasm and at unidentified perinuclear structures. After attaching to the wasp egg control plasmatocytes extend filopodia laterally from their cell periphery; as well as extending lateral filopodia plasmatocytes from Nrg mutants also extend many filopodia from their apical surface. The Drosophila cellular adhesion molecule Neuroglian is expressed in haemocytes and its activity is required for the encapsulation of L. boularli eggs. At the cell periphery of haemocytes Neuroglian may be

The Drosophila cell adhesion molecule Neuroglian regulates Lissencephaly-1 localisation in circulating immunosurveillance cells

PubMed Central

Williams, Michael J

2009-01-01

Background When the parasitoid wasp Leptopilina boulardi lays its eggs in Drosophila larvae phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. This requires these circulating immunosurveillance cells (haemocytes) to change from a non-adhesive to an adhesive state enabling them to bind to the invader. Interestingly, attachment of leukocytes, platelets, and insect haemocytes requires the same adhesion complexes as epithelial and neuronal cells. Results Here evidence is presented showing that the Drosophila L1-type cell adhesion molecule Neuroglian (Nrg) is required for haemocytes to encapsulate L. boulardi wasp eggs. The amino acid sequence FIGQY containing a conserved phosphorylated tyrosine is found in the intracellular domain of all L1-type cell adhesion molecules. This conserved tyrosine is phosphorylated at the cell periphery of plasmatocytes and lamellocytes prior to parasitisation, but dephosphorylated after immune activation. Intriguingly, another pool of Nrg located near the nucleus of plasmatocytes remains phosphorylated after parasitisation. In mammalian neuronal cells phosphorylated neurofascin, another L1-type cell adhesion molecule interacts with a nucleokinesis complex containing the microtubule binding protein lissencephaly-1 (Lis1) [1]. Interestingly in plasmatocytes from Nrg mutants the nucleokinesis regulating protein Lissencephaly-1 (Lis1) fails to localise properly around the nucleus and is instead found diffuse throughout the cytoplasm and at unidentified perinuclear structures. After attaching to the wasp egg control plasmatocytes extend filopodia laterally from their cell periphery; as well as extending lateral filopodia plasmatocytes from Nrg mutants also extend many filopodia from their apical surface. Conclusion The Drosophila cellular adhesion molecule Neuroglian is expressed in haemocytes and its activity is required for the encapsulation of L. boularli eggs. At the cell periphery of

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Haimou; Qin, Gangjian; Liang, Gang

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 mechanismmore » 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.« less

Aspirin-Induced Gastric Lesions Alters EGFR and PECAM-1 Immunoreactivity in Wistar Rats: Modulatory Action of Flavonoid Fraction of Musa Paradisiaca

PubMed Central

Alese, Margaret Olutayo; Adewole, Stephen Olarinde; Akinwunmi, Kemi Feyisayo; Omonisi, Abidemi Emmanuel; Alese, Oluwole Ojo

2017-01-01

AIM: In this study, Epithelial Growth Factor Receptor and Platelet Endothelial Cell Adhesion Molecule-1 were localised to investigate the healing effects of a flavonoid-rich fraction of M. paradisiaca fruit in the gastric corpus of Wistar rats following aspirin-induced gastric lesion. MATERIALS AND METHODS: Mature, unripe fruits of M. paradisiaca were peeled; air dried, pulverised, extracted with 70% methanol, concentrated and partitioned. Ninety male Wistar rats were randomly assigned into 6 groups of 15 rats each. The gastric lesion was induced in groups B, C, D, E and F rats by administration of 400 mg/kg aspirin in distilled water. Group A received distilled water. After 24 hours, flavonoid fraction of M. paradisiaca was administered to groups C, D and E at 100, 200 and 400 mg/kg respectively for 21 days. Group F rats received omeprazole at 1.8 mg/kg for 21 days. Five rats from each group were anaesthetized with ketamine on days 14, 21 and 28. Gastric tissues were excised and fixed in Neutral buffered formalin. This was followed by paraffin wax embedding method and sections stained with haematoxylin and eosin and for immunolocalisation of EGFR and PECAM-1. Data were analysed using descriptive and inferential statistics. RESULTS: There was a significant difference in the ulcer index in the corpus of control and treated rats throughout the experimental period (p = 0.0001). H&E stained sections showed a gradual restoration of the epithelial lining in the treated groups. Immunohistochemical examination showed that M. paradisiaca significantly increased (p < 0.05) reactivity for both EGFR and CD31 across the treatment groups. CONCLUSION: The efficacy of Musa paradisiaca in attenuating the damaging effects of aspirin on the gastric mucosa was observed as there was a significantly increased reactivity for EGFR and PECAM-1 in the gastric corpus in a dose-dependent manner. PMID:28932294

Aspirin-Induced Gastric Lesions Alters EGFR and PECAM-1 Immunoreactivity in Wistar Rats: Modulatory Action of Flavonoid Fraction of Musa Paradisiaca.

PubMed

Alese, Margaret Olutayo; Adewole, Stephen Olarinde; Akinwunmi, Kemi Feyisayo; Omonisi, Abidemi Emmanuel; Alese, Oluwole Ojo

2017-08-15

In this study, Epithelial Growth Factor Receptor and Platelet Endothelial Cell Adhesion Molecule-1 were localised to investigate the healing effects of a flavonoid-rich fraction of M. paradisiaca fruit in the gastric corpus of Wistar rats following aspirin-induced gastric lesion. Mature, unripe fruits of M. paradisiaca were peeled; air dried, pulverised, extracted with 70% methanol, concentrated and partitioned. Ninety male Wistar rats were randomly assigned into 6 groups of 15 rats each. The gastric lesion was induced in groups B, C, D, E and F rats by administration of 400 mg/kg aspirin in distilled water. Group A received distilled water. After 24 hours, flavonoid fraction of M. paradisiaca was administered to groups C, D and E at 100, 200 and 400 mg/kg respectively for 21 days. Group F rats received omeprazole at 1.8 mg/kg for 21 days. Five rats from each group were anaesthetized with ketamine on days 14, 21 and 28. Gastric tissues were excised and fixed in Neutral buffered formalin. This was followed by paraffin wax embedding method and sections stained with haematoxylin and eosin and for immunolocalisation of EGFR and PECAM-1. Data were analysed using descriptive and inferential statistics. There was a significant difference in the ulcer index in the corpus of control and treated rats throughout the experimental period (p = 0.0001). H&E stained sections showed a gradual restoration of the epithelial lining in the treated groups. Immunohistochemical examination showed that M. paradisiaca significantly increased (p < 0.05) reactivity for both EGFR and CD31 across the treatment groups. The efficacy of Musa paradisiaca in attenuating the damaging effects of aspirin on the gastric mucosa was observed as there was a significantly increased reactivity for EGFR and PECAM-1 in the gastric corpus in a dose-dependent manner.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Intercellular Adhesion Molecule-1 Expression by Skeletal Muscle Cells Augments Myogenesis

PubMed Central

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

2014-01-01

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. PMID:25281303

A distinct profile of serum levels of soluble intercellular adhesion molecule-1 and intercellular adhesion molecule-3 in mycosis fungoides and Sézary syndrome.

PubMed

López-Lerma, Ingrid; Estrach, Maria Teresa

2009-08-01

Cell adhesion molecules (CAMs) play a pivotal role in cutaneous localization of T cells. Tissue-selective localization of T lymphocytes to the skin is crucial for immune surveillance and in the pathogenesis of skin disorders. To detect the profile of soluble CAMs in patients with cutaneous T-cell lymphoma (CTCL), we investigated the levels of intercellular adhesion molecule-1 (ICAM-1, soluble ICAM-1 [sICAM-1]); intercellular adhesion molecule-3 (sICAM-3); vascular cell adhesion molecule-1 (sVCAM-1); and E-selectin (sE-selectin) in sera from patients with T-cell-mediated skin diseases. Serum levels of the 4 CAMs were measured by enzyme-linked immunosorbent assay in 42 participants including 11 patients with early stages of CTCL; 7 with advanced stages of CTCL including Sézary syndrome; 12 with inflammatory skin diseases (psoriasis and atopic dermatitis); 8 with skin diseases that may evolve into CTCL; and healthy individuals. Levels were correlated with biological parameters known as prognostic factors in non-Hodgkin lymphomas. In patients with CTCL, significantly increased levels of sICAM-1 and sICAM-3 were found when compared with healthy individuals and patients with inflammatory dermatosis. Soluble E-selectin and sVCAM-1 levels were not increased. There were significant positive correlations between sICAM-1 and sICAM-3 levels and each of them with beta2-microglobulin levels. Limited number of patients was a limitation. There is a distinct profile of soluble CAMs in patients with CTCL. However, future studies with a larger group of patients are needed to confirm these findings. We propose that high sICAM-1 and sICAM-3 levels have important implications in the context of immune response and immune surveillance in these patients.

Indomethacin induced gastropathy in CD18, intercellular adhesion molecule 1, or P-selectin deficient mice

PubMed Central

Morise, Z; Granger, D; Fuseler, J; Anderson, D; Grisham, M

1999-01-01

BACKGROUND—Neutrophil-endothelial cell interactions are thought to play a critical role in the pathophysiology of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy.
AIMS—To optimise a mouse model of NSAID induced gastropathy and to evaluate the importance of adhesion molecules using adhesion molecule deficient mice.
METHODS—Gastropathy was induced in C57BL/6 mice or their adhesion molecule deficient counterparts via oral administration of indomethacin (20 mg/kg). Lesion scores, mucosal permeability, and histopathology were used to assess gastric mucosal injury.
RESULTS—Intragastric administration of indomethacin induced linear haemorrhagic mucosal lesions, primarily in the corpus of the stomach that were first observed at six hours. These lesions continued to develop over the next six hours with maximal lesion scores and mucosal permeabilities at 12 hours. When indomethacin was administered to mice deficient in CD18, intercellular adhesion molecule 1 (ICAM-1), or P-selectin, there were significant decreases in lesion scores compared with their C57BL/6 controls. In addition, mucosal permeabilities were found to be significantly lower in CD18 or ICAM-1 deficient mice observed at 12 hours.
CONCLUSION—Certain leucocyte and endothelial cell adhesion molecules are important determinants for full expression of indomethacin induced gastropathy. It is proposed that this modification of the mouse model may be useful for the investigation of other pathophysiological mechanisms of NSAID induced gastropathy.


Keywords: indomethacin; gastropathy; cyclooxygenase; intercellular adhesion molecule; VCAM; vascular cell adhesion molecule; P-selectin PMID:10486359

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goh, Qingnian; Dearth, Christopher L.; Corbett, Jacob T.

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,more » 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

Cell Adhesion Molecule L1 in Folded (Horseshoe) and Extended Conformations

PubMed Central

Schürmann, Gregor; Haspel, Jeffrey; Grumet, Martin; Erickson, Harold P.

2001-01-01

We have investigated the structure of the cell adhesion molecule L1 by electron microscopy. We were particularly interested in the conformation of the four N-terminal immunoglobulin domains, because x-ray diffraction showed that these domains are bent into a horseshoe shape in the related molecules hemolin and axonin-1. Surprisingly, rotary-shadowed specimens showed the molecules to be elongated, with no indication of the horseshoe shape. However, sedimentation data suggested that these domains of L1 were folded into a compact shape in solution; therefore, this prompted us to look at the molecules by an alternative technique, negative stain. The negative stain images showed a compact shape consistent with the expected horseshoe conformation. We speculate that in rotary shadowing the contact with the mica caused a distortion of the protein, weakening the bonds forming the horseshoe and permitting the molecule to extend. We have thus confirmed that the L1 molecule is primarily in the horseshoe conformation in solution, and we have visualized for the first time its opening into an extended conformation. Our study resolves conflicting interpretations from previous electron microscopy studies of L1. PMID:11408583

Inhibition of TNFα-induced adhesion molecule expression by (Z)-(S)-9-octadecenamide, N-(2-hydroxyethyl,1-methyl).

PubMed

Chen, Caixia; Jin, Xin; Meng, Xianglan; Zheng, Chengwei; Shen, Yanhui; Wang, Yiqing

2011-06-25

Inflammation is a primary event in atherogenesis. Oleoylethanolamide (OEA), a naturally occurring fatty-acid ethanolamide, lowers lipid levels in liver and blood through activation of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPARα). We designed and synthesized (Z)-(S)-9-octadecenamide, N-(2-hydroxyethyl, 1-methyl) (OPA), an OEA analog. The present study investigated the effect of OPA on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC). OPA inhibited expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) stimulated by Tumor Necrosis Factor-α (TNF-α) via activation of PPARα. This inhibition of VCAM-1 and ICAM-1 expression decreased adhesion of monocyte-like cells to stimulated endothelial cells. These results demonstrate that OPA may have anti-inflammatory properties. Our results thus provide new insights into possible future therapeutic approaches to the treatment of atherosclerosis. Copyright © 2011 Elsevier B.V. All rights reserved.

Vascular Cell Adhesion Molecule-1 Expression and Signaling During Disease: Regulation by Reactive Oxygen Species and Antioxidants

PubMed Central

Marchese, Michelle E.; Abdala-Valencia, Hiam

2011-01-01

Abstract The endothelium is immunoregulatory in that inhibiting the function of vascular adhesion molecules blocks leukocyte recruitment and thus tissue inflammation. The function of endothelial cells during leukocyte recruitment is regulated by reactive oxygen species (ROS) and antioxidants. In inflammatory sites and lymph nodes, the endothelium is stimulated to express adhesion molecules that mediate leukocyte binding. Upon leukocyte binding, these adhesion molecules activate endothelial cell signal transduction that then alters endothelial cell shape for the opening of passageways through which leukocytes can migrate. If the stimulation of this opening is blocked, inflammation is blocked. In this review, we focus on the endothelial cell adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Expression of VCAM-1 is induced on endothelial cells during inflammatory diseases by several mediators, including ROS. Then, VCAM-1 on the endothelium functions as both a scaffold for leukocyte migration and a trigger of endothelial signaling through NADPH oxidase-generated ROS. These ROS induce signals for the opening of intercellular passageways through which leukocytes migrate. In several inflammatory diseases, inflammation is blocked by inhibition of leukocyte binding to VCAM-1 or by inhibition of VCAM-1 signal transduction. VCAM-1 signal transduction and VCAM-1-dependent inflammation are blocked by antioxidants. Thus, VCAM-1 signaling is a target for intervention by pharmacological agents and by antioxidants during inflammatory diseases. This review discusses ROS and antioxidant functions during activation of VCAM-1 expression and VCAM-1 signaling in inflammatory diseases. Antioxid. Redox Signal. 15, 1607–1638. PMID:21050132

Increased plasma soluble adhesion molecules; ICAM-1, VCAM-1, and E-selectin levels in patients with slow coronary flow.

PubMed

Turhan, Hasan; Saydam, Gul Sevim; Erbay, Ali Riza; Ayaz, Selime; Yasar, Ayse Saatci; Aksoy, Yuksel; Basar, Nurcan; Yetkin, Ertan

2006-04-04

Inflammation has been reported to be a major contributing factor to many cardiovascular events. In the present study, we aimed to evaluate plasma soluble adhesion molecules; intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin as possible indicators of endothelial activation or inflammation in patients with slow coronary flow. Study population included 17 patients with angiographically proven normal coronary arteries and slow coronary flow in all three coronary vessels (group I, 11 male, 6 female, mean age=48+/-9 years), and 20 subjects with angiographically proven normal coronary arteries without associated slow coronary flow (group II, 11 male, 9 female, mean age=50+/-8 years). Coronary flow rates of all patients and control subjects were documented by Thrombolysis In Myocardial Infarction frame count (TIMI frame count). All patients in group I had TIMI frame counts greater than two standard deviation above those of control subjects (group II) and, therefore, were accepted as exhibiting slow coronary flow. Serum levels of ICAM-1, VCAM-1, and E-selectin were measured in all patients and control subjects using commercially available ELISA kits. Serum ICAM-1, VCAM-1, and E-selectin levels of patients with slow coronary flow were found to be significantly higher than those of control subjects with normal coronary flow (ICAM-1: 545+/-198 ng/ml vs. 242+/-113 ng/ml respectively, p<0.001, VCAM-1: 2040+/-634 ng/ml vs. 918+/-336 ng/ml respectively, p<0.001, E-selectin: 67+/-9 ng/ml vs. 52+/-8 ng/ml respectively, p<0.001). Average TIMI frame count was detected to be significantly correlated with plasma soluble ICAM-1 (r=0.550, p<0.001), VCAM-1 (r=0.569, p<0.001) and E-selectin (r=0.443, p=0.006). Increased levels of soluble adhesion molecules in patients with slow coronary flow may be an indicator of endothelial activation and inflammation and are likely to be in the causal pathway leading to slow coronary flow.

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

House dust mite induces expression of intercellular adhesion molecule-1 in EoL-1 human eosinophilic leukemic cells.

PubMed

Kwon, Byoung Chul; Sohn, Myung Hyun; Kim, Kyung Won; Kim, Eun Soo; Kim, Kyu-Earn; Shin, Myeong Heon

2007-10-01

The house dust mite (HDM) is considered to be the most common indoor allergen associated with bronchial asthma. In this study, we investigated whether crude extract of the HDM Dermatophagoides farinae could activate human eosinophilic leukemic cells (EoL-1) to induce upregulation of cell-surface adhesion molecules. When EoL-1 cells were incubated with D. farinae extract, expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased on the cell surfaces compared to cells incubated with medium alone. In contrast, surface expression of CD11b and CD49d in EoL-1 cells was not affected by D. farinae extract. In addition, pretreatment of cells with NF-kappaB inhibitor (MG-132) or JNK inhibitor (SP600125) significantly inhibited ICAM-1 expression promoted by HDM extract. However, neither p38 MAP kinase inhibitor nor MEK inhibitor prevented HDM-induced ICAM-1 expression in EoL-1 cells. These results suggest that crude extract of D. farinae induces ICAM-1 expression in EoL-1 cells through signaling pathways involving both NF-kappaB and JNK.

House Dust Mite Induces Expression of Intercellular Adhesion Molecule-1 in EoL-1 Human Eosinophilic Leukemic Cells

PubMed Central

Kwon, Byoung Chul; Sohn, Myung Hyun; Kim, Kyung Won; Kim, Eun Soo; Kim, Kyu-Earn

2007-01-01

The house dust mite (HDM) is considered to be the most common indoor allergen associated with bronchial asthma. In this study, we investigated whether crude extract of the HDM Dermatophagoides farinae could activate human eosinophilic leukemic cells (EoL-1) to induce upregulation of cell-surface adhesion molecules. When EoL-1 cells were incubated with D. farinae extract, expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased on the cell surfaces compared to cells incubated with medium alone. In contrast, surface expression of CD11b and CD49d in EoL-1 cells was not affected by D. farinae extract. In addition, pretreatment of cells with NF-κB inhibitor (MG-132) or JNK inhibitor (SP600125) significantly inhibited ICAM-1 expression promoted by HDM extract. However, neither p38 MAP kinase inhibitor nor MEK inhibitor prevented HDM-induced ICAM-1 expression in EoL-1 cells. These results suggest that crude extract of D. farinae induces ICAM-1 expression in EoL-1 cells through signaling pathways involving both NF-κB and JNK. PMID:17982228

The effect of soy protein beverages on serum cell adhesion molecule concentrations in prehypertensive/stage 1 hypertensive individuals.

PubMed

Dettmer, Michelle; Alekel, D Lee; Lasrado, Joanne A; Messina, Mark; Carriquiry, Alicia; Heiberger, Kevin; Stewart, Jeanne W; Franke, Warren

2012-04-01

Prehypertensive and hypertensive individuals are at increased risk of atherosclerotic cardiovascular disease (CVD), in part because hypertension contributes to endothelial dysfunction and increased cell adhesion molecule expression. Soy protein and isoflavones may favorably alter CVD risk factors, and hence the aim of this study was to determine whether intake of cow's milk compared with soy beverage prepared from whole soy bean (WSB) or soy protein isolate (SPI) would lower soluble cell adhesion molecule concentrations as a means of decreasing CVD risk. We enrolled healthy prehypertensive/stage 1 hypertensive men (n = 60; 18-63 years) and premenopausal women (n = 8; 20-48 years). Participants were randomized to 1 of 3 groups for 8 weeks: cow's milk (600 mL/d), SPI beverage (840 mL/d; 30.1 mg total isoflavones/d), or WSB beverage (840 mL/d; 91.4 mg total isoflavones/d). We measured soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and endothelial-leukocyte adhesion molecule-1 (E-selectin) concentrations at baseline and week 8. Soluble CAM concentrations were not altered by treatment and did not differ between prehypertensive and hypertensive participants. However, analysis of variance indicated a treatment × gender interaction (gender effect) for ICAM-1 (p = 0.0037) but not for E-selectin (p = 0.067) or VCAM-1 (p = 0.16). Men had higher concentrations of ICAM-1 and E-selectin, respectively, at baseline (p = 0.0071, p = 0.049) and week 8 (p = 0.0054, p = 0.038) than women did. Neither intake of cow's milk nor soy beverage for 8 weeks altered soluble CAM concentrations in prehypertensive/stage 1 hypertensive individuals, suggesting that neither type of beverage diminished atherosclerotic CVD risk in mildly hypertensive individuals by way of improving circulating CAM concentrations.

The Synaptic Cell Adhesion Molecule, SynCAM1, Mediates Astrocyte-to-Astrocyte and Astrocyte-to-GnRH Neuron Adhesiveness in the Mouse Hypothalamus

PubMed Central

Sandau, Ursula S.; Mungenast, Alison E.; McCarthy, Jack; Biederer, Thomas; Corfas, Gabriel

2011-01-01

We previously identified synaptic cell adhesion molecule 1 (SynCAM1) as a component of a genetic network involved in the hypothalamic control of female puberty. Although it is well established that SynCAM1 is a synaptic adhesion molecule, its contribution to hypothalamic function is unknown. Here we show that, in addition to the expected neuronal localization illustrated by its presence in GnRH neurons, SynCAM1 is expressed in hypothalamic astrocytes. Cell adhesion assays indicated that SynCAM is recognized by both GnRH neurons and astrocytes as an adhesive partner and promotes cell-cell adhesiveness via homophilic, extracellular domain-mediated interactions. Alternative splicing of the SynCAM1 primary mRNA transcript yields four mRNAs encoding membrane-spanning SynCAM1 isoforms. Variants 1 and 4 are predicted to be both N and O glycosylated. Hypothalamic astrocytes and GnRH-producing GT1-7 cells express mainly isoform 4 mRNA, and sequential N- and O-deglycosylation of proteins extracted from these cells yields progressively smaller SynCAM1 species, indicating that isoform 4 is the predominant SynCAM1 variant expressed in astrocytes and GT1-7 cells. Neither cell type expresses the products of two other SynCAM genes (SynCAM2 and SynCAM3), suggesting that SynCAM-mediated astrocyte-astrocyte and astrocyte-GnRH neuron adhesiveness is mostly mediated by SynCAM1 homophilic interactions. When erbB4 receptor function is disrupted in astrocytes, via transgenic expression of a dominant-negative erbB4 receptor form, SynCAM1-mediated adhesiveness is severely compromised. Conversely, SynCAM1 adhesive behavior is rapidly, but transiently, enhanced in astrocytes by ligand-dependent activation of erbB4 receptors, suggesting that erbB4-mediated events affecting SynCAM1 function contribute to regulate astrocyte adhesive communication. PMID:21486931

Organization, regulatory sequences, and alternatively spliced transcripts of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sampaio, S.O.; Mei, C.; Butcher, E.C.

The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is expressed selectively at venular sites of lymphocyte extravasation into mucosal lymphoid tissues and lamina propria, where it directs local lymphocyte trafficking. MAdCAM-1 is a multifunctional type I transmembrane adhesion molecule comprising two distal Ig domains involved in {alpha}4{beta}7 integrin binding, a mucin-like region able to display L-selectin-binding carbohydrates, and a membrane-proximal Ig domain homologous to IgA. We show in this work that the MAdCAM-1 gene is located on chromosome 10 and contains five exons. The signal peptide and each one of the three Ig domains are encoded by a distinct exon, whereasmore » the transmembrane, cytoplasmic tail, and 3{prime}-untranslated region of MAdCAM-1 are combined on a single exon. The mucin-like region and the third Ig domain are encoded together on exon 4. An alternatively spliced MAdCAM-1 mRNA is identified that lacks the mucin/IgA-homologous exon 4-encoded sequences. This short variant of MAdCAM-1 may be specialized to support {alpha}4{beta}7-dependent adhesion strengthening, independent of carbohydrate-presenting function. Sequences 5{prime} of the transcription start site include tandem nuclear factor-KB sites; AP-1, AP-2, and signal peptide-1 binding sites; and an estrogen response element. Our findings reinforce the correspondence between the multidomain structure and versatile functions of this vascular addressin, and suggest an additional level of regulation of carbohydrate-presenting capability, and thus of its importance in lectin-mediated vs. {alpha}4{beta}7-dependent adhesive events in lymphocyte trafficking. 46 refs., 6 figs., 1 tab.« less

Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity.

PubMed Central

Cook-Mills, Joan M; Johnson, Jacob D; Deem, Tracy L; Ochi, Atsuo; Wang, Lei; Zheng, Yi

2004-01-01

VCAM-1 (vascular cell adhesion molecule-1) plays an important role in the regulation of inflammation in atherosclerosis, asthma, inflammatory bowel disease and transplantation. VCAM-1 activates endothelial cell NADPH oxidase, and this oxidase activity is required for VCAM-1-dependent lymphocyte migration. We reported previously that a mouse microvascular endothelial cell line promotes lymphocyte migration that is dependent on VCAM-1, but not on other known adhesion molecules. Here we have investigated the signalling mechanisms underlying VCAM-1 function. Lymphocyte binding to VCAM-1 on the endothelial cell surface activated an endothelial cell calcium flux that could be inhibited with anti-alpha4-integrin and mimicked by anti-VCAM-1-coated beads. VCAM-1 stimulation of calcium responses could be blocked by an inhibitor of intracellular calcium mobilization, a calcium channel inhibitor or a calcium chelator, resulting in the inhibition of NADPH oxidase activity. Addition of ionomycin overcame the calcium channel blocker suppression of VCAM-1-stimulated NADPH oxidase activity, but could not reverse the inhibitory effect imposed by intracellular calcium blockage, indicating that both intracellular and extracellular calcium mobilization are required for VCAM-1-mediated activation of NADPH oxidase. Furthermore, VCAM-1 specifically activated the Rho-family GTPase Rac1, and VCAM-1 activation of NADPH oxidase was blocked by a dominant negative Rac1. Thus VCAM-1 stimulates the mobilization of intracellular and extracellular calcium and Rac1 activity that are required for the activation of NADPH oxidase. PMID:14594451

Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montgomery, K.F.; Tarr, P.I.; Bomsztyk, K.

1991-08-01

Leukocyte adherence to endothelium is in part mediated by the transient expression of endothelial-leukocyte adhesion molecule 1 (ELAM-1) on endothelial surfaces stimulated by tumor necrosis factor {alpha} (TNF), interleukin (IL) 1, or bacterial lipopolysaccharide (LPS). The intracellular factors controlling induction of ELAM-1 mRNA and protein are unknown. In nuclear runoff experiments with cultured human umbilical vein endothelial cells (HUVEC), the authors demonstrate that transcriptional activation of the ELAM-1 gene occurs following stimulation with TNF. Sequence analysis of the 5{prime} flanking region of the ELAM-1 gene reveals consensus DNA-binding sequences for two known transcription factors, NF-{kappa}B and AP-1. Gel mobility shiftmore » assays demonstrate that TNF, IL-1, or LPS induces activation of NF-{kappa}B-like DNA binding activity in HUVEC. Phorbol 12-myristate 13-acetate, a known activator of protein kinase C (PKC), weakly induces NF-{kappa}B-like activity, ELAM-1 mRNA, and ELAM-1 surface expression in HUVEC. However, TNF, IL-1, and LPS do not activate PKC in HUVEC at doses that strongly induce NF-{kappa}B-like protein activation and ELAM-1 gene expression. PKC blockade with H7 does not inhibit activation of these NF-kB-like proteins but does inhibit ELAM-1 gene transcription. They conclude that PKC-independent activation of NF-{kappa}B in HUVEC with TNF, IL-1, or LPS is associated with, but not sufficient for, activation of ELAM-1 gene transcription.« less

Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.

PubMed

Kaneko, Toshihiko; Clark, Richard S J; Ohi, Norihito; Ozaki, Fumihiro; Kawahara, Tetsuya; Kamada, Atsushi; Okano, Kazuo; Yokohama, Hiromitsu; Ohkuro, Masayoshi; Muramoto, Kenzo; Takenaka, Osamu; Kobayashi, Seiichi

2004-06-01

Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.

The profiles of soluble adhesion molecules in the "great obstetrical syndromes".

PubMed

Docheva, Nikolina; Romero, Roberto; Chaemsaithong, Piya; Tarca, Adi L; Bhatti, Gaurav; Pacora, Percy; Panaitescu, Bogdan; Chaiyasit, Noppadol; Chaiworapongsa, Tinnakorn; Maymon, Eli; Hassan, Sonia S; Erez, Offer

2018-02-01

The objective of this study was to determine the profiles of maternal plasma soluble adhesion molecules in patients with preeclampsia, small-for-gestational-age (SGA) fetuses, acute pyelonephritis, preterm labor with intact membranes (PTL), preterm prelabor rupture of the membranes (preterm PROM), and fetal death. A cross-sectional study was conducted to determine maternal plasma concentrations of sE-selectin, sL-selectin, and sP-selectin as well as sICAM-1, sVCAM-1, and sPECAM-1 in patients with (1) an uncomplicated pregnancy (control, n = 100); (2) preeclampsia (n = 94); (3) SGA fetuses (in women without preeclampsia/hypertension, n = 45); (4) acute pyelonephritis (n = 25); (5) PTL (n = 53); (6) preterm PROM (n = 24); and (7) fetal death (n = 34). Concentrations of soluble adhesion molecules and inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-8) were determined with sensitive and specific enzyme-linked immunoassays. In comparison to women with a normal pregnancy, (1) women with preeclampsia had higher median concentrations of sE-selectin, sP-selectin, and sVCAM-1, and a lower concentration of sL-selectin (all p values < .001); (2) patients with SGA fetuses had higher median concentrations of sE-selectin, sP-selectin, and sVCAM-1 (all p values < .05); (3) patients with a fetal death had higher median concentrations of sE-selectin and sP-selectin (all p values < .05); (4) patients with acute pyelonephritis had higher median plasma concentrations of sE-selectin, sICAM-1, and sVCAM-1 (all p values < .001); (5) patients with preeclampsia and acute pyelonephritis, plasma concentrations of sVCAM-1, sE-selectin, and sP-selectin correlated with those of the proinflammatory cytokines TNF-α and interleukin (IL)-8 (all p values < .05); (6) patients with PTL had a higher median concentration of sP-selectin and a lower median concentration of VCAM-1 (all p values < .05); and (7) women with preterm

Sulforaphane suppresses vascular adhesion molecule-1 expression in TNF-α-stimulated mouse vascular smooth muscle cells: involvement of the MAPK, NF-κB and AP-1 signaling pathways.

PubMed

Kim, Ji-Yun; Park, Hye-Jin; Um, Sung Hee; Sohn, Eun-Hwa; Kim, Byung-Oh; Moon, Eun-Yi; Rhee, Dong-Kwon; Pyo, Suhkneung

2012-01-01

Atherosclerosis is a long-term inflammatory disease of the arterial wall. Increased expression of the cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) is associated with increased proliferation of vascular smooth muscle cells (VSMCs), leading to increased neointima or atherosclerotic lesion formation. Therefore, the functional inhibition of adhesion molecules could be a critical therapeutic target of inflammatory disease. In the present study, we investigate the effect of sulforaphane on the expression of VCAM-1 induced by TNF-α in cultured mouse vascular smooth muscle cell lines. Pretreatment of VSMCs for 2h with sulforaphane (1-5μg/ml) dose-dependently inhibited TNF-α-induced adhesion of THP-1 monocytic cells and protein expression of VCAM-1. Sulforaphane also suppressed TNF-α-induced production of intracellular reactive oxygen species (ROS) and activation of p38, ERK and JNK. Furthermore, sulforaphane inhibited NK-κB and AP-1 activation induced by TNF-α. Sulforaphane inhibited TNF-α-induced ΙκΒ kinase activation, subsequent degradation of ΙκΒα and nuclear translocation of p65 NF-κB and decreased c-Jun and c-Fos protein level. This study suggests that sulforaphane inhibits the adhesive capacity of VSMC and downregulates the TNF-α-mediated induction of VCAM-1 in VSMC by inhibiting the MAPK, NF-κB and AP-1 signaling pathways and intracellular ROS production. Thus, sulforaphane may have beneficial effects to suppress inflammation within the atherosclerotic lesion. Copyright © 2011 Elsevier Inc. All rights reserved.

Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression.

PubMed

Graham, Susan M; Rajwans, Nimerta; Jaoko, Walter; Estambale, Benson B A; McClelland, R Scott; Overbaugh, Julie; Liles, W Conrad

2013-07-17

We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. Plasma levels of angiopoietin-1 and angiopoietin-2 (ANG-1, ANG-2) and soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were tested in stored samples from pre-infection, acute infection, and two chronic infection time points. We used nonparametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 < 200 cells/μl, stage IV disease, or antiretroviral therapy initiation) or death. Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all postinfection periods assessed (P < 0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (P = 0.0001), and ANG-1 decreased in chronic infection (P = 0.0004). Among 228 participants followed over 1028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (adjusted hazard ratio 5.36, 95% confidence interval 1.99-14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 postinfection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality.

Early Detection of Junctional Adhesion Molecule-1 (JAM-1) in the Circulation after Experimental and Clinical Polytrauma

PubMed Central

Denk, Stephanie; Wiegner, Rebecca; Hönes, Felix M.; Messerer, David A. C.; Radermacher, Peter; Kalbitz, Miriam; Braumüller, Sonja; McCook, Oscar; Gebhard, Florian; Weckbach, Sebastian; Huber-Lang, Markus

2015-01-01

Severe tissue trauma-induced systemic inflammation is often accompanied by evident or occult blood-organ barrier dysfunctions, frequently leading to multiple organ dysfunction. However, it is unknown whether specific barrier molecules are shed into the circulation early after trauma as potential indicators of an initial barrier dysfunction. The release of the barrier molecule junctional adhesion molecule-1 (JAM-1) was investigated in plasma of C57BL/6 mice 2 h after experimental mono- and polytrauma as well as in polytrauma patients (ISS ≥ 18) during a 10-day period. Correlation analyses were performed to indicate a linkage between JAM-1 plasma concentrations and organ failure. JAM-1 was systemically detected after experimental trauma in mice with blunt chest trauma as a driving force. Accordingly, JAM-1 was reduced in lung tissue after pulmonary contusion and JAM-1 plasma levels significantly correlated with increased protein levels in the bronchoalveolar lavage as a sign for alveolocapillary barrier dysfunction. Furthermore, JAM-1 was markedly released into the plasma of polytrauma patients as early as 4 h after the trauma insult and significantly correlated with severity of disease and organ dysfunction (APACHE II and SOFA score). The data support an early injury- and time-dependent appearance of the barrier molecule JAM-1 in the circulation indicative of a commencing trauma-induced barrier dysfunction. PMID:26556956

Levels of soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-2 in plasma of patients with hemorrhagic fever with renal syndrome, and significance of the changes in level.

PubMed

Qi, Bao-Tai; Wang, Ping; Li, Jie; Ren, Hui-Xun; Xie, Ming

2006-01-01

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral disease characterized by endothelial dysfunction. Vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-2 provide costimulatory signals for the activation of T lymphocytes; these adhesion molecules play key roles in leukocyte adherence and propagation of inflammatory responses. They may be involved in the immunologic response that leads to vascular endothelial cell (VEC) and kidney damage of HFRS patients, and increased levels of soluble (s)VCAM-1 and sICAM-2 in plasma may indicate the severity of HFRS. We examined the presence of sVCAM-1 and sICAM-2 in 52 plasma samples collected from 52 patients. We tested these plasma samples for sVCAM-1 and sICAM-2 by double-antibody sandwich ELISA. We found variable, but persistently elevated, levels of sVCAM-1 and sICAM-2 throughout the various phases and types of the disease, which suggested sVCAM-1 may play an important role in the immunopathological lesions of HFRS and is closely correlated to the severity of HFRS and the degree of kidney damage. sICAM-2 may be associated with the hyperfunctioning of the cellular immune response.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fransen, E.; Vits, L.; Van Camp, G.

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.

[Expression of cell adhesion molecules in acute leukemia cell].

PubMed

Ju, Xiaoping; Peng, Min; Xu, Xiaoping; Lu, Shuqing; Li, Yao; Ying, Kang; Xie, Yi; Mao, Yumin; Xia, Fang

2002-11-01

To investigate the role of cell adhesion molecule in the development and extramedullary infiltration (EI) of acute leukemia. The expressions of neural cell adhesion molecule (NCAM) gene, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) genes in 25 acute leukemia patients bone marrow cells were detected by microarray and reverse transcriptase-polymerase chain reaction (RT-PCR). The expressions of NCAM, ICAM-1 and VCAM-1 gene were significantly higher in acute leukemia cells and leukemia cells with EI than in normal tissues and leukemia cells without EI, respectively, both by cDNA microarray and by RT-PCR. The cDNA microarray is a powerful technique in analysis of acute leukemia cells associated genes. High expressions of cell adhesion molecule genes might be correlated with leukemia pathogenesis and infiltration of acute leukemia cell.

Renoprotective effects of berberine and its potential effect on the expression of β-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats.

PubMed

Tang, Li-Qin; Ni, Wei-Jian; Cai, Ming; Ding, Hai-Hua; Liu, Sheng; Zhang, Shan-Tang

2016-09-01

Berberine has been shown to exert protective effects against diabetic nephropathy (DN), but the mechanisms involved have not been fully characterized. The aim of the present study was to explore the effects of berberine on the expression of β-arrestins, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in DN rat kidneys and investigate the underlying molecular mechanisms. To create the DN model, rats fed a high-fat and high-glucose diet were injected with a single dose of streptozotocin (35 mg/kg, i.p.). Then, DN rats were either treated or not with berberine (50, 100, 200 mg/kg per day, i.g., 8 weeks). Periodic acid-Schiff staining was used to evaluate renal histopathological changes. Renal tissue levels of β-arrestin 1 and β-arrestin 2 were determined by Western blot analysis, whereas immunohistochemistry was used to determine renal ICAM-1 and VCAM-1 levels. Berberine (100, 200 mg/kg) ameliorated the histopathological changes in the diabetic kidney. Western blot analysis revealed significant increases in ICAM-1 and VCAM-1 levels in the kidneys of DN rats, which were reversed by treatment with 100 and 200 mg/kg berberine. In addition, berberine treatment (50, 100, 200 mg/kg) increased diabetic-induced decreases in β-arrestin 1 and β-arrestin 2. Berberine exhibited renoprotective effects in DN rats. The underlying molecular mechanisms may be associated with changes in the levels and regulation of β-arrestin expression, as well as ICAM-1 and VCAM-1 levels in the rat kidney. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

PubMed Central

Zuko, Amila; Oguro-Ando, Asami; Post, Harm; Taggenbrock, Renske L. R. E.; van Dijk, Roland E.; Altelaar, A. F. Maarten; Heck, Albert J. R.; Petrenko, Alexander G.; van der Zwaag, Bert; Shimoda, Yasushi; Pasterkamp, R. Jeroen; Burbach, J. Peter H.

2016-01-01

In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric cis-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from Cntn6-/- mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of Cntn6-/- mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment. PMID:28018171

Changes in the vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and c-reactive protein following administration of aqueous extract of piper sarmentosum on experimental rabbits fed with cholesterol diet

PubMed Central

2011-01-01

Background Inflammation process plays an important role in the development of atherosclerosis. Hypercholesterolemia is one of the major risk factors for atherosclerosis. The present study aimed to evaluate the effect of aqueous extract of Piper sarmentosum (P.s) on inflammatory markers like vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and C-reactive protein (CRP). Methods Forty two male New Zealand white rabbits were divided equally into seven groups; (i) C- control group fed normal rabbit chow (ii) CH- cholesterol diet (1%cholesterol) (iii) X1- 1% cholesterol with water extract of P.s (62.5 mg/kg) (iv) X2- 1% cholesterol with water extract of P.s (125 mg/kg (v) X3- 1% cholesterol with water extract of P.s (250 mg/kg) (vi) X4- 1% cholesterol with water extract of P.s (500 mg/kg) and (vii) SMV group fed with 1% cholesterol supplemented with simvistatin drug (1.2 mg/kg). All animals were treated for 10 weeks. Blood serum was taken for observing the inflammatory markers at the beginning and end of the experiment. Results Rabbits fed with 1% cholesterol diet (CH) showed significant increase in the level of VCAM-1, ICAM-1 and CRP compared to the C group. The levels of VCAM-1, ICAM-1 and CRP in the 1% cholesterol group and supplemented with P.s (500 mg/kg) were significantly reduced compared to the cholesterol group. Similar results were also reported with simvistatin group. Conclusion These results suggest that the supplementation of Piper sarmentosum extract could inhibit inflammatory markers which in turn could prevent atherosclerosis. PMID:21214952

Chlorella 11-Peptide Inhibits the Production of Macrophage-Induced Adhesion Molecules and Reduces Endothelin-1 Expression and Endothelial Permeability

PubMed Central

Shih, Mei Fen; Chen, Lih Chi; Cherng, Jong Yuh

2013-01-01

The inflammation process in large vessels involves the up-regulation of vascular adhesion molecules such as endothelial cell selectin (E-selectin), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) which are also known as the markers of atherosclerosis. We have reported that Chlorella 11-peptide exhibited effective anti-inflammatory effects. This peptide with an amino sequence Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe was further examined for its potential in preventing atherosclerosis in this study. In particular, the roles of Chlorella 11-peptide in lowering the production of vascular adhesion molecules, monocyte chemoattractant protein (MCP-1) and expression of endothelin-1 (ET-1) from endothelia (SVEC4-10 cells) were studied. The production of E-selectin, ICAM-1, VCAM-1 and MCP-1 in SVEC4-10 cells was measured with ELISA. The mRNA expression of ET-1 was analyzed by RT-PCR and agarose gel. Results showed that Chlorella 11-peptide significantly suppressed the levels of E-selectin, ICAM, VCAM, MCP-1 as well as ET-1 gene expression. The inhibition of ICAM-1 and VCAM-1 production by Chlorella 11-peptide was reversed in the presence of protein kinase A inhibitor (H89) which suggests that the cAMP pathway was involved in the inhibitory cause of the peptide. In addition, this peptide was shown to reduce the extent of increased intercellular permeability induced by combination of 50% of lipopolysaccharide (LPS)-activated RAW 264.7 cells medium and 50% normal SEVC cell culture medium (referred to as 50% RAW-conditioned medium). These data demonstrate that Chlorella 11-peptide is a promising biomolecule in preventing chronic inflammatory-related vascular diseases. PMID:24129228

Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.

PubMed

Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia; Khoshnejad, Makan; Tliba, Samira; Christofidou-Solomidou, Melpo; Muzykantov, Vladimir R

2016-07-28

Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Expression of intercellular adhesion molecule-1 by myofibers in mdx mice.

PubMed

Torres-Palsa, Maria J; Koziol, Matthew V; Goh, Qingnian; Cicinelli, Peter A; Peterson, Jennifer M; Pizza, Francis X

2015-11-01

We investigated the extent to which intercellular adhesion molecule-1 (ICAM-1), a critical protein of the inflammatory response, is expressed in skeletal muscles of mdx mice (a murine model of Duchenne muscular dystrophy). Muscles were collected from control and mdx mice at 2-24 weeks of age and analyzed for ICAM-1 expression by means of Western blot and immunofluorescence. Western blot revealed higher expression of ICAM-1 in mdx compared with control muscles through 24 weeks of age. In contrast to control muscles, ICAM-1 was expressed on the membrane of damaged, regenerating, and normal myofibers of mdx mice. CD11b+ myeloid cells also expressed ICAM-1 in mdx muscles, and CD11b+ cells were closely associated with the membrane of myofibers expressing ICAM-1. These findings support a paradigm in which ICAM-1 and its localization to myofibers in muscles of mdx mice contributes to the dystrophic pathology. © 2015 Wiley Periodicals, Inc.

EXPRESSION OF INTERCELLULAR ADHESION MOLECULE-1 BY MYOFIBERS IN mdx MICE

PubMed Central

TORRES-PALSA, MARIA J.; KOZIOL, MATTHEW V.; GOH, QINGNIAN; CICINELLI, PETER A.; PETERSON, JENNIFER M.; PIZZA, FRANCIS X.

2017-01-01

Introduction We investigated the extent to which intercellular adhesion molecule-1 (ICAM-1), a critical protein of the inflammatory response, is expressed in skeletal muscles of mdx mice (a murine model of Duchenne muscular dystrophy). Methods Muscles were collected from control and mdx mice at 2–24 weeks of age and analyzed for ICAM-1 expression by means of Western blot and immunofluorescence. Results Western blot revealed higher expression of ICAM-1 in mdx compared with control muscles through 24 weeks of age. In contrast to control muscles, ICAM-1 was expressed on the membrane of damaged, regenerating, and normal myofibers of mdx mice. CD11b+ myeloid cells also expressed ICAM-1 in mdx muscles, and CD11b+ cells were closely associated with the membrane of myofibers expressing ICAM-1. Conclusions These findings support a paradigm in which ICAM-1 and its localization to myofibers in muscles of mdx mice contributes to the dystrophic pathology. PMID:25728314

Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin.

PubMed

Nawawi, H; Osman, N S; Annuar, R; Khalid, B A K; Yusoff, K

2003-08-01

Adhesion molecules and cytokines are involved in the pathogenesis of intimal injury in atherosclerosis but their relationship with endothelial function remains unclear. The objectives of this study were to examine the effects of atorvastatin on soluble adhesion molecules, interleukin-6 (IL-6) and brachial artery endothelial-dependent flow mediated dilatation (FMD) in patients with familial (FH) and non-familial hypercholesterolaemia (NFH). A total of 74 patients (27 FH and 47 NFH) were recruited. Fasting lipid profiles, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular-cellular adhesion molecule-1 (sVCAM-1), E-selectin, IL-6 and FMD were measured at baseline, 2 weeks, 3 and 9 months post-atorvastatin treatment (FH--80 mg/day, NFH--10 mg/day). In both groups, compared to baseline, sICAM-1 levels were significantly reduced at 2 weeks, further reduced at 3 months and maintained at 9 months (P<0.0001). The IL-6 levels were significantly reduced at 3 months and 9 months compared to baseline for FH (P<0.005) and NFH (P<0.0001). In both groups, the FMD at 2 weeks was higher than baseline (P<0.005), with progressive improvement up to 9 months. FMD was negatively correlated with sICAM-1 and IL-6. In conclusion, both low and high doses of atorvastatin lead to early progressive improvement in endothelial function in patients with primary hypercholesterolaemia. sICAM-1 and IL-6 levels reflect endothelial dysfunction in these patients.

Gastrin-releasing peptide induces monocyte adhesion to vascular endothelium by upregulating endothelial adhesion molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Mi-Kyoung; Park, Hyun-Joo; Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 626-870

Gastrin-releasing peptide (GRP) is a neuropeptide that plays roles in various pathophysiological conditions including inflammatory diseases in peripheral tissues; however, little is known about whether GRP can directly regulate endothelial inflammatory processes. In this study, we showed that GRP promotes the adhesion of leukocytes to human umbilical vein endothelial cells (HUVECs) and the aortic endothelium. GRP increased the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by activating nuclear factor-κB (NF-κB) in endothelial cells. In addition, GRP activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38MAPK, and AKT, and the inhibition of these signaling pathways significantly reduced GRP-inducedmore » monocyte adhesion to the endothelium. Overall, our results suggested that GRP may cause endothelial dysfunction, which could be of particular relevance in the development of vascular inflammatory disorders. - Highlights: • GRP induces adhesion of monocytes to vascular endothelium. • GRP increases the expression of endothelial adhesion molecules through the activation of NF-κB. • ERK1/2, p38MAPK, and Akt pathways are involved in the GRP-induced leukocyte adhesiveness to endothelium.« less

Inhibitors of adhesion molecules expression; the synthesis and pharmacological properties of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives.

PubMed

Kaneko, Toshihiko; Clark, Richard S J; Ohi, Norihito; Kawahara, Tetsuya; Akamatsu, Hiroshi; Ozaki, Fumihiro; Kamada, Atsushi; Okano, Kazuo; Yokohama, Hiromitsu; Muramoto, Kenzo; Ohkuro, Masayoshi; Takenaka, Osamu; Kobayashi, Seiichi

2002-07-01

During a search for novel, orally-active inhibitors of upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), we found a new series of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives to be potent ICAM-1 inhibitors. Of these compounds, N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-N',N'-dimethylsulfamide 7p showed the potent oral inhibitory activities against neutrophil migration in a murine interleukin-1 (IL-1) induced paw inflammation model. The synthesis and structure-activity relationships of these amide derivatives are described.

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)*

PubMed Central

Zhuo, You; Yang, Jeong-Yeh; Moremen, Kelley W.; Prestegard, James H.

2016-01-01

Human carcinoembryonic antigen-related cell adhesion molecule 1 (C?/Au: EACAM1) is a cell-surface signaling molecule involved in cell adhesion, proliferation, and immune response. It is also implicated in cancer angiogenesis, progression, and metastasis. This diverse set of effects likely arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other molecules. Its N-terminal Ig variable (IgV) domain has been suggested to be a principal player in these interactions. Previous crystal structures of the β-sandwich-like IgV domain have been produced using Escherichia coli-expressed material, which lacks native glycosylation. These have led to distinctly different proposals for dimer interfaces, one involving interactions of ABED β-strands and the other involving GFCC′C″ β-strands, with the former burying one prominent glycosylation site. These structures raise questions as to which form may exist in solution and what the effect of glycosylation may have on this form. Here, we use NMR cross-correlation measurements to examine the effect of glycosylation on CEACAM1-IgV dimerization and use residual dipolar coupling (RDC) measurements to characterize the solution structure of the non-glycosylated form. Our findings demonstrate that even addition of a single N-linked GlcNAc at potential glycosylation sites inhibits dimer formation. Surprisingly, RDC data collected on E. coli expressed material in solution indicate that a dimer using the non-glycosylated GFCC′C″ interface is preferred even in the absence of glycosylation. The results open new questions about what other factors may facilitate dimerization of CEACAM1 in vivo, and what roles glycosylation may play in heterophylic interactions. PMID:27471271

Endothelial targeting of high-affinity multivalent polymer nanocarriers directed to intercellular adhesion molecule 1.

PubMed

Muro, Silvia; Dziubla, Thomas; Qiu, Weining; Leferovich, John; Cui, Xiumin; Berk, Erik; Muzykantov, Vladimir R

2006-06-01

Targeting of diagnostic and therapeutic agents to endothelial cells (ECs) provides an avenue to improve treatment of many maladies. For example, intercellular adhesion molecule 1 (ICAM-1), a constitutive endothelial cell adhesion molecule up-regulated in many diseases, is a good determinant for endothelial targeting of therapeutic enzymes and polymer nanocarriers (PNCs) conjugated with anti-ICAM (anti-ICAM/PNCs). However, intrinsic and extrinsic factors that control targeting of anti-ICAM/PNCs to ECs (e.g., anti-ICAM affinity and PNC valency and flow) have not been defined. In this study we tested in vitro and in vivo parameters of targeting to ECs of anti-ICAM/PNCs consisting of either prototype polystyrene or biodegradable poly(lactic-coglycolic) acid polymers (approximately 200 nm diameter spheres carrying approximately 200 anti-ICAM molecules). Anti-ICAM/PNCs, but not control IgG/PNCs 1) rapidly (t1/2 approximately 5 min) and specifically bound to tumor necrosis factor-activated ECs in a dose-dependent manner (Bmax approximately 350 PNC/cell) at both static and physiological shear stress conditions and 2) bound to ECs and accumulated in the pulmonary vasculature after i.v. injection in mice. Anti-ICAM/PNCs displayed markedly higher EC affinity versus naked anti-ICAM (Kd approximately 80 pM versus approximately 8 nM) in cell culture and, probably because of this factor, higher value (185.3 +/- 24.2 versus 50.5 +/- 1.5% injected dose/g) and selectivity (lung/blood ratio 81.0 +/- 10.9 versus 2.1 +/- 0.02, in part due to faster blood clearance) of pulmonary targeting. These results 1) show that reformatting monomolecular anti-ICAM into high-affinity multivalent PNCs boosts their vascular immuno-targeting, which withstands physiological hydrodynamics and 2) support potential anti-ICAM/PNCs utility for medical applications.

Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats.

PubMed

Tayebati, Seyed Khosrow; Tomassoni, Daniele; Di Cesare Mannelli, Lorenzo; Amenta, Francesco

2016-01-01

Endothelial cells represent an important vascular site of signaling and development of damage during ischemia, inflammation and other pathological conditions. Excessive reactive oxygen species production causes pathological activation of endothelium including exposure of cell to adhesion molecules. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members of the immunoglobulin super-family which are present on the surface of endothelial cells. These molecules represent important markers of endothelial inflammation. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with (+/-)-alpha lipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by an increased oxidative stress status in the heart characterized by thiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation increase. The higher oxidative stress also modifies adhesion molecules expression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was increased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly greater in the renal endothelium of SHR. (+/-)-Alpha lipoic acid and (+)-alpha lipoic acid treatment significantly decreased TBARS levels, the nucleic acid oxidation and prevented adhesion molecules expression in cardiac and renal vascular endothelium. These data suggest that endothelial molecules may be used for studying the mechanisms of vascular injury on target organs of hypertension. The effects observed after treatment with (+)-alpha lipoic acid could open new perspectives for countering heart and kidney microvascular injury which represent a common feature in hypertensive end-organs damage.

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. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights

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 Central

Sawicki, Caroline M.; McKim, Daniel B.; Wohleb, Eric S.; Jarrett, Brant L.; Reader, Brenda F.; Norden, Diana M.; Godbout, Jonathan P.; Sheridan, John F.

2014-01-01

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. PMID:25445193

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1).

PubMed

Zhuo, You; Yang, Jeong-Yeh; Moremen, Kelley W; Prestegard, James H

2016-09-16

Human carcinoembryonic antigen-related cell adhesion molecule 1 (C?/Au: EACAM1) is a cell-surface signaling molecule involved in cell adhesion, proliferation, and immune response. It is also implicated in cancer angiogenesis, progression, and metastasis. This diverse set of effects likely arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other molecules. Its N-terminal Ig variable (IgV) domain has been suggested to be a principal player in these interactions. Previous crystal structures of the β-sandwich-like IgV domain have been produced using Escherichia coli-expressed material, which lacks native glycosylation. These have led to distinctly different proposals for dimer interfaces, one involving interactions of ABED β-strands and the other involving GFCC'C″ β-strands, with the former burying one prominent glycosylation site. These structures raise questions as to which form may exist in solution and what the effect of glycosylation may have on this form. Here, we use NMR cross-correlation measurements to examine the effect of glycosylation on CEACAM1-IgV dimerization and use residual dipolar coupling (RDC) measurements to characterize the solution structure of the non-glycosylated form. Our findings demonstrate that even addition of a single N-linked GlcNAc at potential glycosylation sites inhibits dimer formation. Surprisingly, RDC data collected on E. coli expressed material in solution indicate that a dimer using the non-glycosylated GFCC'C″ interface is preferred even in the absence of glycosylation. The results open new questions about what other factors may facilitate dimerization of CEACAM1 in vivo, and what roles glycosylation may play in heterophylic interactions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.

PubMed Central

Marui, N; Offermann, M K; Swerlick, R; Kunsch, C; Rosen, C A; Ahmad, M; Alexander, R W; Medford, R M

1993-01-01

Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis. Images PMID:7691889

The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice

PubMed Central

Barron, Martin J.; Brookes, Steven J.; Draper, Clare E.; Garrod, David; Kirkham, Jennifer; Shore, Roger C.; Dixon, Michael J.

2008-01-01

Nectin-1 is a member of a sub-family of immunoglobulin-like adhesion molecules and a component of adherens junctions. In the current study, we have shown that mice lacking nectin-1 exhibit defective enamel formation in their incisor teeth. Although the incisors of nectin-1-null mice were hypomineralized, the protein composition of the enamel matrix was unaltered. While strong immunostaining for nectin-1 was observed at the interface between the maturation-stage ameloblasts and the underlying cells of the stratum intermedium (SI), its absence in nectin-1-null mice correlated with separation of the cell layers at this interface. Numerous, large desmosomes were present at this interface in wild-type mice; however, where adhesion persisted in the mutant mice, the desmosomes were smaller and less numerous. Nectins have been shown to regulate tight junction formation; however, this is the first report showing that they may also participate in the regulation of desmosome assembly. Importantly, our results show that integrity of the SI–ameloblast interface is essential for normal enamel mineralization. PMID:18703497

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.

A nonpolio enterovirus with respiratory tropism causes poliomyelitis in intercellular adhesion molecule 1 transgenic mice.

PubMed

Dufresne, Andrew T; Gromeier, Matthias

2004-09-14

Coxsackievirus A21 (CAV21) is classified within the species Human enterovirus C (HEV-C) of the Enterovirus genus of picornaviruses. HEV-C share striking homology with the polioviruses (PV), their closest kin among the enteroviruses. Despite a high level of sequence identity, CAV21 and PV cause distinct clinical disease typically attributed to their differential use of host receptors. PV cause poliomyelitis, whereas CAV21 shares a receptor and a propensity to cause upper respiratory tract infections with the major group rhinoviruses. As a model for CAV21 infection, we have developed transgenic mice that express human intercellular adhesion molecule 1, the cell-surface receptor for CAV21. Surprisingly, CAV21 administered to these mice via the intramuscular route causes a paralytic condition consistent with poliomyelitis. The virus appears to invade the CNS by retrograde axonal transport, as has been demonstrated to occur in analogous PV infections. We detected human intercellular adhesion molecule 1 expression on both transgenic mouse and human spinal cord anterior horn motor neurons, indicating that members of HEV-C may share PV's potential to elicit poliomyelitis in humans.

Folic acid deficiency increases delayed neuronal death, DNA damage, platelet endothelial cell adhesion molecule-1 immunoreactivity, and gliosis in the hippocampus after transient cerebral ischemia.

PubMed

Hwang, In Koo; Yoo, Ki-Yeon; Suh, Hong-Won; Kim, Young Sup; Kwon, Dae Young; Kwon, Young-Guen; Yoo, Jun-Hyun; Won, Moo-Ho

2008-07-01

Folic acid deficiency increases stroke risk. In the present study, we examined whether folic acid deficiency enhances neuronal damage and gliosis via oxidative stress in the gerbil hippocampus after transient forebrain ischemia. Animals were exposed to a folic acid-deficient diet (FAD) for 3 months and then subjected to occlusion of both common carotid arteries for 5 min. Exposure to an FAD increased plasma homocysteine levels by five- to eightfold compared with those of animals fed with a control diet (CD). In CD-treated animals, most neurons were dead in the hippocampal CA1 region 4 days after ischemia/reperfusion, whereas, in FAD-treated animals, this occurred 3 days after ischemia/reperfusion. Immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) was performed to examine DNA damage in CA1 neurons in both groups after ischemia, and it was found that 8-OHdG immunoreactivity in both FAD and CD groups peaked at 12 hr after reperfusion, although the immunoreactivity in the FAD group was much greater than that in the CD group. Platelet endothelial cell adhesion molecule-1 (PECAM-1; a final mediator of neutrophil transendothelial migration) immunoreactivity in both groups increased with time after ischemia/reperfusion: Its immunoreactivity in the FAD group was much higher than that in the CD group 3 days after ischemia/reperfusion. In addition, reactive gliosis in the ischemic CA1 region increased with time after ischemia in both groups, but astrocytosis and microgliosis in the FAD group were more severe than in the CD group at all times after ischemia. Our results suggest that folic acid deficiency enhances neuronal damage induced by ischemia. 2008 Wiley-Liss, Inc.

Ankyrin binding activity shared by the neurofascin/L1/NrCAM family of nervous system cell adhesion molecules.

PubMed

Davis, J Q; Bennett, V

1994-11-04

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. Rat neurofascin and NrCAM together comprise over 0.5% of the membrane protein in adult brain tissue. Linkage of these ankyrin-binding cell adhesion molecules to spectrin-based structures may provide a major class of membrane-cytoskeletal connections in adult brain as well as earlier stages of development.

MHC class I, MHC class II and intercellular adhesion molecule-1 (ICAM-1) expression in inflammatory myopathies.

PubMed

Bartoccioni, E; Gallucci, S; Scuderi, F; Ricci, E; Servidei, S; Broccolini, A; Tonali, P

1994-01-01

We investigated the relationship between the MHC-I, MHC-II and intercellular adhesion molecule-1 (ICAM-1) expression on myofibres and the presence of inflammatory cells in muscle specimens of 18 patients with inflammatory myopathies (nine polymyositis, seven dermatomyositis, two inclusion body myositis). We observed MHC-I expression in muscle fibres, infiltrating mononuclear cells and endothelial cells in every specimen. In seven patients, some muscle fibres were MHC-II-positive for the DR antigen, while the DP and DQ antigens were absent. ICAM-1 expression, detected in seven patients, was found in clusters of myofibres, associated with a marked MHC-I positivity and a widespread mononuclear infiltration. Most of the ICAM-1-positive fibres were regenerating fibres. Furthermore, some fibres expressed both ICAM-1 and DR antigens near infiltrating cells. This finding could support the hypothesis that myofibres may themselves be the site of autosensitization.

MHC class I, MHC class II and intercellular adhesion molecule-1 (ICAM-1) expression in inflammatory myopathies.

PubMed Central

Bartoccioni, E; Gallucci, S; Scuderi, F; Ricci, E; Servidei, S; Broccolini, A; Tonali, P

1994-01-01

We investigated the relationship between the MHC-I, MHC-II and intercellular adhesion molecule-1 (ICAM-1) expression on myofibres and the presence of inflammatory cells in muscle specimens of 18 patients with inflammatory myopathies (nine polymyositis, seven dermatomyositis, two inclusion body myositis). We observed MHC-I expression in muscle fibres, infiltrating mononuclear cells and endothelial cells in every specimen. In seven patients, some muscle fibres were MHC-II-positive for the DR antigen, while the DP and DQ antigens were absent. ICAM-1 expression, detected in seven patients, was found in clusters of myofibres, associated with a marked MHC-I positivity and a widespread mononuclear infiltration. Most of the ICAM-1-positive fibres were regenerating fibres. Furthermore, some fibres expressed both ICAM-1 and DR antigens near infiltrating cells. This finding could support the hypothesis that myofibres may themselves be the site of autosensitization. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7507012

Expression of genes encoding IGFBPs, SNARK, CD36, and PECAM1 in the liver of mice treated with chromium disilicide and titanium nitride nanoparticles.

PubMed

Minchenko, Dmytro O; Tsymbal, D O; Yavorovsky, O P; Solokha, N V; Minchenko, O H

2017-04-25

The aim of the present study was to examine the effect of chromium disilicide and titanium nitride nanoparticles on the expression level of genes encoding important regulatory factors (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK/NUAK2, CD36, and PECAM1/CD31) in mouse liver for evaluation of possible toxic effects of these nanoparticles. Male mice received 20 mg chromium disilicide nanoparticles (45 nm) and titanium nitride nanoparticles (20 nm) with food every working day for 2 months. The expression of IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK, CD36, and PECAM1 genes in mouse liver was studied by quantitative polymerase chain reaction. Treatment of mice with chromium disilicide nanoparticles led to down-regulation of the expression of IGFBP2, IGFBP5, PECAM1, and SNARK genes in the liver in comparison with control mice, with more prominent changes for SNARK gene. At the same time, the expression of IGFBP3 and CD36 genes was increased in mouse liver upon treatment with chromium disilicide nanoparticles. We have also shown that treatment with titanium nitride nanoparticles resulted in down-regulation of the expression of IGFBP2 and SNARK genes in the liver with more prominent changes for SNARK gene. At the same time, the expression of IGFBP3, IGFBP4, and CD36 genes was increased in the liver of mice treated with titanium nitride nanoparticles. Furthermore, the effect of chromium disilicide nanoparticles on IGFBP2 and CD36 genes expression was significantly stronger as compared to titanium nitride nanoparticles. The results of this study demonstrate that chromium disilicide and titanium nitride nanoparticles have variable effects on the expression of IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK, CD36, and PECAM1 genes in mouse liver, which may reflect the genotoxic activities of the studied nanoparticles.

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.

Cafestol Inhibits Cyclic-Strain-Induced Interleukin-8, Intercellular Adhesion Molecule-1, and Monocyte Chemoattractant Protein-1 Production in Vascular Endothelial Cells

PubMed Central

Hao, Wen-Rui; Sung, Li-Chin; Chen, Chun-Chao; Chen, Jin-Jer

2018-01-01

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol. PMID:29854096

Nuclear factor I-A represses expression of the cell adhesion molecule L1

PubMed Central

2009-01-01

Background The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression. Results We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse L1 gene. Electrophoretic mobility shift assay (EMSA) showed binding of nuclear factor I-A (NFI-A) to this site. Moreover, for a brain-specific isoform of NFI-A (NFI-A bs), we confirmed the interaction in vivo using chromatin immunoprecipitation (ChIP). Reporter gene assays showed that in neuroblastoma cells, overexpression of NFI-A bs repressed L1 expression threefold. Conclusion Our findings suggest that NFI-A, in particular its brain-specific isoform, represses L1 gene expression, and might act as a second silencer of L1 in addition to the neural restrictive silencer factor (NRSF). PMID:20003413

6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm.

PubMed

Chang, Chih-Zen; Lin, Chih-Lung; Kassel, Neal F; Kwan, Aij-Lie; Howng, Shen-Long

2010-05-01

Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important inflammatory mediators which are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The authors previously found that 6-mercaptopurine (6-mp) was effective in preventing and reversing arterial narrowing in a rodent SAH model. The present study was to examine whether levels of adhesion molecules were altered after treatment with 6-mp in this animal model. Animals were each injected with autologous blood into the cisterna magna, and intraperitoneal treatment with 6-mp (2 mg/kg) was initiated 1 h before (prevention) or later (treatment). The compound was subsequently administered at 24 and 48 h post-SAH. Blood samples were collected at 72 h post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. The basilar arteries were harvested and sliced, and their cross-sectional areas were measured. Morphologically, convolution of the internal elastic lamina, distorted endothelial wall, and myonecrosis of the smooth muscle were prominently observed in the SAH only and vehicle-treated SAH groups, but not in the 6-mp-treated SAH group or in healthy controls. No significant differences were found in the levels of VCAM-1 among all groups. However, the levels of E-selectin were increased in all animals subjected to SAH (SAH only and SAH plus vehicle groups) compared with healthy controls (no SAH), but not in the 6-mp group (SAH plus 6-mp treatment and preventive treatment with 6-mp).Likewise, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and pretreatment and treatment with 6-mp reduced ICAM-1 to control levels. These results show that ICAM-1 and E-selectin may play a role in mediating SAH-induced vasospasm and that a reduction of both adhesive molecules after SAH may partly contribute to the antispastic effect of 6-mp.

Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages.

PubMed

Komohara, Yoshihiro; Ma, Chaoya; Yano, Hiromu; Pan, Cheng; Horlad, Hasita; Saito, Yoichi; Ohnishi, Koji; Fujiwara, Yukio; Okuno, Yutaka; Nosaka, Kisato; Shimosaki, Shunsuke; Morishita, Kazuhiro; Matsuoka, Masao; Wakayama, Tomohiko; Takeya, Motohiro

2017-07-05

Cell adhesion molecule 1 (CADM1) is a cell adhesion molecule that is expressed in brain, liver, lung, testis, and some kinds of cancer cells including adult T-cell leukemia/lymphoma (ATLL). Recent studies have indicated the involvement of CADM1 in cell-cell contact between cytotoxic T-lymphocytes and virus infected cells. We previously reported that cell-cell interaction between lymphoma cells and macrophages induces lymphoma cell proliferation. In the present study, we investigated whether CADM1 is associated with cell-cell interaction between several human lymphoma cell lines and macrophages.CADM1 expression was observed in the ATLL cell lines, ATN-1, ATL-T, and ATL-35T, and in the B cell lymphoma cell lines, TL-1, DAUDI, and SLVL, using western blotting. Significant cell-cell interaction between macrophages and ATN-1, ATL-T, ATL-35T and MT-2, DAUDI, and SLVL cells, as assessed by induction of cell proliferation, was observed. Immunohistochemical analysis of human biopsy samples indicated CADM1 expression in 10 of 14 ATLL cases; however, no case of follicular lymphoma or diffuse large B-cell lymphoma was positive for CADM1. Finally, the interaction of macrophages with cells of the CADM1-negative ED ATLL cell line and CADM1-transfected ED cells was tested. However, significant cell-cell interaction between macrophage and CADM1-transfected ED cells was not observed. We conclude that CADM1 was not associated with cell-cell interaction between lymphoma cells and macrophages, although CADM1 may be a useful marker of ATLL for diagnostic procedures.

Intercellular adhesion molecule-1 blockade attenuates inflammatory response and improves microvascular perfusion in rat pancreas grafts.

PubMed

Preissler, Gerhard; Eichhorn, Martin; Waldner, Helmut; Winter, Hauke; Kleespies, Axel; Massberg, Steffen

2012-10-01

After pancreas transplantation (PTx), early capillary malperfusion and leukocyte recruitment indicate the manifestation of severe ischemia/reperfusion injury (IRI). Oscillatory blood-flow redistribution (intermittent capillary perfusion, IP), leading to an overall decrease in erythrocyte flux, precedes complete microvascular perfusion failure with persistent blood flow cessation. We addressed the role of intercellular adhesion molecule-1 (ICAM-1) for leukocyte-endothelial interactions (LEIs) after PTx and evaluated the contribution of IP and malperfusion. Pancreas transplantation was performed in rats after 18-hour preservation, receiving either isotype-matched IgG or monoclonal anti-ICAM-1 antibodies (10 mg/kg intravenously) once before reperfusion. Leukocyte-endothelial interaction, IP, erythrocyte flux, and functional capillary density, respectively, were examined in vivo during 2-hour reperfusion. Nontransplanted animals served as controls. Tissue samples were analyzed by histomorphometry. In grafts of IgG-treated animals, IP was encountered already at an early stage after reperfusion and steadily increased over 2 hours, whereas erythrocyte flux declined continuously. In contrast, inhibition of ICAM-1 significantly improved erythrocyte flux and delayed IP appearance by 2 hours. Further, anti-ICAM-1 significantly reduced LEI and leukocyte tissue infiltration when compared to IgG; edema development was less pronounced in response to anti-ICAM-1 monoclonal antibody. Intercellular adhesion molecule-1 blockade significantly attenuates IRI via immediate reduction of LEI and concomitant improvement of capillary perfusion patterns, emphasizing its central role during IRI in PTx.

Intercellular Adhesion Molecule 1 Knockout Abrogates Radiation Induced Pulmonary Inflammation

NASA Astrophysics Data System (ADS)

Hallahan, Dennis E.; Virudachalam, Subbulakshmi

1997-06-01

Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration

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

Allergen-stimulated T lymphocytes from allergic patients induce vascular cell adhesion molecule-1 (VCAM-1) expression and IL-6 production by endothelial cells.

PubMed Central

Delneste, Y; Jeannin, P; Gosset, P; Lassalle, P; Cardot, E; Tillie-Leblond, I; Joseph, M; Pestel, J; Tonnel, A B

1995-01-01

Adhesion of inflammatory cells to endothelium is a critical step for their transvascular migration to inflammatory sites. To evaluate the relationship between T lymphocytes (TL) and vascular endothelium, supernatants from allergen-stimulated TL obtained from patients sensitive to Dermatophagoides pteronyssinus (Dpt) versus healthy subjects were added to endothelial cell (EC) cultures. TL were stimulated by autologous-activated antigen-presenting cells (APC) previously fixed in paraformaldehyde to prevent monokine secretion. Two parameters were measured: the expression of adhesion molecule and the production of IL-6. Related allergen-stimulated TL supernatants from allergic patients induced an increase of VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) expression when supernatants of the control groups (TL exposed to an unrelated allergen or not stimulated or TL obtained from healthy subjects) did not. E-selectin expression was not modulated whatever the supernatant added to EC culture. IL-6 production by EC was significantly enhanced after activation with related allergen-stimulated TL supernatants from allergics compared with control supernatants. Induction of VCAM-1 expression was inhibited by adding neutralizing antibodies against IL-4, whereas IL-6 production and ICAM-1 expression were inhibited by anti-interferon-gamma (IFN-gamma) antibodies. Enhanced production of IL-4 and IFN-gamma was detected in related allergen-stimulated TL supernatants from allergic subjects compared with the different supernatants. These data suggest that allergen-specific TL present in the peripheral blood of allergic patients are of Th1 and Th2 subtypes. Their stimulation in allergic patients may lead to the activation of endothelial cells and thereby participate in leucocyte recruitment towards the inflammatory site. PMID:7542574

Outer membrane protein A of Escherichia coli K1 selectively enhances the expression of intercellular adhesion molecule-1 in brain microvascular endothelial cells.

PubMed

Selvaraj, Suresh K; Periandythevar, Parameswaran; Prasadarao, Nemani V

2007-04-01

Escherichia coli K1 meningitis is a serious central nervous system disease with unchanged mortality and morbidity rates for last few decades. Intercellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule involved in leukocyte trafficking toward inflammatory stimuli at the vascular endothelium; however, the effect of E. coli invasion of endothelial cells on the expression of ICAM-1 is not known. We demonstrate here that E. coli K1 invasion of human brain microvascular endothelial cells (HBMEC) selectively up-regulates the expression of ICAM-1, which occurs only in HBMEC invaded by the bacteria. The interaction of outer membrane protein A (OmpA) of E. coli with its receptor, Ecgp, on HBMEC was critical for the up-regulation of ICAM-1 and was depend on PKC-alpha and PI3-kinase signaling. Of note, the E. coli-induced up-regulation of ICAM-1 was not due to the cytokines secreted by HBMEC upon bacterial infection. Activation of NF-kappaB was required for E. coli mediated expression of ICAM-1, which was significantly inhibited by over-expressing the dominant negative forms of PKC-alpha and p85 subunit of PI3-kinase. The increased expression of ICAM-1 also enhanced the binding of THP-1 cells to HBMEC. Taken together, these data suggest that localized increase in ICAM-1 expression in HBMEC invaded by E. coli requires a novel interaction between OmpA and its receptor, Ecgp.

Ox-LDL Promotes Migration and Adhesion of Bone Marrow-Derived Mesenchymal Stem Cells via Regulation of MCP-1 Expression

PubMed Central

Wang, Congrui; Wang, Huaibin; Lu, Ming; Li, Yonghai; Feng, Huigen; Yuan, Zhiqing

2013-01-01

Bone marrow-derived mesenchymal stem cells (bmMSCs) are the most important cell source for stem cell transplant therapy. The migration capacity of MSCs is one of the determinants of the efficiency of MSC-based transplant therapy. Our recent study has shown that low concentrations of oxidized low-density lipoprotein (ox-LDL) can stimulate proliferation of bmMSCs. In this study, we investigated the effects of ox-LDL on bmMSC migration and adhesion, as well as the related mechanisms. Our results show that transmigration rates of bmMSCs and cell-cell adhesion between bmMSCs and monocytes are significantly increased by treatments with ox-LDL in a dose- and time-dependent manner. Expressions of ICAM-1, PECAM-1, and VCAM-1 as well as the levels of intracellular Ca2+ are also markedly increased by ox-LDL in a dose-dependent manner. Cytoskeleton analysis shows that ox-LDL treatment benefits to spreading of bmMSCs and organization of F-actin fibers after being plated for 6 hours. More interestingly, treatments with ox-LDL also markedly increase expressions of LOX-1, MCP-1, and TGF-β; however, LOX-1 antibody and MCP-1 shRNA markedly inhibit ox-LDL-induced migration and adhesion of bmMSCs, which suggests that ox-LDL-induced bmMSC migration and adhesion are dependent on LOX-1 activation and MCP-1 expression. PMID:23956504

Exosomes from iPSCs Delivering siRNA Attenuate Intracellular Adhesion Molecule-1 Expression and Neutrophils Adhesion in Pulmonary Microvascular Endothelial Cells.

PubMed

Ju, Zhihai; Ma, Jinhui; Wang, Chen; Yu, Jie; Qiao, Yeru; Hei, Feilong

2017-04-01

The pro-inflammatory activation of pulmonary microvascular endothelial cells resulting in continuous expression of cellular adhesion molecules, and subsequently recruiting primed neutrophils to form a firm neutrophils-endothelium (PMN-EC) adhesion, has been examined and found to play a vital role in acute lung injury (ALI). RNA interference (RNAi) is a cellular process through harnessing a natural pathway silencing target gene based on recognition and subsequent degradation of specific mRNA sequences. It opens a promising approach for precision medicine. However, this application was hampered by many obstacles, such as immunogenicity, instability, toxicity problems, and difficulty in across the biological membrane. In this study, we reprogrammed urine exfoliated renal epithelial cells into human induced pluripotent stem cells (huiPSCs) and purified the exosomes (Exo) from huiPSCs as RNAi delivery system. Through choosing the episomal system to deliver transcription factors, we obtained a non-integrating huiPSCs. Experiments in both vitro and vivo demonstrated that these huiPSCs possess the pluripotent properties. The exosomes of huiPSCs isolated by differential centrifugation were visualized by transmission electron microscopy (TEM) showing a typical exosomal appearance with an average diameter of 122 nm. Immunoblotting confirmed the presence of the typical exosomal markers, including CD63, TSG 101, and Alix. Co-cultured PKH26-labeled exosomes with human primary pulmonary microvascular endothelial cells (HMVECs) confirmed that they could be internalized by recipient cells at a time-dependent manner. Then, electroporation was used to introduce siRNA against intercellular adhesion molecule-1 (ICAM-1) into exosomes to form an Exo/siRNA compound. The Exo/siRNA compound efficiently delivered the target siRNA into HMVECs causing selective gene silencing, inhibiting the ICAM-1 protein expression, and PMN-EC adhesion induced by lipopolysaccharide (LPS). These data suggest

Stability validation of paraformaldehyde-fixed samples for the assessment of the platelet PECAM-1, P-selectin, and PAR-1 thrombin receptor by flow cytometry.

PubMed

Atar, Oliver D; Eisert, Christian; Pokov, Ilya; Serebruany, Victor L

2010-07-01

Sample fixation for storage and/or transportation represents an unsolved challenge for multicenter clinical trials assessing serial changes in platelet activity, or monitoring various antiplatelet regimens. Whole blood flow cytometry represents a major advance in defining platelet function, although special training and expensive equipment is required. We sought to determine how fixation with 2% paraformaldehyde (PFA), and storage of blood samples over 1 week affects the flow cytometry readings for both intact and thrombin-activating four major surface platelet receptors. Whole blood platelet expression of PECAM-1, P-selectin, PAR-1 inactive receptor (SPAN-12), and cleaved (WEDE-15) epitope was assessed immediately after blood draw, after staining with 2% PFA, and at day 1, 3, 5, and 7. The study was performed in 6 volunteers with multiple risk factors for vascular disease, not receiving any antiplatelet agents. Staining with PFA resulted in a slight decrease of fluorescence intensity, especially for PECAM-1, while antigen expression at day 1, 3 and 5 remains consistent, and highly reproducible. At day 7 there was a small but inconsistent trend towards diminished fluorescence intensity. The platelet data were consistent while validated with the isotype-matched irrelevant antibody. These data suggest that there is a 5 day window to perform final flow cytometry readings of whole blood PFA-fixed inactivated platelet samples. In contrast, thrombin activation cause gradual loss of flow cytometry signal, and cannot be recommended for long-term storage. This is critical logistic information for conducting multicenter platelet substudies within the framework of major clinical trials.

A Functional Analysis on the Interspecies Interaction between Mouse LFA-1 and Human Intercellular Adhesion Molecule-1 at the Cell Level

PubMed Central

Núñez, David; Comas, Laura; Lanuza, Pilar M.; Sánchez-Martinez, Diego; Pérez-Hernández, Marta; Catalán, Elena; Domingo, María Pilar; Velázquez-Campoy, Adrián; Pardo, Julián; Gálvez, Eva M.

2017-01-01

The interaction between intercellular adhesion molecules (ICAM) and the integrin leukocyte function-associated antigen-1 (LFA-1) is crucial for the regulation of several physiological and pathophysiological processes like cell-mediated elimination of tumor or virus infected cells, cancer metastasis, or inflammatory and autoimmune processes. Using purified proteins it was reported a species restriction for the interaction of ICAM-1 and LFA-1, being mouse ICAM-1 able to interact with human LFA-1 but not human ICAM-1 with mouse LFA-1. However, in vivo results employing tumor cells transfected with human ICAM-1 suggest that functionally mouse LFA-1 can recognize human ICAM-1. In order to clarify the interspecies cross-reactivity of the ICAM-1/LFA-1 interaction, we have performed functional studies analyzing the ability of human soluble ICAM-1 and human/mouse LFA-1 derived peptides to inhibit cell aggregation and adhesion as well as cell-mediated cytotoxicity in both mouse and human systems. In parallel, the affinity of the interaction between mouse LFA-1-derived peptides and human ICAM-1 was determined by calorimetry assays. According to the results obtained, it seems that human ICAM-1 is able to interact with mouse LFA-1 on intact cells, which should be taking into account when using humanized mice and xenograft models for the study of immune-related processes. PMID:29312326

A Functional Analysis on the Interspecies Interaction between Mouse LFA-1 and Human Intercellular Adhesion Molecule-1 at the Cell Level.

PubMed

Núñez, David; Comas, Laura; Lanuza, Pilar M; Sánchez-Martinez, Diego; Pérez-Hernández, Marta; Catalán, Elena; Domingo, María Pilar; Velázquez-Campoy, Adrián; Pardo, Julián; Gálvez, Eva M

2017-01-01

The interaction between intercellular adhesion molecules (ICAM) and the integrin leukocyte function-associated antigen-1 (LFA-1) is crucial for the regulation of several physiological and pathophysiological processes like cell-mediated elimination of tumor or virus infected cells, cancer metastasis, or inflammatory and autoimmune processes. Using purified proteins it was reported a species restriction for the interaction of ICAM-1 and LFA-1, being mouse ICAM-1 able to interact with human LFA-1 but not human ICAM-1 with mouse LFA-1. However, in vivo results employing tumor cells transfected with human ICAM-1 suggest that functionally mouse LFA-1 can recognize human ICAM-1. In order to clarify the interspecies cross-reactivity of the ICAM-1/LFA-1 interaction, we have performed functional studies analyzing the ability of human soluble ICAM-1 and human/mouse LFA-1 derived peptides to inhibit cell aggregation and adhesion as well as cell-mediated cytotoxicity in both mouse and human systems. In parallel, the affinity of the interaction between mouse LFA-1-derived peptides and human ICAM-1 was determined by calorimetry assays. According to the results obtained, it seems that human ICAM-1 is able to interact with mouse LFA-1 on intact cells, which should be taking into account when using humanized mice and xenograft models for the study of immune-related processes.

Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta.

PubMed Central

Maubert, B; Guilbert, L J; Deloron, P

1997-01-01

Late stages of Plasmodium falciparum-infected erythrocytes (IRBCs) frequently sequester in the placentas of pregnant women, a phenomenon associated with low birth weight of the offspring. To investigate the physiological mechanism of this sequestration, we developed an in vitro assay for studying the cytoadherence of IRBCs to cultured term human trophoblasts. The capacity for binding to the syncytiotrophoblast varied greatly among P. falciparum isolates and was mediated by intercellular adhesion molecule 1 (ICAM-1), as binding was totally inhibited by 84H10, a monoclonal antibody specific for ICAM-1. Binding of the P. falciparum line RP5 to the syncytiotrophoblast involves chondroitin-4-sulfate (CSA), as this binding was dramatically impaired by addition of free CSA to the binding medium or by preincubation of the syncytiotrophoblast with chondroitinase ABC. ICAM-1 and CSA were visualized on the syncytiotrophoblast by immunofluorescence, while CD36, E-selectin, and vascular cell adhesion molecule 1 were not expressed even on tumor necrosis factor alpha (TNF-alpha)-stimulated syncytiotrophoblast tissue, and monoclonal antibodies against these cell adhesion molecules did not inhibit cytoadherence. ICAM-1 expression and cytoadherence of wild isolates was upregulated by TNF-alpha, a cytokine that can be secreted by the numerous mononuclear phagocytes present in malaria-infected placentas. These results suggest that cytoadherence may be involved in the placental sequestration and broaden the understanding of the physiopathology of the malaria-infected placenta. PMID:9119459

Clinical significance of circulating vascular cell adhesion molecule-1 to white matter disintegrity in Alzheimer's dementia.

PubMed

Huang, Chi-Wei; Tsai, Meng-Han; Chen, Nai-Ching; Chen, Wei-Hsi; Lu, Yan-Ting; Lui, Chun-Chung; Chang, Ya-Ting; Chang, Wen-Neng; Chang, Alice Y W; Chang, Chiung-Chih

2015-11-25

Endothelial dysfunction leads to worse cognitive performance in Alzheimer's dementia (AD). While both cerebrovascular risk factors and endothelial dysfunction lead to activation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin, it is not known whether these biomarkers extend the diagnostic repertoire in reflecting intracerebral structural damage or cognitive performance. A total of 110 AD patients and 50 age-matched controls were enrolled. Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured and correlated with the cognitive performance, white matter macro-structural changes, and major tract-specific fractional anisotropy quantification. The AD patients were further stratified by clinical dementia rating score (mild dementia, n=60; moderate-to-severe dementia, n=50). Compared with the controls, plasma levels of VCAM-1 (p< 0.001), ICAM-1 (p=0.028) and E-selectin (p=0.016) were significantly higher in the patients, but only VCAM-1 levels significantly reflected the severity of dementia (p< 0.001). In addition, only VCAM-1 levels showed an association with macro- and micro- white matter changes especially in the superior longitudinal fasciculus (p< 0.001), posterior thalamic radiation (p=0.002), stria terminalis (p=0.002) and corpus callosum (p=0.009), and were independent of, age and cortical volume. These tracts show significant association with MMSE, short term memory and visuospatial function. Meanwhile, while VCAM-1 level correlated significantly with short-term memory (p=0.026) and drawing (p=0.025) scores in the AD patients after adjusting for age and education, the significance disappeared after adjusting for global FA. Endothelial activation, especially VCAM-1, was of clinical significance in AD that reflects macro- and micro-structural changes and poor short term memory and visuospatial function.

Rapid detection of urinary soluble intercellular adhesion molecule-1 for determination of lupus nephritis activity.

PubMed

Wang, Yanyun; Tao, Ye; Liu, Yi; Zhao, Yi; Song, Chao; Zhou, Bin; Wang, Tao; Gao, Linbo; Zhang, Lin; Hu, Huaizhong

2018-06-01

The current methods of monitoring the activity of lupus nephritis (LN) may cause unnecessary hospital visits or delayed immunosuppressive therapy. We aimed to find a urinary biomarker that could be developed as a home-based test for monitoring the activity of LN.Urine samples were collected immediately before a renal biopsy from patients of suspected active LN, and also from patients with inactive LN, systemic lupus erythematous without LN or healthy controls. Biomarker search was conducted on a cytokine antibody array and confirmation was done by quantitative evaluation with enzyme-linked immunosorbent assay. The Mann-Whiney test or Student t test was used to compare the levels of 9 cytokines between different groups. The sensitivity and specificity of each cytokine for diagnosis of LN was evaluated by receiver operating characteristic curve. A rapid test based on colloidal gold immunochromatography was then developed for bedside or home use. Furthermore, an experimental e-healthcare system was constructed for recording and sharing the results of the rapid test a cloud-assisted internet of things (IoT) consisting of a sensing device, an IoT device and a cloud server.Adiponectin (Acrp30), soluble intercellular cell adhesion molecule-1 (sICAM-1), neural cell adhesion molecule 1 (NCAM-1), and CD26 were significantly higher in urine samples of active LN patients. sICAM-1 appeared more sensitive and specific among these candidates. When the cut-off value of sICAM-1 was set at 1.44 ng/mL, the sensitivity reached 98.33% with a specificity at 85.71%. The sICAM-1 strip test showed comparable sensitivity of 95% and a specificity of 83.3% for assessing the LN activity. Meanwhile, the e-healthcare system was able to conveniently digitize and share the sICAM-1 rapid test results.sICAM-1 appeared to be an excellent biomarker for monitoring LN activity. The e-healthcare system with cloud-assisted IoT could assist the digitalization and sharing of the bedside or home-based s

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 firstmore » 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.« less

The cell adhesion molecule CHL1 interacts with patched-1 to regulate apoptosis during postnatal cerebellar development.

PubMed

Katic, Jelena; Loers, Gabriele; Tosic, Jelena; Schachner, Melitta; Kleene, Ralf

2017-08-01

The immunoglobulin superfamily adhesion molecule close homolog of L1 (CHL1) plays important roles during nervous system development. Here, we identified the hedgehog receptor patched-1 (PTCH1) as a novel CHL1-binding protein and showed that CHL1 interacts with the first extracellular loop of PTCH1 via its extracellular domain. Colocalization and co-immunoprecipitation of CHL1 with PTCH1 suggest an association of CHL1 with this major component of the hedgehog signaling pathway. The trans -interaction of CHL1 with PTCH1 promotes neuronal survival in cultures of dissociated cerebellar granule cells and of organotypic cerebellar slices. An inhibitor of the PTCH1-regulated hedgehog signal transducer, smoothened (SMO), and inhibitors of RhoA and Rho-associated kinase (ROCK) 1 and 2 prevent CHL1-dependent survival of cultured cerebellar granule cells and survival of cerebellar granule and Purkinje cells in organotypic cultures. In histological sections from 10- and 14-day-old CHL1-deficient mice, enhanced apoptosis of granule, but not Purkinje, cells was observed. The results of the present study indicate that CHL1 triggers PTCH1-, SMO-, RhoA- and ROCK-dependent signal transduction pathways to promote neuronal survival after cessation of the major morphogenetic events during mouse cerebellar development. © 2017. Published by The Company of Biologists Ltd.

Regulation of Bacteria-Induced Intercellular Adhesion Molecule-1 by CCAAT/Enhancer Binding Proteins

PubMed Central

Manzel, Lori J.; Chin, Cecilia L.; Behlke, Mark A.; Look, Dwight C.

2009-01-01

Direct interaction between bacteria and epithelial cells may initiate or amplify the airway response through induction of epithelial defense gene expression by nuclear factor-κB (NF-κB). However, multiple signaling pathways modify NF-κB effects to modulate gene expression. In this study, the effects of CCAAT/enhancer binding protein (C/EBP) family members on induction of the leukocyte adhesion glycoprotein intercellular adhesion molecule-1 (ICAM-1) was examined in primary cultures of human tracheobronchial epithelial cells incubated with nontypeable Haemophilus influenzae. Increased ICAM-1 gene transcription in response to H. influenzae required gene sequences located at −200 to −135 in the 5′-flanking region that contain a C/EBP-binding sequence immediately upstream of the NF-κB enhancer site. Constitutive C/EBPβ was found to have an important role in epithelial cell ICAM-1 regulation, while the adjacent NF-κB sequence binds the RelA/p65 and NF-κB1/p50 members of the NF-κB family to induce ICAM-1 expression in response to H. influenzae. The expression of C/EBP proteins is not regulated by p38 mitogen-activated protein kinase activation, but p38 affects gene transcription by increasing the binding of TATA-binding protein to TATA-box–containing gene sequences. Epithelial cell ICAM-1 expression in response to H. influenzae was decreased by expressing dominant-negative protein or RNA interference against C/EBPβ, confirming its role in ICAM-1 regulation. Although airway epithelial cells express multiple constitutive and inducible C/EBP family members that bind C/EBP sequences, the results indicate that C/EBPβ plays a central role in modulation of NF-κB–dependent defense gene expression in human airway epithelial cells after exposure to H. influenzae. PMID:18703796

Effects of dietary glutamine on adhesion molecule expression and oxidative stress in mice with streptozotocin-induced type 1 diabetes.

PubMed

Tsai, Pei-Hsuan; Liu, Jun-Jen; Chiu, Wan-Chun; Pai, Man-Hui; Yeh, Sung-Ling

2011-02-01

Glutamine (Gln) is known to have immunomodulatory effects. Previous studies reported that Gln promotes insulin secretion in type 2 diabetes. However, the effects of Gln on insulin-deficient type 1 diabetes are not clear. This study investigated the effects of dietary Gln supplementation on adhesion molecule expression and oxidative damage in type 1 diabetic mice. There were 1 normal control (NC) group and 2 diabetic groups in this study. Mice in the NC group were fed a regular chow diet. One diabetic group (DM) was fed a common semipurified diet while the other diabetic group received a diet in which part of the casein was replaced by Gln (DM-Gln), which provided 25% of the total amino acid nitrogen for 6 wk. Diabetes was induced by an intraperitoneal injection of streptozotocin at a dose of 150 mg/kg body weight. Blood samples and the liver and kidneys of the animals were collected at the end of the study for further analysis. Plasma glucose, fructosamine contents and adhesion molecule expressions were significantly higher in the diabetic groups than in the NC group. The DM group had higher leukocyte CD11a/CD18 expression. In diabetic mice, nitrotyrosine concentrations and myeloperoxidase activities were higher and the reduced to oxidized glutathione ratio was lower in liver and/or kidney. These alterations were not found in diabetic mice supplemented with Gln. These results suggest that supplemental dietary Gln increased the antioxidant potential and consequently decreased leukocyte adhesion molecule expression and oxidative stress in organs of mice with type 1 diabetes. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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

Human Dermal Mast Cells Contain and Release Tumor Necrosis Factor α, which Induces Endothelial Leukocyte Adhesion Molecule 1

NASA Astrophysics Data System (ADS)

Walsh, Laurence J.; Trinchieri, Giorgio; Waldorf, Heidi A.; Whitaker, Diana; Murphy, George F.

1991-05-01

Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-α within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-α protein and TNF-α mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-α. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion.

Reduced Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Level in Obesity.

PubMed

Heinrich, Garrett; Muturi, Harrison T; Rezaei, Khadijeh; Al-Share, Qusai Y; DeAngelis, Anthony M; Bowman, Thomas A; Ghadieh, Hilda E; Ghanem, Simona S; Zhang, Deqiang; Garofalo, Robert S; Yin, Lei; Najjar, Sonia M

2017-01-01

Impairment of insulin clearance is being increasingly recognized as a critical step in the development of insulin resistance and metabolic disease. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Null deletion or liver-specific inactivation of Ceacam1 in mice causes a defect in insulin clearance, insulin resistance, steatohepatitis, and visceral obesity. Immunohistological analysis revealed reduction of hepatic CEACAM1 in obese subjects with fatty liver disease. Thus, we aimed to determine whether this occurs at the hepatocyte level in response to systemic extrahepatic factors and whether this holds across species. Northern and Western blot analyses demonstrate that CEACAM1 mRNA and protein levels are reduced in liver tissues of obese individuals compared to their lean age-matched counterparts. Furthermore, Western analysis reveals a comparable reduction of CEACAM1 protein in primary hepatocytes derived from the same obese subjects. Similar to humans, Ceacam1 mRNA level, assessed by quantitative RT-PCR analysis, is significantly reduced in the livers of obese Zucker ( fa/fa , ZDF) and Koletsky ( f/f ) rats relative to their age-matched lean counterparts. These studies demonstrate that the reduction of hepatic CEACAM1 in obesity occurs at the level of hepatocytes and identify the reduction of hepatic CEACAM1 as a common denominator of obesity across multiple species.

Inhibitory effects of clotrimazole on TNF-alpha-induced adhesion molecule expression and angiogenesis.

PubMed

Thapa, Dinesh; Lee, Jong Suk; Park, Min-A; Cho, Mi-Yeon; Park, Young-Joon; Choi, Han Gon; Jeong, Tae Cheon; Kim, Jung-Ae

2009-04-01

Cell adhesion molecules play a pivotal role in chronic inflammation and pathological angiogenesis. In the present study, we investigated the inhibitory effects of clotrimazole (CLT) on tumor necrosis factor (TNF)-alpha-induced changes in adhesion molecule expression. CLT dose-dependently inhibited monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expressions in TNF-alpha-stimulated HT29 colonic epithelial cells. This inhibitory action of CLT correlated with a significant reduction in TNF-alpha-induced adhesion of monocytes to HT29 cells, which was comparable to the inhibitory effects of anti-ICAM-1 and VCAM-1 monoclonal antibodies on monocyte-epithelial adhesion. These inhibitory actions of CLT were, at least in part, attributable to the inhibition of redox sensitive NF-kappaB activation, as CLT inhibited TNF-alpha-induced ROS generation as well as NF-kappaB nuclear translocation and activation in HT29 cells. Furthermore, the inhibition of TNF-alpha-induced monocyte adhesion was also mimicked by the specific NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). Inflammatory mediators including TNF-alpha have known to promote angiogenesis, which in turn further contributes to inflammatory pathology. Therefore, we additionally evaluated whether CLT modulates TNF-alpha-induced angiogenesis using in vivo chick chorioallantoic membrane (CAM) assay. The CAM assay showed that CLT dose-dependently attenuated TNF-alpha-induced angiogenesis, and the effect was correlated with decreased inflammation of the CAM tissue. In conclusion, our results suggest that CLT can inhibit TNF-alpha-triggered expression of adhesion molecules, ICAM-1 and VCAM-1, and angiogenesis during inflammation.

N-glycosylation at the SynCAM (synaptic cell adhesion molecule) immunoglobulin interface modulates synaptic adhesion.

PubMed

Fogel, Adam I; Li, Yue; Giza, Joanna; Wang, Qing; Lam, Tukiet T; Modis, Yorgo; Biederer, Thomas

2010-11-05

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.

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

PubMed Central

Fogel, Adam I.; Li, Yue; Giza, Joanna; Wang, Qing; Lam, TuKiet T.; Modis, Yorgo; Biederer, Thomas

2010-01-01

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 Asn60. Structural modeling of the corresponding SynCAM 1 Ig1 domain indicates that its glycosylation sites Asn70/Asn104 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 Asn60 reduces adhesion, N-glycans at Asn70/Asn104 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. PMID:20739279

Localization of intercellular adhesion molecule-1 (ICAM-1) in the lungs of silica-exposed mice.

PubMed Central

Nario, R C; Hubbard, A K

1997-01-01

Intercellular adhesion molecule-1 (ICAM-1) is expressed on a variety of cells including endothelial cells, alveolar epithelial cells, and alveolar macrophages. Endothelial/epithelial cell ICAM-1 participates in the migration of leukocytes out of the blood in response to pulmonary inflammation, whereas alveolar macrophage ICAM-1 may represent cell activation. Our previous studies have shown that there is increased expression of ICAM-1 in lung tissue during acute inflammation following intratracheal injection with silica particles (2 mg/mouse). This increased expression was shown to play a role, in part, in the migration of neutrophils from the circulation into the tissue parenchyma. The aim of the current work is to localize expression of ICAM-1 during acute inflammation in lungs of mice exposed to either silica or the nuisance dust, titanium dioxide. In silica-exposed mice, a significant increase in ICAM-1 was detected on day-1 and localized by immunohistochemistry to aggregates of pulmonary macrophages and to type II epithelial cells. Areas of the lung with increased ICAM-1 expression also showed increased tumor necrosis factor alpha expression. Immunocytochemical staining of bronchoalveolar lavage (BAL) cells demonstrated increased ICAM-1 expression associated with alveolar macrophages 3, 5, and 7 days following silica exposure. Finally, soluble ICAM-1 levels in the BAL fluid were significantly increased in mice exposed to silica on the same days. Titanium dioxide exposure elicited a minimal increase in expression of ICAM-1 in the lungs. These data demonstrate that exposure to the toxic particle silica specifically increases ICAM-1 expression localized to pulmonary macrophages and type II epithelial cells. Images Figure 2. B Figure 2. A Figure 2. D Figure 2. C Figure 3. A Figure 3. B Figure 5. B Figure 5. A Figure 5. C PMID:9400721

Involvement of adhesion molecules (CD11a-ICAM-1) in vascular endothelial cell injury elicited by PMA-stimulated neutrophils.

PubMed

Fujita, H; Morita, I; Murota, S

1991-06-14

Protective effect of anti-CD11a and anti-ICAM-1 antibodies on the cytotoxicity induced by PMA-stimulated neutrophils was studied using cultured endothelial cells isolated from bovine carotid artery. Anti-CD11a antibody and anti-ICAM-1 antibody inhibited the endothelial cell injury induced by the activated neutrophils in a dose dependent manner. On the other hand, both antibodies themselves had no effect on either the luminol chemiluminescence released out of the activated neutrophils or the adhesion of the neutrophils to the endothelial cell monolayer. These data suggest that these adhesion molecules play some important roles in the vascular endothelial cell injury elicited by activated neutrophils.

Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules.

PubMed

Zhao, Yan; Yuan, Zuyi; Liu, Yan; Xue, Jiahong; Tian, Yuling; Liu, Weimin; Zhang, Weiping; Shen, Yan; Xu, Wei; Liang, Xiao; Chen, Tao

2010-03-01

Adhesion molecules have been implicated in the development and progression of atherosclerosis. Cannabinoids have been reported to modulate the migration and adhesion molecules expression of various cell types. Here we examined the effects of WIN55212-2, a cannabinoid receptor 1 (CB1-R)/cannabinoid receptor 2 (CB2-R) agonist on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice, which are vulnerable because of their high plasma cholesterol and triacylglycerol levels, focusing on the expression of endothelial adhesion molecules. In the aorta of ApoE-/- mice, WIN55212-2 significantly reduced aortic root plaque area. The mechanism for this seemed to be reduced infiltration of macrophages into the atherosclerotic plaque which was also associated with reduced expression of vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin in the aorta. In vitro studies revealed reduced cell adhesion of a monocytic cell line (U937) to human umbilical vein endothelial cells after incubation with WIN55212-2. The reduction in macrophage adhesion also correlated with significant reductions in the expression of VCAM-1, ICAM-1, and P-selectin, indicating that reduced infiltration of macrophages in atherosclerotic plaques may occur as a result of the direct effect of WIN55212-2 on adhesion molecules in macrophages and endothelial cells. In conclusion, WIN55212-2 seems to have direct anti-atherosclerotic effects in an animal model of atherosclerosis. These effects were at least partly due to effects on the expression of VCAM-1, ICAM-1, and P-selectin, which led to reduced macrophage adhesion and infiltration. Furthermore, the protective effects completely blocked by the highly selective CB2 receptor antagonist AM630 suggest that these beneficial effects of WIN55212-2 may be mediated through the CB2 receptor.

Lycopene inhibits NF-κB activation and adhesion molecule expression through Nrf2-mediated heme oxygenase-1 in endothelial cells.

PubMed

Yang, Po-Min; Chen, Huang-Zhi; Huang, Yu-Ting; Hsieh, Chia-Wen; Wung, Being-Sun

2017-06-01

The endothelial expression of cell adhesion molecules plays a leading role in atherosclerosis. Lycopene, a carotenoid with 11 conjugated double bonds, has been shown to have anti-inflammatory properties. In the present study, we demonstrate a putative mechanism for the anti-inflammatory effects of lycopene. We demonstrate that lycopene inhibits the adhesion of tumor necrosis factor α (TNFα)-stimulated monocytes to endothelial cells and suppresses the expression of intercellular cell adhesion molecule-1 (ICAM-1) at the transcriptional level. Moreover, lycopene was found to exert its inhibitory effects by blocking the degradation of the inhibitory protein, IκBα, following 6 h of pre-treatment. In TNFα-stimulated endothelial cells, nuclear factor-κB (NF-κB) nuclear translocation and transcriptional activity were abolished by up to 12 h of lycopene pre-treatment. We also found that lycopene increased the intracellular glutathione (GSH) level and glutamate-cysteine ligase expression. Subsequently, lycopene induced nuclear factor-erythroid 2 related factor 2 (Nrf2) activation, leading to the increased expression of downstream of heme oxygenase-1 (HO-1). The use of siRNA targeting HO-1 blocked the inhibitory effects of lycopene on IκB degradation and ICAM-1 expression. The inhibitory effects of lycopene thus appear to be mediated through its induction of Nrf2-mediated HO-1 expression. Therefore, the findings of the present study indicate that lycopene suppresses the activation of TNFα-induced signaling pathways through the upregulation of Nrf2-mediated HO-1 expression.

Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 (ICAM)-1) expression and neutrophil adhesion.

PubMed Central

Huang, G T; Eckmann, L; Savidge, T C; Kagnoff, M F

1996-01-01

The acute host response to gastrointestinal infection with invasive bacteria is characterized by an accumulation of neutrophils in the lamina propria, and neutrophil transmigration to the luminal side of the crypts. Intestinal epithelial cells play an important role in the recruitment of inflammatory cells to the site of infection through the secretion of chemokines. However, little is known regarding the expression, by epithelial cells, of molecules that are involved in interactions between the epithelium and neutrophils following bacterial invasion. We report herein that expression of ICAM-1 on human colon epithelial cell lines, and on human enterocytes in an in vivo model system, is upregulated following infection with invasive bacteria. Increased ICAM-1 expression in the early period (4-9 h) after infection appeared to result mainly from a direct interaction between invaded bacteria and host epithelial cells since it co-localized to cells invaded by bacteria, and the release of soluble factors by epithelial cells played only a minor role in mediating increased ICAM-1 expression. Furthermore, ICAM-1 was expressed on the apical side of polarized intestinal epithelial cells, and increased expression was accompanied by increased neutrophil adhesion to these cells. ICAM-1 expression by intestinal epithelial cells following infection with invasive bacteria may function to maintain neutrophils that have transmigrated through the epithelium in close contact with the intestinal epithelium, thereby reducing further invasion of the mucosa by invading pathogens. PMID:8755670

The Lymphocyte Function–associated Antigen 1 I Domain Is a Transient Binding Module for Intercellular Adhesion Molecule (ICAM)-1 and ICAM-3 in Hydrodynamic Flow

PubMed Central

Knorr, Ruth; Dustin, Michael L.

1997-01-01

The I domain of lymphocyte function–associated antigen (LFA)-1 contains an intercellular adhesion molecule (ICAM)-1 and ICAM-3 binding site, but the relationship of this site to regulated adhesion is unknown. To study the adhesive properties of the LFA-1 I domain, we stably expressed a GPI-anchored form of this I domain (I-GPI) on the surface of baby hamster kidney cells. I-GPI cells bound soluble ICAM-1 (sICAM-1) with a low avidity and affinity. Flow cell experiments demonstrated a specific rolling interaction of I-GPI cells on bilayers containing purified full length ICAM-1 or ICAM-3. The LFA-1 activating antibody MEM-83, or its Fab fragment, decreased the rolling velocity of I-GPI cells on ICAM-1–containing membranes. In contrast, the interaction of I-GPI cells with ICAM-3 was blocked by MEM-83. Rolling of I-GPI cells was dependent on the presence of Mg2+. Mn2+ only partially substituted for Mg2+, giving rise to a small fraction of rolling cells and increased rolling velocity. This suggests that the I domain acts as a transient, Mg2+-dependent binding module that cooperates with another Mn2+-stimulated site in LFA-1 to give rise to the stable interaction of intact LFA-1 with ICAM-1. PMID:9271587

Brain endothelial adhesion molecule expression in experimental colitis.

PubMed

Sans, M; Kawachi, S; Soriano, A; Palacín, A; Morise, Z; Granger, D N; Piqué, J M; Grisham, M B; Panés, J

2001-04-01

1) To determine if endothelial expression of adhesion molecules involved in leukocyte recruitment is increased in the brain and other organs in four different models of experimental colitis, and 2) to investigate whether leukocyte infiltration occurs in the brain of colitic animals. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was quantified, using the dual radiolabeled antibody technique in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis, in mice with dextran sulfate sodium (DSS)-induced colitis, in SCID mice reconstituted with CD45RBhigh T-cells, and in IL-10-/- mice. Leukocyte infiltration in the brain of TNBS-induced colitic rats was assessed by myeloperoxidase activity and immunohistochemical staining with anti-CD45 monoclonal antibody. Marked upregulation of brain endothelial VCAM-1 (2- to 5.5-fold) was consistently found in colitic animals in the four models studied. Brain VCAM-1 strongly correlated with colon VCAM-1 and colon weight. By contrast, upregulation of brain ICAM-1 in colitic animals was only observed in the CD45RBhigh transfer (3-fold) and the TNBS-induced (1.5-fold models). Heart and muscle VCAM-1 and ICAM-1 were not upregulated in colitic animals in the majority of models studied. There was no leukocyte infiltration into the brain of TNBS-induced colitic rats. Our study demonstrates a marked and specific upregulation of endothelial VCAM-1 in the brain of colitic animals. This activation of cerebral endothelial cells was not associated with an infiltration of leukocytes into brain tissue.

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.

Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening

NASA Technical Reports Server (NTRS)

Lammerding, Jan; Kazarov, Alexander R.; Huang, Hayden; Lee, Richard T.; Hemler, Martin E.

2003-01-01

The tetraspanin CD151 molecule associates specifically with laminin-binding integrins, including alpha6beta1. To probe strength of alpha6beta1-dependent adhesion to laminin-1, defined forces (0-1.5 nN) were applied to magnetic laminin-coated microbeads bound to NIH 3T3 cells. For NIH 3T3 cells bearing wild-type CD151, adhesion strengthening was observed, as bead detachment became more difficult over time. In contrast, mutant CD151 (with the C-terminal region replaced) showed impaired adhesion strengthening. Static cell adhesion to laminin-1, and detachment of beads coated with fibronectin or anti-alpha6 antibody were all unaffected by CD151 mutation. Hence, CD151 plays a key role in selectively strengthening alpha6beta1 integrin-mediated adhesion to laminin-1.

Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

PubMed

Norris, S; White, M; Mankan, A K; Lawless, M W

2010-04-01

Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

Targeting of adhesion molecules as a therapeutic strategy in multiple myeloma.

PubMed

Neri, Paola; Bahlis, Nizar J

2012-09-01

Multiple myeloma (MM) is a clonal disorder of plasma cells that remains, for the most part, incurable despite the advent of several novel therapeutic agents. Tumor cells in this disease are cradled within the bone marrow (BM) microenvironment by an array of adhesive interactions between the BM cellular residents, the surrounding extracellular matrix (ECM) components such as fibronectin (FN), laminin, vascular cell adhesion molecule-1 (VCAM-1), proteoglycans, collagens and hyaluronan, and a variety of adhesion molecules on the surface of MM cells including integrins, hyaluronan receptors (CD44 and RHAMM) and heparan sulfate proteoglycans. Several signaling responses are activated by these interactions, affecting the survival, proliferation and migration of MM cells. An important consequence of these direct adhesive interactions between the BM/ECM and MM cells is the development of drug resistance. This phenomenon is termed "cell adhesion-mediated drug resistance" (CAM-DR) and it is thought to be one of the major mechanisms by which MM cells escape the cytotoxic effects of therapeutic agents. This review will focus on the adhesion molecules involved in the cross-talk between MM cells and components of the BM microenvironment. The complex signaling networks downstream of these adhesive molecules mediated by direct ligand binding or inside-out soluble factors signaling will also be reviewed. Finally, novel therapeutic strategies targeting these molecules will be discussed. Identification of the mediators of MM-BM interaction is essential to understand MM biology and to elucidate novel therapeutic targets for this disease.

Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule Are Induced by Ionizing Radiation on Lymphatic Endothelium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodriguez-Ruiz, María E., E-mail: mrruiz@unav.es; Radiation Oncology, University Clinic, University of Navarra, Pamplona; Garasa, Saray

Purpose/Objectives: The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells. Materials/Methods: Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using amore » Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFβ in this process anti-TGFβ blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFβ and /or anti-ICAM1 blocking mAb. Results: We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFβ. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC. Conclusion: Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to

Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule Are Induced by Ionizing Radiation on Lymphatic Endothelium.

PubMed

Rodriguez-Ruiz, María E; Garasa, Saray; Rodriguez, Inmaculada; Solorzano, Jose Luis; Barbes, Benigno; Yanguas, Alba; Teijeira, Alvaro; Etxeberria, Iñaki; Aristu, José Javier; Halin, Cornelia; Melero, Ignacio; Rouzaut, Ana

2017-02-01

The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells. Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using a Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFβ in this process anti-TGFβ blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFβ and /or anti-ICAM1 blocking mAb. We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFβ. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC. Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to immunotherapy. Copyright © 2016 Elsevier Inc. All rights reserved.

The neural cell adhesion molecule (NCAM) associates with and signals through p21-activated kinase 1 (Pak1).

PubMed

Li, Shen; Leshchyns'ka, Iryna; Chernyshova, Yana; Schachner, Melitta; Sytnyk, Vladimir

2013-01-09

The Neural cell adhesion molecule (NCAM) plays an important role in regulation of nervous system development. To expand our understanding of the molecular mechanisms via which NCAM influences differentiation of neurons, we used a yeast two-hybrid screening to search for new binding partners of NCAM and identified p21-activated kinase 1 (Pak1). We show that NCAM interacts with Pak1 in growth cones of neurons. The autophosphorylation and activity of Pak1 were enhanced when isolated growth cones were incubated with NCAM function triggering antibodies, which mimic the interaction between NCAM and its extracellular ligands. The association of Pak1 with cell membranes, the efficiency of Pak1 binding to its activators, and Pak1 activity were inhibited in brains of NCAM-deficient mice. NCAM-dependent Pak1 activation was abolished after lipid raft disruption, suggesting that NCAM promotes Pak1 activation in the lipid raft environment. Phosphorylation of the downstream Pak1 effectors LIMK1 and cofilin was reduced in growth cones from NCAM-deficient neurons, which was accompanied by decreased levels of filamentous actin and inhibited filopodium mobility in the growth cones. Dominant-negative Pak1 inhibited and constitutively active Pak1 enhanced the ability of neurons to increase neurite outgrowth in response to the extracellular ligands of NCAM. Our combined observations thus indicate that NCAM activates Pak1 to drive actin polymerization to promote neuronal differentiation.

Niacin results in reduced monocyte adhesion in patients with type 2 diabetes mellitus.

PubMed

Tavintharan, S; Woon, K; Pek, L T; Jauhar, N; Dong, X; Lim, S C; Sum, C F

2011-03-01

Patients with type 2 diabetes have increased expression of cell adhesion molecules (CAMs). CAMs and monocyte adhesion mediate essential processes in atherogenesis. It remains unclear if monocytes from patients on niacin have reduced adhesion function. We studied the variation of monocyte adhesion in patients with type 2 diabetes and low HDL-cholesterol, taking either extended release niacin (Niaspan®, Abbott Laboratories) or controls not on niacin. Biochemical parameters including adiponectin, CAMs and fresh monocytes from whole blood for adhesion assays, were studied at baseline and 12-weeks. Niacin 1500 mg daily raised HDL-cholesterol from 0.8 mmol/l (95% CI: 0.7-0.9) to 0.9 mmol/l (95% CI: 0.8-1.1), p=0.10, and significantly reduced PECAM-1 by 24.9% (95% CI: 10.9-39.0; p<0.05), increased adiponectin by 30.5% (95% CI: 14.1-47.0; p<0.05), with monocyte adhesion reduced by 9.2% (95%CI: 0.7-17.7; p<0.05) in endothelial cells treated in basal conditions, and 7.8% (95% CI: 3.1-12.5; p<0.05) after TNF-α stimulation. Monocytes isolated from patients on niacin had reduced adhesion to endothelial cells. Our findings suggest niacin has broad range of effects apart from lipid-modification, and these could be important in cardiovascular risk reduction. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness.

PubMed

Saladi, Srinivas Vinod; Keenen, Bridget; Marathe, Himangi G; Qi, Huiling; Chin, Khew-Voon; de la Serna, Ivana L

2010-10-22

Metastatic melanoma is an aggressive malignancy that is resistant to therapy and has a poor prognosis. The progression of primary melanoma to metastatic disease is a multi-step process that requires dynamic regulation of gene expression through currently uncharacterized epigenetic mechanisms. Epigenetic regulation of gene expression often involves changes in chromatin structure that are catalyzed by chromatin remodeling enzymes. Understanding the mechanisms involved in the regulation of gene expression during metastasis is important for developing an effective strategy to treat metastatic melanoma. SWI/SNF enzymes are multisubunit complexes that contain either BRG1 or BRM as the catalytic subunit. We previously demonstrated that heterogeneous SWI/SNF complexes containing either BRG1 or BRM are epigenetic modulators that regulate important aspects of the melanoma phenotype and are required for melanoma tumorigenicity in vitro. To characterize BRG1 expression during melanoma progression, we assayed expression of BRG1 in patient derived normal skin and in melanoma specimen. BRG1 mRNA levels were significantly higher in stage IV melanomas compared to stage III tumors and to normal skin. To determine the role of BRG1 in regulating the expression of genes involved in melanoma metastasis, we expressed BRG1 in a melanoma cell line that lacks BRG1 expression and examined changes in extracellular matrix and adhesion molecule expression. We found that BRG1 modulated the expression of a subset of extracellular matrix remodeling enzymes and adhesion proteins. Furthermore, BRG1 altered melanoma adhesion to different extracellular matrix components. Expression of BRG1 in melanoma cells that lack BRG1 increased invasive ability while down-regulation of BRG1 inhibited invasive ability in vitro. Activation of metalloproteinase (MMP) 2 expression greatly contributed to the BRG1 induced increase in melanoma invasiveness. We found that BRG1 is recruited to the MMP2 promoter and

TM9/Phg1 and SadA proteins control surface expression and stability of SibA adhesion molecules in Dictyostelium.

PubMed

Froquet, Romain; le Coadic, Marion; Perrin, Jackie; Cherix, Nathalie; Cornillon, Sophie; Cosson, Pierre

2012-02-01

TM9 proteins form a family of conserved proteins with nine transmembrane domains essential for cellular adhesion in many biological systems, but their exact role in this process remains unknown. In this study, we found that genetic inactivation of the TM9 protein Phg1A dramatically decreases the surface levels of the SibA adhesion molecule in Dictyostelium amoebae. This is due to a decrease in sibA mRNA levels, in SibA protein stability, and in SibA targeting to the cell surface. A similar phenotype was observed in cells devoid of SadA, a protein that does not belong to the TM9 family but also exhibits nine transmembrane domains and is essential for cellular adhesion. A contact site A (csA)-SibA chimeric protein comprising only the transmembrane and cytosolic domains of SibA and the extracellular domain of the Dictyostelium surface protein csA also showed reduced stability and relocalization to endocytic compartments in phg1A knockout cells. These results indicate that TM9 proteins participate in cell adhesion by controlling the levels of adhesion proteins present at the cell surface.

Cell adhesion molecules, the extracellular matrix and oral squamous carcinoma.

PubMed

Lyons, A J; Jones, J

2007-08-01

Carcinomas are characterized by invasion of malignant cells into the underlying connective tissue and migration of malignant cells to form metastases at distant sites. These processes require alterations in cell-cell and cell-extracellular matrix interactions. As cell adhesion molecules play a role in cell-cell and cell-extracellular matrix adhesion and interactions they are involved in the process of tumour invasion and metastases. In epithelial tissues, receptors of the integrin family mediate adhesion to the adjacent matrix whereas cadherins largely mediate intercellular adhesion. These and other cell adhesion molecules such as intercellular adhesion molecule-1, CD44, dystroglycans and selectins, are involved and undergo changes in carcinomas, which provide possible targets for anti-cancer drug treatments. In the extracellular matrix that is associated with tumours, laminin 5, oncofetal fibronectin and tenascin C appear. The degree of expression of some of these moieties indicates prognosis in oral cancer and offer targets for antibody-directed radiotherapy. Metalloproteases which degrade the extracellular matrix are increased in carcinomas, and their activity is necessary for tumour angiogenesis and consequent invasion and metastases. Metalloprotease inhibitors have begun to produce decreases in mortality in clinical trials. This report provides a brief overview of our current understanding of cell adhesion molecules, the extracellular matrix, tumour invasion and metastasis.

Soluble adhesion molecules in human cancers: sources and fates.

PubMed

van Kilsdonk, Jeroen W J; van Kempen, Léon C L T; van Muijen, Goos N P; Ruiter, Dirk J; Swart, Guido W M

2010-06-01

Adhesion molecules endow tumor cells with the necessary cell-cell contacts and cell-matrix interactions. As such, adhesion molecules are involved in cell signalling, proliferation and tumor growth. Rearrangements in the adhesion repertoire allow tumor cells to migrate, invade and form metastases. Besides these membrane-bound adhesion molecules several soluble adhesion molecules are detected in the supernatant of tumor cell lines and patient body fluids. Truncated soluble adhesion molecules can be generated by several conventional mechanisms, including alternative splicing of mRNA transcripts, chromosomal translocation, and extracellular proteolytic ectodomain shedding. Secretion of vesicles (ectosomes and exosomes) is an alternative mechanism mediating the release of full-length adhesion molecules. Soluble adhesion molecules function as modulators of cell adhesion, induce proteolytic activity and facilitate cell signalling. Additionally, adhesion molecules present on secreted vesicles might be involved in the vesicle-target cell interaction. Based on currently available data, released soluble adhesion molecules contribute to cancer progression and therefore should not be regarded as unrelated and non-functional side products of tumor progression. 2010 Elsevier GmbH. All rights reserved.

Correlation of leukocyte adhesiveness, adhesion molecule expression and leukocyte-induced contraction following balloon angioplasty

PubMed Central

Kennedy, Simon; McPhaden, Allan R; Wadsworth, Roger M; Wainwright, Cherry L

2000-01-01

The aim of this study was to examine the changes in leukocyte adhesion and leukocyte-induced contraction in balloon-injured rabbit subclavian artery and to correlate these changes with vessel morphology and expression of adhesion molecules on the injured arteries.Rabbits were anaesthetized and their left subclavian arteries were injured by balloon inflation and withdrawal followed by sacrifice at 2, 24, 48 h or 8 days after injury. The left and right subclavian arteries were removed and leukocytes were isolated from autologous rabbit blood. Leukocyte-induced contraction was measured in 5-HT precontracted artery rings and leukocyte adhesion was measured using 51Cr-labelled leukocytes. Immunocytochemistry using paraffin-embedded tissue was employed to detect changes in the expression of adhesion molecules on injured arteries.Autologous leukocytes caused a contraction of rabbit subclavian artery rings, which was prevented by L-NAME (10−3 M). Balloon-induced injury abolished the contractile response to leukocytes, which correlated with loss of carbachol-induced relaxationBalloon injury markedly enhanced the adhesiveness of the subclavian artery for leukocytes, most notably at 24 and 48 h after injury (1.7 and 1.8 fold respectively). Increased leukocyte adhesion at these two time points correlated with an upregulation of E-selectin, P-selectin and VCAM-1 expression on the remaining endothelium of the injured artery.Vessel morphology revealed that balloon inflation had induced an infiltration of inflammatory cells into the vessel wall, the greatest increase being seen at 24 h after injury.It is concluded that an increase in the expression of E-selectin, P-selectin and VCAM-1 following balloon-induced injury leads to enhanced leukocyte adhesion and migration into the injured vessel. PMID:10781003

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.

PubMed

Ramer, Robert; Bublitz, Katharina; Freimuth, Nadine; Merkord, Jutta; Rohde, Helga; Haustein, Maria; Borchert, Philipp; Schmuhl, Ellen; Linnebacher, Michael; Hinz, Burkhard

2012-04-01

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.

Investigating single molecule adhesion by atomic force spectroscopy.

PubMed

Stetter, Frank W S; Kienle, Sandra; Krysiak, Stefanie; Hugel, Thorsten

2015-02-27

Atomic force spectroscopy is an ideal tool to study molecules at surfaces and interfaces. An experimental protocol to couple a large variety of single molecules covalently onto an AFM tip is presented. At the same time the AFM tip is passivated to prevent unspecific interactions between the tip and the substrate, which is a prerequisite to study single molecules attached to the AFM tip. Analyses to determine the adhesion force, the adhesion length, and the free energy of these molecules on solid surfaces and bio-interfaces are shortly presented and external references for further reading are provided. Example molecules are the poly(amino acid) polytyrosine, the graft polymer PI-g-PS and the phospholipid POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine). These molecules are desorbed from different surfaces like CH3-SAMs, hydrogen terminated diamond and supported lipid bilayers under various solvent conditions. Finally, the advantages of force spectroscopic single molecule experiments are discussed including means to decide if truly a single molecule has been studied in the experiment.

Investigating Single Molecule Adhesion by Atomic Force Spectroscopy

PubMed Central

Stetter, Frank W. S.; Kienle, Sandra; Krysiak, Stefanie; Hugel, Thorsten

2015-01-01

Atomic force spectroscopy is an ideal tool to study molecules at surfaces and interfaces. An experimental protocol to couple a large variety of single molecules covalently onto an AFM tip is presented. At the same time the AFM tip is passivated to prevent unspecific interactions between the tip and the substrate, which is a prerequisite to study single molecules attached to the AFM tip. Analyses to determine the adhesion force, the adhesion length, and the free energy of these molecules on solid surfaces and bio-interfaces are shortly presented and external references for further reading are provided. Example molecules are the poly(amino acid) polytyrosine, the graft polymer PI-g-PS and the phospholipid POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine). These molecules are desorbed from different surfaces like CH3-SAMs, hydrogen terminated diamond and supported lipid bilayers under various solvent conditions. Finally, the advantages of force spectroscopic single molecule experiments are discussed including means to decide if truly a single molecule has been studied in the experiment. PMID:25867282

Cryptotanshinone inhibits oxidized LDL-induced adhesion molecule expression via ROS dependent NF-κB pathways

PubMed Central

Zhao, Wenwen; Wu, Chuanhong; Chen, Xiuping

2016-01-01

ABSTRACT Adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, play important roles in the initial stage of atherosclerosis. Cryptotanshinone (CPT), a natural compound isolated from Salvia miltiorrhiza Bunge, exhibits anti-atherosclerotic activity although the underlying mechanisms remain elusive. In this study, the protective effect of CPT against oxidized low-density lipoprotein (ox-LDL)-induced adhesion molecule expression was investigated in human umbilical vein endothelial cells. Ox-LDL significantly induced ICAM-1, VCAM-1, and E-selectin expression at the mRNA and protein levels but reduced eNOS phosphorylation and NO generation, which were reversed by CPT pretreatment. Sodium nitroprusside, a NO donor, N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger, and BAY117082, a NF-κB inhibitor, inhibited ox-LDL-induced ICAM-1, VCAM-1, and E-selectin expression. Ox-LDL-induced ROS production was significantly inhibited by CPT and NAC. Furthermore, ox-LDL activated the NF-κB signaling pathway by inducing phosphorylation of IKKβ and IκBα, promoting the interaction of IKKβ and IκBα, and increasing p65 nuclear translocation, which were significantly inhibited by CPT. In addition, CPT, NAC, and BAY117082 inhibited ox-LDL-induced membrane expression of ICAM-1, VCAM-1, E-selectin, and endothelial–monocyte adhesion and restored eNOS phosphorylation and NO generation. Results suggested that CPT inhibited ox-LDL-induced adhesion molecule expression by decreasing ROS and inhibiting the NF-κB pathways, which provides new insight into the anti-atherosclerotic mechanism of CPT. PMID:26647279

An epigenetic signature of adhesion molecules predicts poor prognosis of ovarian cancer patients

PubMed Central

Chang, Ping-Ying; Liao, Yu-Ping; Wang, Hui-Chen; Chen, Yu-Chih; Huang, Rui-Lan; Wang, Yu-Chi; Yuan, Chiou-Chung; Lai, Hung-Cheng

2017-01-01

DNA methylation is a promising biomarker for cancer. The epigenetic effects of cell adhesion molecules may affect the therapeutic outcome and the present study examined their effects on survival in ovarian cancer. We integrated methylomics and genomics datasets in The Cancer Genome Atlas (n = 391) and identified 106 highly methylated adhesion-related genes in ovarian cancer tissues. Univariate analysis revealed the methylation status of eight genes related to progression-free survival. In multivariate Cox regression analysis, four highly methylated genes (CD97, CTNNA1, DLC1, HAPLN2) and three genes (LAMA4, LPP, MFAP4) with low methylation were significantly associated with poor progression-free survival. Low methylation of VTN was an independent poor prognostic factor for overall survival after adjustment for age and stage. Patients who carried any two of CTNNA1, DLC1 or MFAP4 were significantly associated with poor progression-free survival (hazard ratio: 1.59; 95% confidence interval: 1.23, 2.05). This prognostic methylation signature was validated in a methylomics dataset generated in our lab (n = 37, hazard ratio: 16.64; 95% confidence interval: 2.68, 103.14) and in another from the Australian Ovarian Cancer Study (n = 91, hazard ratio: 2.43; 95% confidence interval: 1.11, 5.36). Epigenetics of cell adhesion molecules is related to ovarian cancer prognosis. A more comprehensive methylomics of cell adhesion molecules is needed and may advance personalized treatment with adhesion molecule-related drugs. PMID:28881822

Cell Adhesion Molecule and Lymphocyte Activation Marker Expression during Experimental Vaginal Candidiasis

PubMed Central

Wormley, Floyd L.; Chaiban, Joseph; Fidel, Paul L.

2001-01-01

Cell-mediated immunity by Th1-type CD4+ T cells is the predominant host defense mechanism against mucosal candidiasis. However, studies using an estrogen-dependent murine model of vaginal candidiasis have demonstrated little to no change in resident vaginal T cells during infection and no systemic T-cell infiltration despite the presence of Candida-specific systemic Th1-type responses in infected mice. The present study was designed to further investigate these observations by characterizing T-cell activation and cell adhesion molecule expression during primary and secondary C. albicans vaginal infections. While flow cytometry analysis of activation markers showed some evidence for activation of CD3+ draining lymph node and/or vaginal lymphocytes during both primary and secondary vaginal Candida infection, CD3+ cells expressing the homing receptors and integrins α4β7, αM290β7, and α4β1 in draining lymph nodes of mice with primary and secondary infections were reduced compared to results for uninfected mice. At the local level, few vaginal lymphocytes expressed integrins, with only minor changes observed during both primary and secondary infections. On the other hand, immunohistochemical analysis of vaginal cell adhesion molecule expression showed increases in mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1 expression during both primary and secondary infections. Altogether, these data suggest that although the vaginal tissue is permissive to cellular infiltration during a vaginal Candida infection, the reduced numbers of systemic cells expressing the reciprocal cellular adhesion molecules may preempt cellular infiltration, thereby limiting Candida-specific T-cell responses against infection. PMID:11447188

Regulation of T-lymphocyte motility, adhesion and de-adhesion by a cell surface mechanism directed by low density lipoprotein receptor-related protein 1 and endogenous thrombospondin-1.

PubMed

Talme, Toomas; Bergdahl, Eva; Sundqvist, Karl-Gösta

2014-06-01

T lymphocytes are highly motile and constantly reposition themselves between a free-floating vascular state, transient adhesion and migration in tissues. The regulation behind this unique dynamic behaviour remains unclear. Here we show that T cells have a cell surface mechanism for integrated regulation of motility and adhesion and that integrin ligands and CXCL12/SDF-1 influence motility and adhesion through this mechanism. Targeting cell surface-expressed low-density lipoprotein receptor-related protein 1 (LRP1) with an antibody, or blocking transport of LRP1 to the cell surface, perturbed the cell surface distribution of endogenous thrombospondin-1 (TSP-1) while inhibiting motility and potentiating cytoplasmic spreading on intercellular adhesion molecule 1 (ICAM-1) and fibronectin. Integrin ligands and CXCL12 stimulated motility and enhanced cell surface expression of LRP1, intact TSP-1 and a 130,000 MW TSP-1 fragment while preventing formation of a de-adhesion-coupled 110 000 MW TSP-1 fragment. The appearance of the 130 000 MW TSP-1 fragment was inhibited by the antibody that targeted LRP1 expression, inhibited motility and enhanced spreading. The TSP-1 binding site in the LRP1-associated protein, calreticulin, stimulated adhesion to ICAM-1 through intact TSP-1 and CD47. Shear flow enhanced cell surface expression of intact TSP-1. Hence, chemokines and integrin ligands up-regulate a dominant motogenic pathway through LRP1 and TSP-1 cleavage and activate an associated adhesion pathway through the LRP1-calreticulin complex, intact TSP-1 and CD47. This regulation of T-cell motility and adhesion makes pro-adhesive stimuli favour motile responses, which may explain why T cells prioritize movement before permanent adhesion.

Plasma levels of soluble intercellular adhesion molecule-1 as a biomarker for disease severity of patients with community-acquired pneumonia.

PubMed

Chang, Pin-Yu; Tsao, Shih-Ming; Chang, Jer-Hwa; Chien, Ming-Hsien; Hung, Wen-Yueh; Huang, Yi-Wen; Yang, Shun-Fa

2016-12-01

Community-acquired pneumonia (CAP) is characterized as an acute inflammation of the lung associated with the activation of macrophages and neutrophils. Intercellular adhesion molecule-1 (ICAM-1) is an essential adhesion molecule involved in immune cell recruitment in lung inflammation. We investigated whether ICAM-1 is a useful biomarker for assessing the disease severity of hospitalized adult patients with CAP. Plasma soluble ICAM-1 (sICAM-1) levels were measured in 78 patients with CAP and 69 healthy controls by using a commercial enzyme-linked immunosorbent assay. The pneumonia severity index scores were used to determine CAP severity in patients upon initial hospitalization. The sICAM-1 and C-reactive protein (CRP) levels decreased significantly in patients with CAP after antibiotic treatment. The plasma concentration of sICAM-1 alone, but not CRP, was correlated with CAP severity according to the pneumonia severity index scores (r=0.431, p<0.001). The sICAM-1 levels in patients with CAP with high mortality risk were significantly higher than those in patients with CAP with medium or low mortality risk. Moreover, the sICAM-1 level showed a significant correlation with the length of hospital stay (r=0.488, p<0.001). Mechanistic investigations found that bacterial lipopolysaccharide induced upregulation of ICAM-1 expression through the c-Jun N-terminal kinase pathway in RAW264.7 macrophages. Plasma sICAM-1 levels may play a role in the diagnosis and clinical assessment of CAP severity. Copyright © 2016 Elsevier B.V. All rights reserved.

Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients.

PubMed

Haller, H; Ziegler, E M; Homuth, V; Drab, M; Eichhorn, J; Nagy, Z; Busjahn, A; Vetter, K; Luft, F C

1997-01-01

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia. 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]i in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]i was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca2+]i in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]i concentrations were correlated with the ICAM-1 expression in preeclamptic patients (r = .80, P < .001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i

Neural cell adhesion molecule-deficient beta-cell tumorigenesis results in diminished extracellular matrix molecule expression and tumour cell-matrix adhesion.

PubMed

Håkansson, Joakim; Xian, Xiaojie; He, Liqun; Ståhlberg, Anders; Nelander, Sven; Samuelsson, Tore; Kubista, Mikael; Semb, Henrik

2005-01-01

To understand by which mechanism neural cell adhesion molecule (N-CAM) limits beta tumour cell disaggregation and dissemination, we searched for potential downstream genes of N-CAM during beta tumour cell progression by gene expression profiling. Here, we show that N-CAM-deficient beta-cell tumorigenesis is associated with changes in the expression of genes involved in cell-matrix adhesion and cytoskeletal dynamics, biological processes known to affect the invasive and metastatic behaviour of tumour cells. The extracellular matrix (ECM) molecules emerged as the primary target, i.e. N-CAM deficiency resulted in down-regulated mRNA expression of a broad range of ECM molecules. Consistent with this result, deficient deposition of major ECM stromal components, such as fibronectin, laminin 1 and collagen IV, was observed. Moreover, N-CAM-deficient tumour cells displayed defective matrix adhesion. These results offer a potential mechanism for tumour cell disaggregation during N-CAM-deficient beta tumour cell progression. Prospective consequences of these findings for the role of N-CAM in beta tumour cell dissemination are discussed.

Inhibitory effect of indigo naturalis on tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells.

PubMed

Chang, Hsin-Ning; Pang, Jong-Hwei Su; Yang, Sien-Hung; Hung, Chi-Feng; Chiang, Chi-Hsin; Lin, Tung-Yi; Lin, Yin-Ku

2010-09-14

The use of indigo naturalis to treat psoriasis has proved effective in our previous clinical studies. The present study was designed to examine the anti-inflammatory effect of indigo naturalis in primary cultured human umbilical vein endothelial cells (HUVECs). Pretreatment of cells with indigo naturalis extract attenuated TNF-α-induced increase in Jurkat T cell adhesion to HUVECs as well as decreased the protein and messenger (m)RNA expression levels of vascular cell adhesion molecule-1 (VCAM-1) on HUVECs. Indigo naturalis extract also inhibited the protein expression of activator protein-1 (AP-1)/c-Jun, a critical transcription factor for the activation of VCAM-1 gene expression. Since the reduction of lymphocyte adhesion to vascular cells by indigo naturalis extract could subsequently reduce the inflammatory reactions caused by lymphocyte infiltration in the epidermal layer and help to improve psoriasis, this study provides a potential mechanism for the anti-inflammatory therapeutic effect of indigo naturalis extract in psoriasis.

Cell-contact-dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts.

PubMed

Mori, Masato; Hashimoto, Motomu; Matsuo, Takashi; Fujii, Takao; Furu, Moritoshi; Ito, Hiromu; Yoshitomi, Hiroyuki; Hirose, Jun; Ito, Yoshinaga; Akizuki, Shuji; Nakashima, Ran; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Ohmura, Koichiro; Mimori, Tsuneyo

2017-05-01

To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4 +  T cells. Naïve CD4 +  T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4 +  T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4 +  T cells, CD161 +  or CD161 - naïve CD4 +  T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. SF enhanced naïve CD4 +  T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4 +  T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161 +  naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CD4 +  T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

Magnolol reduced TNF-α-induced vascular cell adhesion molecule-1 expression in endothelial cells via JNK/p38 and NF-κB signaling pathways.

PubMed

Liang, Chan-Jung; Lee, Chiang-Wen; Sung, Hsin-Ching; Chen, Yung-Hsiang; Wang, Shu-Huei; Wu, Pei-Jhen; Chiang, Yao-Chang; Tsai, Jaw-Shiun; Wu, Chau-Chung; Li, Chi-Yuan; Chen, Yuh-Lien

2014-01-01

Expression of cell adhesion molecules by the endothelium and the attachment of leukocytes to these cells play major roles in inflammation and cardiovascular disorders. Magnolol, a major active component of Magnolia officinalis, has antioxidative and anti-inflammatory properties. In the present study, the effects of magnolol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAECs) and the related mechanisms were investigated. TNF-α induced VCAM-1 protein expression and mRNA stability were significantly decreased in HAECs pre-treated with magnolol. Magnolol significantly reduced the phosphorylation of ERK, JNK, and p38 in TNF-α-treated HAECs. The decrease in VCAM-1 expression in response to TNF-α treatment was affected by JNK and p38 inhibitors, not by an ERK inhibitor. Magnolol also attenuates NF-κB activation and the translocation of HuR (an RNA binding protein) in TNF-α-stimulated HAECs. The VCAM-1 expression was weaker in the aortas of TNF-α-treated apo-E deficient mice with magnolol treatment. These data demonstrate that magnolol inhibits TNF-α-induced JNK/p38 phosphorylation, HuR translocation, NF-κB activation, and thereby suppresses VCAM-1 expression resulting in reduced leukocyte adhesion. Taken together, these results suggest that magnolol has an anti-inflammatory property and may play an important role in the prevention of atherosclerosis and inflammatory responses.

Further studies of iron adhesion: ( 1 1 1 ) surfaces

NASA Astrophysics Data System (ADS)

Spencer, Michelle J. S.; Hung, Andrew; Snook, Ian K.; Yarovsky, Irene

2002-08-01

Adhesion between ideal bulk-terminated bcc Fe(1 1 1) match and mismatch interfaces was simulated using density functional theory (DFT) within the plane-wave pseudopotential representation. Interfaces were modelled using the supercell approach where the interfacial separation was varied by changing the size of the vacuum spacer between image cells in the z-direction. The adhesive energy values were calculated for discrete interfacial separations and the data was fitted to the universal binding energy relation (UBER) [Rose et al., Phys. Rev. B 28 (1983) 1835]. The parameters obtained from these fits allowed the work of separation ( Wsep) to be determined and a comparison to be made of the adhesion properties of the match and mismatch interfaces. The results were also compared to those obtained previously for the (1 0 0) and (1 1 0) surfaces.

The roles of cell adhesion molecules in tumor suppression and cell migration: a new paradox.

PubMed

Moh, Mei Chung; Shen, Shali

2009-01-01

In addition to mediating cell adhesion, many cell adhesion molecules act as tumor suppressors. These proteins are capable of restricting cell growth mainly through contact inhibition. Alterations of these cell adhesion molecules are a common event in cancer. The resulting loss of cell-cell and/or cell-extracellular matrix adhesion promotes cell growth as well as tumor dissemination. Therefore, it is conventionally accepted that cell adhesion molecules that function as tumor suppressors are also involved in limiting tumor cell migration. Paradoxically, in 2005, we identified an immunoglobulin superfamily cell adhesion molecule hepaCAM that is able to suppress cancer cell growth and yet induce migration. Almost concurrently, CEACAM1 was verified to co-function as a tumor suppressor and invasion promoter. To date, the reason and mechanism responsible for this exceptional phenomenon remain unclear. Nevertheless, the emergence of these intriguing cell adhesion molecules with conflicting roles may open a new chapter to the biological significance of cell adhesion molecules.

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

Intercellular adhesion molecules (ICAMs) and spermatogenesis

PubMed Central

Xiao, Xiang; Mruk, Dolores D.; Cheng, C. Yan

2013-01-01

BACKGROUND During the seminiferous epithelial cycle, restructuring takes places at the Sertoli–Sertoli and Sertoli–germ cell interface to accommodate spermatogonia/spermatogonial stem cell renewal via mitosis, cell cycle progression and meiosis, spermiogenesis and spermiation since developing germ cells, in particular spermatids, move ‘up and down’ the seminiferous epithelium. Furthermore, preleptotene spermatocytes differentiated from type B spermatogonia residing at the basal compartment must traverse the blood–testis barrier (BTB) to enter the adluminal compartment to prepare for meiosis at Stage VIII of the epithelial cycle, a process also accompanied by the release of sperm at spermiation. These cellular events that take place at the opposite ends of the epithelium are co-ordinated by a functional axis designated the apical ectoplasmic specialization (ES)—BTB—basement membrane. However, the regulatory molecules that co-ordinate cellular events in this axis are not known. METHODS Literature was searched at http://www.pubmed.org and http://scholar.google.com to identify published findings regarding intercellular adhesion molecules (ICAMs) and the regulation of this axis. RESULTS Members of the ICAM family, namely ICAM-1 and ICAM-2, and the biologically active soluble ICAM-1 (sICAM-1) are the likely regulatory molecules that co-ordinate these events. sICAM-1 and ICAM-1 have antagonistic effects on the Sertoli cell tight junction-permeability barrier, involved in Sertoli cell BTB restructuring, whereas ICAM-2 is restricted to the apical ES, regulating spermatid adhesion during the epithelial cycle. Studies in other epithelia/endothelia on the role of the ICAM family in regulating cell movement are discussed and this information has been evaluated and integrated into studies of these proteins in the testis to create a hypothetical model, depicting how ICAMs regulate junction restructuring events during spermatogenesis. CONCLUSIONS ICAMs are crucial

Adhesion molecules and receptors

USDA-ARS?s Scientific Manuscript database

Adhesion molecules are necessary for leukocyte trafficking and differentiation. They serve to initiate cell-cell interactions under conditions of shear, and they sustain the cell-cell and cell-matrix interactions needed for cellular locomotion. They also can serve directly as signaling molecules act...

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1.

PubMed Central

Arruda, E; Crump, C E; Marlin, S D; Merluzzi, V J; Hayden, F G

1992-01-01

We studied the in vitro antirhinovirus activity of a soluble form of intercellular adhesion molecule-1 (sICAM-1). sICAM-1 inhibited the cytopathic effect of 10 representative human rhinovirus (HRV) serotypes of the major receptor group with, 50% effective concentrations (EC50s) of 0.1 to 7.9 micrograms/ml. Cell type-dependent variation in the inhibitory activity of sICAM-1 was observed for two major receptor group serotypes in HeLa cells (EC50, greater than 32 micrograms/ml), and no inhibitory effect was observed for two serotypes which use different cell receptors. Yield reduction assays showed that sICAM-1 inhibited the replication of HRV serotype 39 (HRV-39) in human adenoid explants in a concentration-dependent manner. No direct inactivation of infectivity of HRV-39 (EC50, 0.5 microgram/ml) was observed after incubation with sICAM-1 (32 micrograms/ml) for up to 24 h. Single-cycle-of-replication experiments with the addition of sICAM-1 at 10 micrograms/ml at different times showed that the inhibitory effect occurs only when sICAM-1 is added within 30 min after infection. In experiments in which absorption was carried out at 4 degrees C and then a single cycle of replication incubation was carried out at 33 degrees C, it was found that sICAM-1 at 10 micrograms/ml was inhibitory only when it was present during the absorption period. Our data show that sICAM-1 is inhibitory for representative major receptor group serotypes of HRV in two cell lines and human respiratory epithelium, that the interaction of sICAM-1 with HRV is readily reversible by dilution, and that the inhibitory effect of sICAM-1 on virus replication is present early in the infection cycle. PMID:1358025

The endometrial cell surface and implantation. Expression of the polymorphic mucin MUC-1 and adhesion molecules during the endometrial cycle.

PubMed

Aplin, J D; Seif, M W; Graham, R A; Hey, N A; Behzad, F; Campbell, S

1994-09-30

The cell surface mucin MUC-1 is present in endometrial epithelial cells and their associated apical glycocalyx and is also released into gland lumens as a secretory product. MUC-1 mRNA and core protein are found at low levels in the proliferative phase of the cycle, but their abundance increases after ovulation. Endometrial MUC-1 has been found to carry sialokeratan sulphate chains and these show a dramatically increased abundance in cells and secretions in the post-ovulatory phase of the cycle, reaching a maximum in secretions 6-7 days after the LH peak. The apical epithelium also contains adhesion receptor molecules of the integrin and CD44 families. MUC-1 is large and highly glycosylated and probably extends farther from the cell surface than these 'conventional' glycoprotein receptors. It has the potential to inhibit sterically receptor-mediated cell-cell adhesion. However, it is also possible that MUC-1 displays specific (e.g., glycan) recognition structures for the initial attachment of the blastocyst or that the embryo may create a specialised microenvironment in which to implant.

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

PubMed Central

Strazza, Marianne; Azoulay-Alfaguter, Inbar; Peled, Michael; Smrcka, Alan V.; Skolnik, Edward Y.; Srivastava, Shekhar; Mor, Adam

2017-01-01

Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)–expressing cells. Structure–function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs. PMID:28213494

Soluble endothelium-associated adhesion molecules in patients with Graves' disease.

PubMed Central

Wenisch, C; Myskiw, D; Parschalk, B; Hartmann, T; Dam, K; Graninger, W

1994-01-01

The targeting and recruitment of inflammatory cells to vascular endothelium in Graves' disease (GD) is mediated by intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). We have studied serum levels of soluble ICAM-1 (sICAM-1), soluble ELAM-1 (sELAM-1), and soluble VCAM-1 (sVCAM-1) in patients with GD (n = 21) and in patients with iodine-deficient goitre (IDG) (n = 23). The serum levels of sICAM-1 were markedly elevated in patients with GD before treatment with thiamazole (median 560 ng/ml versus 185 ng/ml in patients with IDG). In addition, elevated serum concentrations of sELAM-1 (median 85 ng/ml versus 33 ng/ml, respectively) and sVCAM-1 (median 42 ng/ml versus 15 ng/ml, respectively) were observed in patients with GD (P < 0.01 for all). The serum levels of sELAM-1 and sVCAM-1 dropped significantly after initiation of therapy and were within the normal range after 4, and 8 weeks of therapy, respectively. Serum levels of sICAM-1 were elevated even after 8 weeks of therapy. Serum levels of sVACM-1 and sICAM-1 correlated with the serum concentrations of anti-thyroid-stimulating hormone (TSH)-receptor antibodies (TSHR-R) (n = 21; r = 0.929 and r = 0.810, respectively) and anti-thyroid peroxidase antibodies (TPO-Ab) (n = 21; r = 0.673 and r = 0.750, respectively). However, no correlation between sELAM-1 and TPO-Ab, TSHR-R, and anti-thyroglobulin antibodies (Tg-Ab), respectively, could be found. In addition to thyroid hormones and autoantibodies, serum concentrations of sELAM-1 and sVCAM-1, but not sICAM-1, could be useful as clinical markers for disease activity. PMID:7525128

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.

The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo.

PubMed

Martin, Veronica; Mrkusich, Eli; Steinel, Martin C; Rice, Jason; Merritt, David J; Whitington, Paul M

2008-04-08

Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the extracellular substrate. Rather, we suggest that Neuroglian

The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo

PubMed Central

Martin, Veronica; Mrkusich, Eli; Steinel, Martin C; Rice, Jason; Merritt, David J; Whitington, Paul M

2008-01-01

Background Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. Results We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. Conclusion We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the extracellular substrate. Rather, we

Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1.

PubMed

Bieber, A J; Snow, P M; Hortsch, M; Patel, N H; Jacobs, J R; Traquina, Z R; Schilling, J; Goodman, C S

1989-11-03

Drosophila neuroglian is an integral membrane glycoprotein that is expressed on a variety of cell types in the Drosophila embryo, including expression on a large subset of glial and neuronal cell bodies in the central and peripheral nervous systems and on the fasciculating axons that extend along them. Neuroglian cDNA clones were isolated by expression cloning. cDNA sequence analysis reveals that neuroglian is a member of the immunoglobulin superfamily. The extracellular portion of the protein consists of six immunoglobulin C2-type domains followed by five fibronectin type III domains. Neuroglian is closely related to the immunoglobulin-like vertebrate neural adhesion molecules and, among them, shows most extensive homology to mouse L1. Its homology to L1 and its embryonic localization suggest that neuroglian may play a role in neural and glial cell adhesion in the developing Drosophila embryo. We report here on the identification of a lethal mutation in the neuroglian gene.

Suppression of endothelial cell adhesion by XJP-1, a new phenolic compound derived from banana peel.

PubMed

Fu, Rong; Yan, Tianhua; Wang, Qiujuan; Guo, Qinglong; Yao, Hequan; Wu, Xiaoming; Li, Yang

2012-01-01

The adhesion of monocytes to activated vascular endothelial cells is a critical event in the initiation of atherosclerosis. Adhesion is mediated by oxidized low-density lipoprotein (ox-LDL) which up-regulates inflammatory markers on endothelial cells. Here we report that (±) 7, 8-dihydroxy-3-methyl-isochromanone-4 (XJP-1), an inhibitor of ox-LDL-induced adhesion of monocytes to endothelial cells blocks cellular functions which are associated with adhesion. We show that XJP-1 down-regulates ox-LDL-induced over-expression of adhesion molecules (ICAM-1 and VCAM-1) in a dose-dependent manner in human umbilical vein endothelial cells (HUVECs), attenuates ox-LDL-induced up-regulation of low-density lipoprotein receptor (LOX)-1, decreases generation of reactive oxygen species (ROS), blocks translocation of nuclear factor-kappa B (NF-κB) activity, and prevents activation of c-Jun N-terminal kinase (JNK)/p38 pathways in endothelial cells. These findings suggest that XJP-1 may attenuate ox-LDL-induced endothelial adhesion of monocytes by blocking expression of adhesion molecules through suppressing ROS/NF-κB, JNK and p38 pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

αMβ2-integrin-intercellular adhesion molecule-1 interactions drive the flow-dependent trafficking of Guillain-Barré syndrome patient derived mononuclear leukocytes at the blood-nerve barrier in vitro

PubMed Central

Yosef, Nejla; Ubogu, Eroboghene E.

2012-01-01

The mechanisms of hematogenous leukocyte trafficking at the human blood-nerve barrier (BNB) are largely unknown. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the pathogenesis of Guillain-Barré syndrome (GBS). We developed a cytokine-activated human in vitro BNB model using primary endoneurial endothelial cells. Endothelial treatment with 10 U/mL tissue necrosis factor-α and 20 U/mL interferon-γ resulted in de novo expression of proinflammatory chemokines CCL2, CXCL9, CXCL11 and CCL20, with increased expression of CXCL2-3, CXCL8 and CXCL10 relative to basal levels. Cytokine treatment induced/ enhanced ICAM-1, E- and P-selectin, vascular cell adhesion molecule-1 and the alternatively spliced pro-adhesive fibronectin variant, fibronectin connecting segment-1 expression in a time-dependent manner, without alterations in junctional adhesion molecule-A expression. Lymphocytes and monocytes from untreated GBS patients express ICAM-1 counterligands, αM- and αL-integrin, with differential regulation of αM-integrin expression compared to healthy controls. Under flow conditions that mimic capillary hemodynamics in vivo, there was a >3-fold increase in total GBS patient and healthy control mononuclear leukocyte adhesion/ migration at the BNB following cytokine treatment relative to the untreated state. Function neutralizing monoclonal antibodies against human αM-integrin (CD11b) and ICAM-1 reduced untreated GBS patient mononuclear leukocyte trafficking at the BNB by 59% and 64.2% respectively. Monoclonal antibodies against αL-integrin (CD11a) and human intravenous immunoglobulin reduced total leukocyte adhesion/migration by 22.8% and 17.6% respectively. This study demonstrates differential regulation of αM-integrin on circulating mononuclear cells in GBS, as well as an important role for αM-integrin-ICAM-1 interactions in pathogenic GBS patient leukocyte trafficking at the human BNB in vitro. PMID:22552879

Impact of simulated microgravity on the secretory and adhesive activity of cultured human vascular endothelial cells.

NASA Astrophysics Data System (ADS)

Rudimov, Evgeny; Buravkova, Ludmila; Pogodina, Margarita; Andrianova, Irina

The layer of vascular endothelial cells (ECs) is a dynamic,disseminated organ that perform the function of an interface between the blood and vascular wall. The endothelial monolayer is able to quickly respond to changes in the microenvironment due to its synthesis of vasoactive substances, chemokines, adhesion molecules expression, etc. ECs are highly sensitive to gravitational changes and capable of short-term and long-term responses (Sangha et al., 2001; Buravkova et al., 2005; Infanger et al., 2006, 2007. However, the question remains how to reflect the impact of microgravity on endothelium under the inflammatory process. Therefore, the aim of this study was to investigate secretory and adhesive activity of human umbilical vein endothelial cells (HUVECs) during simulated microgravity and TNF-a activation. HUVECs were isolated according to Gimbrone et al. (1978) in modification A. Antonov (1981) and used for experiments at 2-4 passages. HUVECs were activated by low level of TNF-a (2 ng/ml). Microgravity was generated by Random Positioning Machine (RPM, Dutch Space, Leiden) placed into the thermostat at 37°C. After 24 hours of clinorotation we measured adhesion molecules expression on the cell surface (ICAM-1, VCAM-1, PECAM-1, E-selectin, CD144, endoglin (CD105)) and cell viability using a flow cytometry. To evaluate the level of target gene expression was used the real time RT-PCR. IL-6 and IL-8 concentration was measured in the conditioned medium of HUVECs by using the ELISA test. We found that simulated microgravity within 24 hours caused a decrease of ICAM-1, CD144, and E-selectin expression, at the same time not affect the cell viability, endoglin and PECAM-1 expression on the surface HUVEC. Furthermore, there were no changes of the level of IL-6 and IL-8 gene expression and their products in the culture medium. TNF-activated HUVECs showed an increase in gene expression of interleukins and molecules involved in the adhesion process, which also was confirmed

HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion.

PubMed

Patzak, Irene M; Königsberger, Sebastian; Suzuki, Akira; Mak, Tak W; Kiefer, Friedemann

2010-11-01

The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.

Endocytic pathways downregulate the L1-type cell adhesion molecule neuroglian to promote dendrite pruning in Drosophila.

PubMed

Zhang, Heng; Wang, Yan; Wong, Jack Jing Lin; Lim, Kah-Leong; Liou, Yih-Cherng; Wang, Hongyan; Yu, Fengwei

2014-08-25

Pruning of unnecessary axons and/or dendrites is crucial for maturation of the nervous system. However, little is known about cell adhesion molecules (CAMs) that control neuronal pruning. In Drosophila, dendritic arborization neurons, ddaCs, selectively prune their larval dendrites. Here, we report that Rab5/ESCRT-mediated endocytic pathways are critical for dendrite pruning. Loss of Rab5 or ESCRT function leads to robust accumulation of the L1-type CAM Neuroglian (Nrg) on enlarged endosomes in ddaC neurons. Nrg is localized on endosomes in wild-type ddaC neurons and downregulated prior to dendrite pruning. Overexpression of Nrg alone is sufficient to inhibit dendrite pruning, whereas removal of Nrg causes precocious dendrite pruning. Epistasis experiments indicate that Rab5 and ESCRT restrain the inhibitory role of Nrg during dendrite pruning. Thus, this study demonstrates the cell-surface molecule that controls dendrite pruning and defines an important mechanism whereby sensory neurons, via endolysosomal pathway, downregulate the cell-surface molecule to trigger dendrite pruning. Copyright © 2014 Elsevier Inc. All rights reserved.

A novel leukocyte adhesion deficiency caused by expressed but nonfunctional β2 integrins Mac-1 and LFA-1

PubMed Central

Hogg, Nancy; Stewart, Mairi P.; Scarth, Sarah L.; Newton, Rebecca; Shaw, Jacqueline M.; Law, S.K. Alex; Klein, Nigel

1999-01-01

In the leukocyte adhesion deficiency (LAD)-1 syndrome, there is diminished expression of β2(CD18) integrins. This is caused by lesions in the β2-subunit gene and gives rise to recurrent bacterial infections, impaired pus formation, and poor wound healing. We describe a patient with clinical features compatible with a moderately severe phenotype of LAD-1 but who expresses the β2 integrins lymphocyte function– associated molecule (LFA)-1 and Mac-1 at 40%–60% of normal levels. This level of expression should be adequate for normal integrin function, but both the patient's Mac-1 on neutrophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule (ICAM)-1, respectively, or to display a β2-integrin activation epitope after adhesion-inducing stimuli. Unexpectedly, divalent cation treatment induced the patient's T cells to bind to ICAM-2 and ICAM-3. Sequencing of the patient's two CD18 alleles revealed the mutations S138P and G273R. Both mutations are in the β2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion–dependent adhesion site (MIDAS) motif. After K562 cell transfection with α subunits, the mutated S138P β subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. In summary, the patient described here exhibits failure of the β2 integrins to function despite adequate levels of cell-surface expression. PMID:9884339

Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation.

PubMed

Fogel, Adam I; Stagi, Massimiliano; Perez de Arce, Karen; Biederer, Thomas

2011-09-16

Synapses are specialized adhesion sites between neurons that are connected by protein complexes spanning the synaptic cleft. These trans-synaptic interactions can organize synapse formation, but their macromolecular properties and effects on synaptic morphology remain incompletely understood. Here, we demonstrate that the synaptic cell adhesion molecule SynCAM 1 self-assembles laterally via its extracellular, membrane-proximal immunoglobulin (Ig) domains 2 and 3. This cis oligomerization generates SynCAM oligomers with increased adhesive capacity and instructs the interactions of this molecule across the nascent and mature synaptic cleft. In immature neurons, cis assembly promotes the adhesive clustering of SynCAM 1 at new axo-dendritic contacts. Interfering with the lateral self-assembly of SynCAM 1 in differentiating neurons strongly impairs its synaptogenic activity. At later stages, the lateral oligomerization of SynCAM 1 restricts synaptic size, indicating that this adhesion molecule contributes to the structural organization of synapses. These results support that lateral interactions assemble SynCAM complexes within the synaptic cleft to promote synapse induction and modulate their structure. These findings provide novel insights into synapse development and the adhesive mechanisms of Ig superfamily members.

Generation and Nuclear Translocation of Sumoylated Transmembrane Fragment of Cell Adhesion Molecule L1

PubMed Central

Lutz, David; Wolters-Eisfeld, Gerrit; Joshi, Gunjan; Djogo, Nevena; Jakovcevski, Igor; Schachner, Melitta; Kleene, Ralf

2012-01-01

The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys1172 or of the nuclear localization signal at Lys1147 abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system. PMID:22431726

Gold nanoparticles functionalized with a fragment of the neural cell adhesion molecule L1 stimulate L1-mediated functions

NASA Astrophysics Data System (ADS)

Schulz, Florian; Lutz, David; Rusche, Norman; Bastús, Neus G.; Stieben, Martin; Höltig, Michael; Grüner, Florian; Weller, Horst; Schachner, Melitta; Vossmeyer, Tobias; Loers, Gabriele

2013-10-01

The neural cell adhesion molecule L1 is involved in nervous system development and promotes regeneration in animal models of acute and chronic injury of the adult nervous system. To translate these conducive functions into therapeutic approaches, a 22-mer peptide that encompasses a minimal and functional L1 sequence of the third fibronectin type III domain of murine L1 was identified and conjugated to gold nanoparticles (AuNPs) to obtain constructs that interact homophilically with the extracellular domain of L1 and trigger the cognate beneficial L1-mediated functions. Covalent conjugation was achieved by reacting mixtures of two cysteine-terminated forms of this L1 peptide and thiolated poly(ethylene) glycol (PEG) ligands (~2.1 kDa) with citrate stabilized AuNPs of two different sizes (~14 and 40 nm in diameter). By varying the ratio of the L1 peptide-PEG mixtures, an optimized layer composition was achieved that resulted in the expected homophilic interaction of the AuNPs. These AuNPs were stable as tested over a time period of 30 days in artificial cerebrospinal fluid and interacted with the extracellular domain of L1 on neurons and Schwann cells, as could be shown by using cells from wild-type and L1-deficient mice. In vitro, the L1-derivatized particles promoted neurite outgrowth and survival of neurons from the central and peripheral nervous system and stimulated Schwann cell process formation and proliferation. These observations raise the hope that, in combination with other therapeutic approaches, L1 peptide-functionalized AuNPs may become a useful tool to ameliorate the deficits resulting from acute and chronic injuries of the mammalian nervous system.The neural cell adhesion molecule L1 is involved in nervous system development and promotes regeneration in animal models of acute and chronic injury of the adult nervous system. To translate these conducive functions into therapeutic approaches, a 22-mer peptide that encompasses a minimal and functional L1

Interactions between the L1 cell adhesion molecule and ezrin support traction-force generation and can be regulated by tyrosine phosphorylation.

PubMed

Sakurai, Takeshi; Gil, Orlando D; Whittard, John D; Gazdoiu, Mihaela; Joseph, Todd; Wu, James; Waksman, Adam; Benson, Deanna L; Salton, Stephen R; Felsenfeld, Dan P

2008-09-01

An Ig superfamily cell-adhesion molecule, L1, forms an adhesion complex at the cell membrane containing both signaling molecules and cytoskeletal proteins. This complex mediates the transduction of extracellular signals and generates actin-mediated traction forces, both of which support axon outgrowth. The L1 cytoplasmic region binds ezrin, an adapter protein that interacts with the actin cytoskeleton. In this study, we analyzed L1-ezrin interactions in detail, assessed their role in generating traction forces by L1, and identified potential regulatory mechanisms controlling ezrin-L1 interactions. The FERM domain of ezrin binds to the juxtamembrane region of L1, demonstrated by yeast two-hybrid interaction traps and protein binding analyses in vitro. A lysine-to-leucine substitution in this domain of L1 (K1147L) shows reduced binding to the ezrin FERM domain. Additionally, in ND7 cells, the K1147L mutation inhibits retrograde movement of L1 on the cell surface that has been linked to the generation of the traction forces necessary for axon growth. A membrane-permeable peptide consisting of the juxtamembrane region of L1 that can disrupt endogenous L1-ezrin interactions inhibits neurite extension of cerebellar cells on L1 substrates. Moreover, the L1-ezrin interactions can be modulated by tyrosine phosphorylation of the L1 cytoplasmic region, namely, Y1151, possibly through Src-family kinases. Replacement of this tyrosine together with Y1176 with either aspartate or phenylalanine changes ezrin binding and alters colocalization with ezrin in ND7 cells. Collectively, these data suggest that L1-ezrin interactions mediated by the L1 juxtamembrane region are involved in traction-force generation and can be regulated by the phosphorylation of L1. (c) 2008 Wiley-Liss, Inc.

Expression of Inflammation-related Intercellular Adhesion Molecules in Cardiomyocytes In Vitro and Modulation by Pro-inflammatory Agents.

PubMed

El-Battrawy, Ibrahim; Tülümen, Erol; Lang, Siegfried; Akin, Ibrahim; Behnes, Michael; Zhou, Xiabo; Mavany, Martin; Bugert, Peter; Bieback, Karen; Borggrefe, Martin; Elmas, Elif

2016-01-01

Cell-surface adhesion molecules regulate multiple intercellular and intracellular processes and play important roles in inflammation by facilitating leukocyte endothelial transmigration. Whether cardiomyocytes express surface-adhesion molecules related to inflammation and the effect of pro-inflammatory mediators remain unknown. In the present study, the expression of different cell-adhesion molecules (CD11a, CD11b, CD31, CD62P, CD162, F11 receptor and mucosal vascular addressin cell adhesion molecule 1 (MADCAM1)) and the effect of pro-inflammatory mediators were investigated in an in vitro model of human cardiomyocytes. Cells were supplied as a primary culture of cardiac alpha actin-positive cells from human heart tissue. The cells were incubated for 24 h with 1 U/ml thrombin or 700 ng/ml lipopolysaccharide (LPS) or with a combination of both. The expression of the cell adhesion molecules was measured by flow cytometry. In cultured human cardiomyocytes, 22.8% of cells expressed CD31, 7.1% MADCAM1 and 2.6% F11R. CD11a, CD11b, CD62P and CD162 were expressed by fewer than 2% of the cells at baseline. CD31 expression increased on incubation of cardiomyocytes with thrombin by 26% (p<0.05) and with LPS by 26% (p=0.06). The combination of thrombin and LPS did not result in increased levels of CD31 (p>0.10). The pro-inflammatory agents LPS and thrombin had no effect on the expression of MADCAM1 and F11R. Inflammation-related cell-adhesion molecules CD31, MADCAM1 and F11R were shown to be expressed on the surface of human cardiomyocytes in an in vitro model. Incubation with LPS or thrombin resulted in increased expression of CD31, however, it did not modify the expression of the cell adhesion molecules MADCAM1 and F11R. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity.

PubMed

Giangreco, Adam; Hoste, Esther; Takai, Yoshimi; Rosewell, Ian; Watt, Fiona M

2012-02-01

Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8-restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC-matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-γ. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia.

Naringin suppress chondrosarcoma migration through inhibition vascular adhesion molecule-1 expression by modulating miR-126.

PubMed

Tan, Tzu-Wei; Chou, Ying-Erh; Yang, Wei-Hung; Hsu, Chin-Jung; Fong, Yi-Chin; Tang, Chih-Hsin

2014-09-01

Chondrosarcoma, a primary malignant bone cancer, has a potent capacity to invade locally and cause distant metastasis, especially to the lungs. Patients diagnosed with it have poor prognosis. Naringin, polymethoxylated flavonoid commonly found in citrus fruits, has anti-oxidant, anti-inflammatory and anti-tumor activity; whether naringin regulates migration of chondrosarcoma is largely unknown. Here we report that naringin does not expedite apoptosis in human chondrosarcoma. By contrast, at noncytotoxic concentrations, naringin suppressed migration and invasion of chondrosarcoma cells. Vascular cell adhesion molecule-1 (VCAM-1) of the immunoglobulin superfamily is linked with metastasis; we found incubation of chondrosarcoma cells with naringin reducing mRNA transcription for, and cell surface expression of, VCAM-1. We also observed that naringin enhancing miR-126 expression, and miR-126 inhibitor reversed the naringin-inhibited cell motility and VCAM-1 expression. Therefore, naringin inhibits migration and invasion of human chondrosarcoma via down-regulation of VCAM-1 by increasing miR-126. Thus, naringin may be a novel anti-migration agent for the treatment of migration in chondrosarcoma. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Corticotropin-Releasing Hormone Modulates Human Trophoblast Invasion through Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 Regulation

PubMed Central

Bamberger, Ana-Maria; Minas, Vassilis; Kalantaridou, Sophia N.; Radde, Jessica; Sadeghian, Helen; Löning, Thomas; Charalampopoulos, Ioannis; Brümmer, Jens; Wagener, Christoph; Bamberger, Christoph M.; Schulte, Heinrich M.; Chrousos, George P.; Makrigiannakis, Antonis

2006-01-01

Abnormalities in the process of trophoblast invasion may result in abnormal placentation. Both the embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH), which promotes implantation. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is expressed in extravillous trophoblasts (EVTs) of normal human placenta, may also function in tro-phoblast/endometrial interactions. We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression. We examined cultures of freshly isolated human EVTs, which express CEACAM1, and an EVT-based hybridoma cell line, which is devoid of endogenous CEACAM1. CRH inhibited EVT invasion in Matrigel invasion assays, and this effect was blocked by the CRH receptor type 1 (CRHR1)-specific antagonist antalarmin. Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner. After transfection of the hybridoma cell line with a CEACAM1 expression vector, the invasiveness of these cells was strongly enhanced. This effect was inhibited by addition of blocking monoclonal antibody against CEACAM1. Furthermore, blocking of endogenous CEACAM1 in EVTs inhibited the invasive potential of these cells. Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta. PMID:16400017

Intercellular Adhesion Molecule-5 Induces Dendritic Outgrowth by Homophilic Adhesion

PubMed Central

Tian, Li; Nyman, Henrietta; Kilgannon, Patrick; Yoshihara, Yoshihiro; Mori, Kensaku; Andersson, Leif C.; Kaukinen, Sami; Rauvala, Heikki; Gallatin, W. Michael; Gahmberg, Carl G.

2000-01-01

Intercellular adhesion molecule-5 (ICAM-5) is a dendritically polarized membrane glycoprotein in telencephalic neurons, which shows heterophilic binding to leukocyte β2-integrins. Here, we show that the human ICAM-5 protein interacts in a homophilic manner through the binding of the immunoglobulin domain 1 to domains 4–5. Surface coated ICAM-5-Fc promoted dendritic outgrowth and arborization of ICAM- 5–expressing hippocampal neurons. During dendritogenesis in developing rat brain, ICAM-5 was in monomer form, whereas in mature neurons it migrated as a high molecular weight complex. The findings indicate that its homophilic binding activity was regulated by nonmonomer/monomer transition. Thus, ICAM-5 displays two types of adhesion activity, homophilic binding between neurons and heterophilic binding between neurons and leukocytes. PMID:10893271

Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury

PubMed Central

Eisner, Mark D.; Parsons, Polly E.; Thompson, B. Taylor; Conner, Edward R.; Matthay, Michael A.; Ware, Lorraine B.

2009-01-01

Objective To determine if levels of soluble intercellular adhesion molecule-1 (sICAM-1), a marker of alveolar epithelial and endothelial injury, differ in patients with hydrostatic pulmonary edema and acute lung injury (ALI) and are associated with clinical outcomes in patients with ALI. Design, setting, and participants Measurement of sICAM-1 levels in (1) plasma and edema fluid from 67 patients with either hydrostatic pulmonary edema or ALI enrolled in an observational, prospective single center study, and (2) in plasma from 778 patients with ALI enrolled in a large multi-center randomized controlled trial of ventilator strategy. Results In the single-center study, levels of sICAM-1 were significantly higher in both edema fluid and plasma (median 938 and 545 ng/ml, respectively) from ALI patients compared to hydrostatic edema patients (median 384 and 177 ng/ml, P < 0.03 for both comparisons). In the multi-center study, higher plasma sICAM-1 levels were associated with poor clinical outcomes in both unadjusted and multivariable models. Subjects with ALI whose plasma sICAM-1 levels increased over the first 3 days of the study had a higher risk of death, after adjusting for other important predictors of outcome (odds ratio 1.48; 95% CI 1.03–2.12, P = 0.03). Conclusions Both plasma and edema fluid levels of sICAM-1 are higher in patients with ALI than in patients with hydrostatic pulmonary edema. Higher plasma sICAM-1 levels and increasing sICAM-1 levels over time are associated with poor clinical outcomes in ALI. Measurement of sICAM-1 levels may be useful for identifying patients at highest risk of poor outcomes from ALI. PMID:18670758

Cyclic Stretching of Mesangial Cells Up-Regulates Intercellular Adhesion Molecule-1 and Leukocyte Adherence

PubMed Central

Riser, Bruce L.; Varani, James; Cortes, Pedro; Yee, Jerry; Dame, Michael; Sharba, Abdul K.

2001-01-01

Intraglomerular hypertension is a primary causal factor in the progressive glomerulosclerosis that characterizes diabetic nephropathy or severe renal ablation. However, inflammation of the glomerular mesangium also participates in at least the early phase of these diseases. In glomerulonephritis, where inflammation is thought to be the predominant causal factor, intraglomerular hypertension is also often present. Mesangial cells (MCs) are critical in orchestrating key functions of the glomerulus including extracellular matrix metabolism, cytokine production, and interaction with leukocytes. Because MCs are subject to increased stretching when intraglomerular hypertension is present, and in glomerulonephritis MC/leukocyte interactions seem to be mediated primarily via the up-regulation of intercellular adhesion molecule-1 (ICAM-1), we examine the possibility that cyclic stretching is a stimulus for increased MC ICAM-1 activity. We demonstrate that the normal low levels of MC ICAM-1 mRNA and protein are dramatically up-regulated by even short intervals of cyclic stretch. This effect is dose- and time-dependent, and requires little amplitude and a brief period of elongation for significant induction. Stretch-induced MC ICAM-1 also leads to a marked elevation in phagocytic leukocyte adherence. This stimulated adherence is equal or greater than that induced by the inflammatory cytokine tumor necrosis factor-α, whereas an additive effect occurs when both are applied in combination. Our results indicate that stretch-induced ICAM-1 may provide a direct link between hypertension and inflammation in the progression of injury and glomerulosclerosis in diabetes, renal ablation, and other forms of glomerulonephritis. PMID:11141473

Low-calorie cranberry juice supplementation reduces plasma oxidized LDL and cell adhesion molecule concentrations in men.

PubMed

Ruel, Guillaume; Pomerleau, Sonia; Couture, Patrick; Lemieux, Simone; Lamarche, Benoît; Couillard, Charles

2008-02-01

Elevated circulating concentrations of oxidized LDL (OxLDL) and cell adhesion molecules are considered to be relevant markers of oxidative stress and endothelial activation which are implicated in the development of CVD. On the other hand, it has been suggested that dietary flavonoid consumption may be cardioprotective through possible favourable impacts on LDL particle oxidation and endothelial activation. The present study was undertaken to determine the effect of the daily consumption of low-calorie cranberry juice cocktail on plasma OxLDL, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin concentrations in men. Thirty men (mean age 51 (sd 10) years) were recruited and asked to consume increasing daily doses of cranberry juice cocktail (125, 250 and 500 ml/d) over three successive periods of 4 weeks. Plasma OxLDL and adhesion molecule concentrations were measured by ELISA before and after each phase. We noted a significant decrease in plasma OxLDL concentrations following the intervention (P < 0.0001). We also found that plasma ICAM-1 (P < 0.0001) and VCAM-1 (P < 0.05) concentrations decreased significantly during the course of the study. In summary, the present results show that daily cranberry juice cocktail consumption is associated with decreases in plasma OxLDL, ICAM-1 and VCAM-1 concentrations in men.

γ-Oryzanol reduces adhesion molecule expression in vascular endothelial cells via suppression of nuclear factor-κB activation.

PubMed

Sakai, Satoshi; Murata, Takahisa; Tsubosaka, Yoshiki; Ushio, Hideki; Hori, Masatoshi; Ozaki, Hiroshi

2012-04-04

γ-Oryzanol (γ-ORZ) is a mixture of phytosteryl ferulates purified from rice bran oil. In this study, we examined whether γ-ORZ represents a suppressive effect on the lipopolysaccharide (LPS)-induced adhesion molecule expression on vascular endothelium. Treatment with LPS elevated the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in bovine aortic endothelial cells (BAECs). Pretreatment with γ-ORZ dose-dependently decreased the LPS-mediated expression of these genes. Western blotting also revealed that pretreatment with γ-ORZ dose-dependently inhibited LPS-induced VCAM-1 expression in human umbilical vein endothelial cells. Consistently, pretreatment with γ-ORZ dose-dependently reduced LPS-induced U937 monocyte adhesion to BAECs. In immunofluorescence, LPS caused nuclear factor-κB (NF-κB) nuclear translocation in 40% of BAECs, which indicates NF-κB activation. Pretreatment with γ-ORZ, as well as its components (cycloartenyl ferulate, ferulic acid, or cycloartenol), dose-dependently inhibited LPS-mediated NF-κB activation. Collectively, our results suggested that γ-ORZ reduced LPS-mediated adhesion molecule expression through NF-κB inhibition in vascular endothelium.

Induction of mast cell accumulation by chymase via an enzymatic activity- and intercellular adhesion molecule-1-dependent mechanism.

PubMed

Zhang, Huiyun; Wang, Junling; Wang, Ling; Zhan, Mengmeng; Li, Shigang; Fang, Zeman; Xu, Ciyan; Zheng, Yanshan; He, Shaoheng

2018-02-01

Chymase is a unique, abundant secretory product of mast cells and a potent chemoattractant for eosinophils, monocytes and neutrophils, but little is known of its influence on mast cell accumulation. A mouse peritoneal inflammation model, cell migration assay and flowcytometry analysis, were used to investigate the role of chymase in recruiting mast cells. Chymase increased, by up to 5.4-fold, mast cell numbers in mouse peritoneum. Inhibitors of chymase, heat-inactivation of the enzyme, sodium cromoglycate and terfenadine, and pretreatment of mice with anti-intercellular adhesion molecule 1, anti-L-selectin, anti-CD11a and anti-CD18 antibodies dramatically diminished the chymase-induced increase in mast cell accumulation. These findings indicate that this effect of chymase is dependent on its enzymatic activity and activation of adhesion molecules. In addition, chymase provoked a significant increase in 5-HT and eotaxin release (up to 1.8- and 2.2-fold, respectively) in mouse peritoneum. Since 5-HT, eotaxin and RANTES can induce marked mast cell accumulation, these indirect mechanisms may also contribute to chymase-induced mast cell accumulation. Moreover, chymase increased the trans-endothelium migration of mast cells in vitro indicating it also acts as a chemoattractant. The finding that mast cells accumulate in response to chymase implies further that chymase is a major pro-inflammatory mediator of mast cells. This effect of chymase, a major product of mast cell granules, suggests a novel self-amplification mechanism for mast cell accumulation in allergic inflammation. Mast cell stabilizers and inhibitors of chymase may have potential as a treatment of allergic disorders. © 2017 The British Pharmacological Society.

Ultrasound-microbubble-mediated intercellular adhesion molecule-1 small interfering ribonucleic acid transfection attenuates neointimal formation after arterial injury in mice.

PubMed

Suzuki, Jun-ichi; Ogawa, Masahito; Takayama, Kiyoshi; Taniyama, Yoshiaki; Morishita, Ryuichi; Hirata, Yasunobu; Nagai, Ryozo; Isobe, Mitsuaki

2010-03-02

The purpose of this study was to investigate the efficiency of small interfering ribonucleic acid (siRNA) in murine arteries. We transfected it using a nonviral ultrasound-microbubble-mediated in vivo gene delivery system. siRNA is an effective methodology to suppress gene function. The siRNA can be synthesized easily; however, a major obstacle in the use of siRNA as therapeutics is the difficulty involved in effective in vivo delivery. To investigate the efficiency of nonviral ultrasound-microbubble-mediated in vivo siRNA delivery, we used a fluorescein-labeled siRNA, green fluorescent protein (GFP) siRNA, and intercellular adhesion molecule (ICAM)-1 siRNA in murine arteries. Murine femoral arteries were injured using flexible wires to establish arterial injury. The fluorescein-labeled siRNA and GFP siRNA showed that this nonviral approach could deliver siRNA into target arteries effectively without any tissue damage and systemic adverse effects. ICAM-1 siRNA transfection into murine injured arteries significantly suppressed the development of neointimal formation in comparison to those in the control group. Immunohistochemistry revealed that accumulation of T cells and adhesion molecule positive cells was observed in nontreated injured arteries, whereas siRNA suppressed accumulation. The nonviral ultrasound-microbubble delivery of siRNA ensures effective transfection into target arteries. ICAM-1 siRNA has the potential to suppress arterial neointimal formation. Transfection of siRNA can be beneficial for the clinical treatment of cardiovascular and other inflammatory diseases. Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets.

PubMed

Colombo, Federico; Meldolesi, Jacopo

2015-11-01

L1 cell adhesion molecule (L1-CAM) and neural cell adhesion molecule (N-CAM), key members of the immunoglobulin-like CAM (Ig-CAM) family, were first recognized to play critical roles in surface interactions of neurons, by binding with each other and with extracellular matrix (ECM) proteins. Subsequently, adhesion was recognized to include signaling due to both activation of β-integrin, with the generation of intracellular cascades, and integration with the surface cytoskeleton. The importance of the two Ig-CAMs was revealed by their activation of the tyrosine kinase receptors of fibroblast growth factor (FGF), epidermal growth factor (EGF), and nerve growth factor (NGF). Based on these complex signaling properties, L1-CAM and N-CAM have become of great potential pharmacological interest in neurons and cancers. Treatment of neurodegenerative disorders and cognitive deficits of neurons is aimed to increase the cell Ig-CAM tone, possibly provided by synthetic/mimetic peptides. In cancer cells, where Ig-CAMs are often overexpressed, the proteins are employed for prognosis. The approaches to therapy are based on protein downregulation, antibodies, and adoptive immunotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

Soluble forms of the cell adhesion molecule L1 produced by insect and baculovirus-transduced mammalian cells enhance Schwann cell motility.

PubMed

Lavdas, Alexandros A; Efrose, Rodica; Douris, Vassilis; Gaitanou, Maria; Papastefanaki, Florentia; Swevers, Luc; Thomaidou, Dimitra; Iatrou, Kostas; Matsas, Rebecca

2010-12-01

For biotechnological applications, insect cell lines are primarily known as hosts for the baculovirus expression system that is capable to direct synthesis of high levels of recombinant proteins through use of powerful viral promoters. Here, we demonstrate the implementation of two alternative approaches based on the baculovirus system for production of a mammalian recombinant glycoprotein, comprising the extracellular part of the cell adhesion molecule L1, with potential important therapeutic applications in nervous system repair. In the first approach, the extracellular part of L1 bearing a myc tag is produced in permanently transformed insect cell lines and purified by affinity chromatography. In the second approach, recombinant baculoviruses that express L1-Fc chimeric protein, derived from fusion of the extracellular part of L1 with the Fc part of human IgG1, under the control of a mammalian promoter are used to infect mammalian HEK293 and primary Schwann cells. Both the extracellular part of L1 bearing a myc tag accumulating in the supernatants of insect cultures as well as L1-Fc secreted by transduced HEK293 or Schwann cells are capable of increasing the motility of Schwann cells with similar efficiency in a gap bridging bioassay. In addition, baculovirus-transduced Schwann cells show enhanced motility when grafted on organotypic cultures of neonatal brain slices while they retain their ability to myelinate CNS axons. This proof-of-concept that the migratory properties of myelin-forming cells can be modulated by recombinant protein produced in insect culture as well as by means of baculovirus-mediated adhesion molecule expression in mammalian cells may have beneficial applications in the field of CNS therapies. ©2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Nephrin phosphorylation regulates podocyte adhesion through the PINCH-1-ILK-α-parvin complex

PubMed Central

Zha, Dongqing; Chen, Cheng; Liang, Wei; Chen, Xinghua; Ma, Tean; Yang, Hongxia; van Goor, Harry; Ding, Guohua

2013-01-01

Nephrin, a structural molecule, is also a signaling molecule after phosphorylation. Inhibition of nephrin phosphorylation is correlated with podocyte injury. The PINCH-1-ILK-α-parvin (PIP) complex plays a crucial role in cell adhesion and cytoskeleton formation. We hypothesized that nephrin phosphorylation influenced cytoskeleton and cell adhesion in podocytes by regulating the PIP complex. The nephrin phosphorylation, PIP complex formation, and F-actin in Wistar rats intraperitoneally injected with puromycin aminonucleoside were gradually decreased but increased with time, coinciding with the recovery from glomerular/podocyte injury and proteinuria. In cultured podocytes, PIP complex knockdown resulted in cytoskeleton reorganization and decreased cell adhesion and spreading. Nephrin and its phosphorylation were unaffected after PIP complex knockdown. Furthermore, inhibition of nephrin phosphorylation suppressed PIP complex expression, disorganized podocyte cytoskeleton, and decreased cell adhesion and spreading. These findings indicate that alterations in nephrin phosphorylation disorganize podocyte cytoskeleton and decrease cell adhesion through a PIP complex-dependent mechanism. [BMB Reports 2013; 46(4): 230-235] PMID:23615266

Rac1 Recruitment to the Archipelago Structure of the Focal Adhesion through the Fluid Membrane as Revealed by Single-Molecule Analysis

PubMed Central

Shibata, Akihiro C E; Chen, Limin H; Nagai, Rie; Ishidate, Fumiyoshi; Chadda, Rahul; Miwa, Yoshihiro; Naruse, Keiji; Shirai, Yuki M; Fujiwara, Takahiro K; Kusumi, Akihiro

2013-01-01

The focal adhesion (FA) is an integrin-based structure built in/on the plasma membrane (PM), linking the extracellular matrix to the actin stress-fibers, working as cell migration scaffolds. Previously, we proposed the archipelago architecture of the FA, in which FA largely consists of fluid membrane, dotted with small islands accumulating FA proteins: membrane molecules enter the inter-island channels in the FA zone rather freely, and the integrins in the FA-protein islands rapidly exchanges with those in the bulk membrane. Here, we examined how Rac1, a small G-protein regulating FA formation, and its activators αPIX and βPIX, are recruited to the FA zones. PIX molecules are recruited from the cytoplasm to the FA zones directly. In contrast, majorities of Rac1 molecules first arrive from the cytoplasm on the general inner PM surface, and then enter the FA zones via lateral diffusion on the PM, which is possible due to rapid Rac1 diffusion even within the FA zones, slowed only by a factor of two to four compared with that outside. The constitutively-active Rac1 mutant exhibited temporary and all-time immobilizations in the FA zone, suggesting that upon PIX-induced Rac1 activation at the FA-protein islands, Rac1 tends to be immobilized at the FA-protein islands. © 2013 Wiley Periodicals, Inc PMID:23341328

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1

PubMed Central

Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichy, Boris; Pospisilova, Sarka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasche, Christoph

2013-01-01

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APCmin polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APCmin polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. PMID:23146664

Structural Requirements for Outside-In and Inside-Out Signaling by Drosophila Neuroglian, a Member of the L1 Family of Cell Adhesion Molecules

PubMed Central

Hortsch, Michael; Homer, Diahann; Malhotra, Jyoti Dhar; Chang, Sherry; Frankel, Jason; Jefford, Gregory; Dubreuil, Ronald R.

1998-01-01

Expression of the Drosophila cell adhesion molecule neuroglian in S2 cells leads to cell aggregation and the intracellular recruitment of ankyrin to cell contact sites. We localized the region of neuroglian that interacts with ankyrin and investigated the mechanism that limits this interaction to cell contact sites. Yeast two-hybrid analysis and expression of neuroglian deletion constructs in S2 cells identified a conserved 36-amino acid sequence that is required for ankyrin binding. Mutation of a conserved tyrosine residue within this region reduced ankyrin binding and extracellular adhesion. However, residual recruitment of ankyrin by this mutant neuroglian molecule was still limited to cell contacts, indicating that the lack of ankyrin binding at noncontact sites is not caused by tyrosine phosphorylation. A chimeric molecule, in which the extracellular domain of neuroglian was replaced with the corresponding domain from the adhesion molecule fasciclin II, also selectively recruited ankyrin to cell contacts. Thus, outside-in signaling by neuroglian in S2 cells depends on extracellular adhesion, but does not depend on any unique property of its extracellular domain. We propose that the recruitment of ankyrin to cell contact sites depends on a physical rearrangement of neuroglian in response to cell adhesion, and that ankyrin binding plays a reciprocal role in stabilizing the adhesive interaction. PMID:9660878

Structural requirements for outside-in and inside-out signaling by Drosophila neuroglian, a member of the L1 family of cell adhesion molecules.

PubMed

Hortsch, M; Homer, D; Malhotra, J D; Chang, S; Frankel, J; Jefford, G; Dubreuil, R R

1998-07-13

Expression of the Drosophila cell adhesion molecule neuroglian in S2 cells leads to cell aggregation and the intracellular recruitment of ankyrin to cell contact sites. We localized the region of neuroglian that interacts with ankyrin and investigated the mechanism that limits this interaction to cell contact sites. Yeast two-hybrid analysis and expression of neuroglian deletion constructs in S2 cells identified a conserved 36-amino acid sequence that is required for ankyrin binding. Mutation of a conserved tyrosine residue within this region reduced ankyrin binding and extracellular adhesion. However, residual recruitment of ankyrin by this mutant neuroglian molecule was still limited to cell contacts, indicating that the lack of ankyrin binding at noncontact sites is not caused by tyrosine phosphorylation. A chimeric molecule, in which the extracellular domain of neuroglian was replaced with the corresponding domain from the adhesion molecule fasciclin II, also selectively recruited ankyrin to cell contacts. Thus, outside-in signaling by neuroglian in S2 cells depends on extracellular adhesion, but does not depend on any unique property of its extracellular domain. We propose that the recruitment of ankyrin to cell contact sites depends on a physical rearrangement of neuroglian in response to cell adhesion, and that ankyrin binding plays a reciprocal role in stabilizing the adhesive interaction.

Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect.

PubMed

Greineder, Colin F; Brenza, Jacob B; Carnemolla, Ronald; Zaitsev, Sergei; Hood, Elizabeth D; Pan, Daniel C; Ding, Bi-Sen; Esmon, Charles T; Chacko, Ann Marie; Muzykantov, Vladimir R

2015-08-01

Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood-tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other's binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications. © FASEB.

Function-blocking antibodies to human vascular adhesion protein-1: a potential anti-inflammatory therapy.

PubMed

Kirton, Christopher M; Laukkanen, Marja-Leena; Nieminen, Antti; Merinen, Marika; Stolen, Craig M; Armour, Kathryn; Smith, David J; Salmi, Marko; Jalkanen, Sirpa; Clark, Michael R

2005-11-01

Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazide-sensitive amine oxidase and as an adhesion molecule. Blockade of VAP-1 has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.

The Prognostic Value of Soluble Intercellular Adhesion Molecule 1 Plasma Level in Children With Acute Lung Injury.

PubMed

Al-Biltagi, Mohammed A; Abo-Elezz, Ahmed Ahmed Abd ElBasset; Abu-Ela, Khaled Talaat; Suliman, Ghada Abudelmomen; Sultan, Tamer Gomaa Hassan

2017-06-01

The objective of this study was to evaluate the prognostic significance of soluble intercellular adhesion molecule 1 (sICAM-1) measurement in plasma for the prediction of outcome of acute lung injury (ALI) in children that may allow early recognition of critical cases. The study was performed as a prospective, controlled cohort study involving 40 children with ALI and 30 healthy children. The plasma level of sICAM-1 was measured at days 1 and 3 of development of ALI for the patient group and measured only once for the control group. C-Reactive protein was measured in both groups on day 1 only. There was significant increase in sICAM-1 in the patient group than in the control group ( P = .001*). The mortality rate reached 55% in children with ALI. The ceased group had significantly higher plasma sICAM-1 levels both at days 1 and 3 than the survived group ( P < .001*), and there was positive correlation between plasma sICAM-1 level and both duration of mechanical ventilation and the death rate, but more significant correlation was observed with plasma sICAM-1 levels at day 3 than day 1. Plasma sICAM-1 level served as a good predictor biomarker for both mechanical ventilation duration and the mortality risk in children with ALI.

The Differential Expression of Adhesion Molecule and Extracellular Matrix Genes in Mesenchymal Stromal Cells after Interaction with Cord Blood Hematopoietic Progenitors.

PubMed

Buravkova, L B; Andreeva, E R; Lobanova, M V; Cotnezova, E V; Grigoriev, A I

2018-03-01

The dynamics of the expression of genes encoding adhesion molecules, molecules of the connective tissue matrix, and its remodeling enzymes was studied in multipotent mesenchymal stromal cells (MSCs) from human adipose tissue after interaction with cord blood hematopoietic progenitors (HSPCs). An upregulation of ICAM1 and VCAM1, directly proportional to the coculture time (24-72 h), was found. After 72 h of culturing, a downregulation of the genes encoding the majority of matrix molecules (SPP1; COL6A2,7A1; MMP1,3; TIMP1,3; and HAS1) and cell-matrix adhesion molecules (ITGs) was revealed. The detected changes may ensure the realization of the stromal MSC function due to improvement of adhesion and transmigration of HSPCs into the subcellular space.

Effects of thalidomide on the expression of adhesion molecules in rat liver cirrhosis.

PubMed

Lv, Peng; Paul, Shelley Chireyath; Xiao, Yanjv; Liu, Shiquan; Luo, Hesheng

2006-01-01

This study was to evaluate the effects of thalidomide on expression of adhesion molecules in liver cirrhosis. The cirrhosis was induced in Wistar rats by intraperitoneal injection of CCl(4), and thalidomide (10 mg/kg/day or 100 mg/kg/day) was given by intragastric administration for 8 weeks. Liver histopathology and immunohistochemistry were significantly improved and the expressions of ICAM-1, VCAM-1, E-selectin, and TNF-alpha mRNA and protein were decreased significantly in rats treated with a high dose of thalidomide. Close positive correlation was observed in the expression of the TNF-alpha mRNA and that of ICAM-1, VCAM-1, and E-selectin mRNA, respectively. These results indicate that thalidomide exerts its effect on the downregulation of adhesion molecules via TNF-alpha signaling pathway to inhibit liver fibrosis.

Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation

NASA Astrophysics Data System (ADS)

Yamagata, Atsushi; Yoshida, Tomoyuki; Sato, Yusuke; Goto-Ito, Sakurako; Uemura, Takeshi; Maeda, Asami; Shiroshima, Tomoko; Iwasawa-Okamoto, Shiho; Mori, Hisashi; Mishina, Masayoshi; Fukai, Shuya

2015-04-01

Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as `splice-insert signaling codes'. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP.

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

PubMed

Scalici, Jennifer M; Arapovic, Sanja; Saks, Erin J; Atkins, Kristen A; Petroni, Gina; Duska, Linda R; Slack-Davis, Jill K

2017-05-15

Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression. A retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression-free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups. Mesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society. © 2016

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.

PubMed

Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichy, Boris; Pospisilova, Sarka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasche, Christoph

2013-01-15

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. Copyright © 2012 Elsevier Inc. All rights reserved.

Single molecule force spectroscopy reveals the adhesion mechanism of hydrophobins

NASA Astrophysics Data System (ADS)

Cao, Yi; Li, Bing; Qin, Meng; Wang, Wei

Hydrophobins are a special class of amphiphilic proteins produced by filamentous fungi. They show outstanding interfacial self-assembly and adhesion properties, which are critical to their biological function. Such feature also inspires their broad applications in bio-engineering, surface modification, and nanotechnology. However, the biophysical properties of hydrophobins are not well understood. We combined atomic force microscopy based single molecule force spectroscopy and protein engineering to directly quantify the adhesion strength of a hydorphobin (HFB1) to various surfaces in both the monomer and oligomer states to reveal the molecular determinant of the adhesion strength of hydrophobins. We found that the monomer HFB1 showed distinct adhesion properties towards hydrophobic and hydrophilic surfaces. The adhesion to hydrophobic surfaces (i.e. graphite and gold) was significantly higher than that to the hydrophilic ones (e.g. mica and silicon). However, when self-assembled monolayers were formed, the adhesion strengths to various surfaces were similar and were ubiquitously stronger than the monomer cases. We hypothesized that the interactions among hydrophobins in the monolayer played significant roles for the enhance adhesion strengths. Extracting any single hydrophobin monomers from the surface required the break of interactions not only with the surface but also with the neighboring units. We proposed that such a mechanism may be widely explored in nature for many biofilms for surface adhesion. May also inspire the design of novel adhesives.

Ethanol does not inhibit the adhesive activity of Drosophila neuroglian or human L1 in Drosophila S2 tissue culture cells.

PubMed

Vallejo, Y; Hortsch, M; Dubreuil, R R

1997-05-02

Members of the L1 family of homophilic neural cell adhesion molecules are thought to play an important role in nervous system development and function. It is also suggested that L1 is a direct target of ethanol in fetal alcohol syndrome, since ethanol inhibits the aggregation of cultured cells expressing L1 (Ramanathan, R., Wilkemeyer, M. F., Mittel, B., Perides, G., and Charness, M. E. (1996) J. Cell Biol. 133, 381-390). If ethanol acts directly on the homophilic adhesive function of the L1 molecule, then inhibition of aggregation by ethanol should be observed in any cell type that expresses L1. Here we examined the effect of physiologically relevant concentrations of ethanol on the aggregation of Drosophila S2 cells that expressed either neuroglian (the Drosophila homolog of L1) or human L1. The aggregation of these S2 cells is known to be solely dependent on the homophilic interactions between L1 or neuroglian molecules. Neither cell adhesion molecule was affected when cell aggregation assays were carried out in the presence of >/=38 mM ethanol. The recruitment of membrane skeleton assembly at sites of cell-cell contact (a transmembrane signaling function of human L1) was also unaffected by the presence of ethanol. Thus the previously described inhibition of cell adhesion by ethanol in L1-expressing cells cannot be explained by a simple direct effect on the adhesive activity of L1 family members.

Intercellular adhesion molecule, plasma adiponectin and albuminuria in type 2 diabetic patients.

PubMed

Lenghel, Alina Ramona; Kacso, Ina Maria; Bondor, Cosmina Ioana; Rusu, Crina; Rahaian, Rodica; Gherman Caprioara, Mirela

2012-01-01

Our study addressed the influence of early inflammatory stages of diabetic kidney disease: leukocyte adhesion and monocyte activation (as assessed by intercellular leukocyte adhesion molecule-ICAM-1 and monocyte chemoatractant protein-MCP-1) on the degree of albuminuria. Plasma levels of adiponectin, a possible anti-inflammatory counteracting mechanism, were also studied in correlation to the above-mentioned cytokines. 79 consecutive type 2 diabetic outpatients and 46 controls were included. Routine laboratory analysis, urinary albumin to creatinine ratio (uACR), plasma adiponectin, plasma ICAM-1 and urinary MPC-1 were assessed. In multiple regression ICAM-1 (p=0.004) and adiponectin (p=0.04) were the main determinants of uACR. Plasma adiponectin positively correlated to ICAM-1 (p=0.03, r=0.24). In albuminuric patients (uACR ≥30 mg/g) plasma adiponectin was significantly higher compared to normoalbuminuric ones (uACR <30 mg/g). In albuminuric patients the main determinants of uACR were plasma ICAM-1 and adiponectin. In multiple regression ICAM-1 is the only one that retains statistical significance (p=0.02). Urinary MCP-1 did not correlate to uACR. In our type 2 diabetic patients, plasma levels of ICAM-1 and adiponectin are predictive for albuminuria. Urinary MCP-1 does not correlated to uACR. Plasma adiponectin positively correlates to adhesion molecule ICAM-1 in our cohort. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Effects of Thalidomide on the Expression of Adhesion Molecules in Rat Liver Cirrhosis

PubMed Central

Lv, Peng; Paul, Shelley Chireyath; Xiao, Yanjv; Liu, Shiquan; Luo, Hesheng

2006-01-01

This study was to evaluate the effects of thalidomide on expression of adhesion molecules in liver cirrhosis. The cirrhosis was induced in Wistar rats by intraperitoneal injection of CCl4, and thalidomide (10 mg/kg/day or 100 mg/kg/day) was given by intragastric administration for 8 weeks. Liver histopathology and immunohistochemistry were significantly improved and the expressions of ICAM-1, VCAM-1, E-selectin, and TNF-α mRNA and protein were decreased significantly in rats treated with a high dose of thalidomide. Close positive correlation was observed in the expression of the TNF-α mRNA and that of ICAM-1, VCAM-1, and E-selectin mRNA, respectively. These results indicate that thalidomide exerts its effect on the downregulation of adhesion molecules via TNF-α signaling pathway to inhibit liver fibrosis. PMID:17047296

Cytotoxicity, oxidative stress and expression of adhesion molecules in human umbilical vein endothelial cells exposed to dust from paints with or without nanoparticles.

PubMed

Mikkelsen, Lone; Jensen, Keld A; Koponen, Ismo K; Saber, Anne T; Wallin, Håkan; Loft, Steffen; Vogel, Ulla; Møller, Peter

2013-03-01

Nanoparticles in primary form and nanoproducts might elicit different toxicological responses. We compared paint-related nanoparticles with respect to effects on endothelial oxidative stress, cytotoxicity and cell adhesion molecule expression. Primary human umbilical vein endothelial cells were exposed to primary nanoparticles (fine, photocatalytic or nanosized TiO(2), aluminium silicate, carbon black, nano-silicasol or axilate) and dust from sanding reference- or nanoparticle-containing paints. Most of the samples increased cell surface expressions of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1), but paint sanding dust samples generally generated less response than primary particles of TiO(2) and carbon black. We found no relationship between the expression of adhesion molecules, cytotoxicity and production of reactive oxygen species. In conclusion, sanding dust from nanoparticle-containing paint did not generate more oxidative stress or expression of cell adhesion molecules than sanding dust from paint without nanoparticles, whereas the primary particles had the largest effect on mass basis.

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. Copyright © 2015 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyung Gyun; Kim, Ji Young; Hwang, Yong Pil

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 hasmore » 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.« less

Cell adhesion molecules in context

PubMed Central

2011-01-01

Cell adhesion molecules (CAMs) are now known to mediate much more than adhesion between cells and between cells and the extracellular matrix. Work by many researchers has illuminated their roles in modulating activation of molecules such as receptor tyrosine kinases, with subsequent effects on cell survival, migration and process extension. CAMs are also known to serve as substrates for proteases that can create diffusible fragments capable of signaling independently from the CAM. The diversity of interactions is further modulated by membrane rafts, which can co-localize or separate potential signaling partners to affect the likelihood of a given signaling pathway being activated. Given the ever-growing number of known CAMs and the fact that their heterophilic binding in cis or in trans can affect their interactions with other molecules, including membrane-bound receptors, one would predict a wide range of effects attributable to a particular CAM in a particular cell at a particular stage of development. The function(s) of a given CAM must therefore be considered in the context of the history of the cell expressing it and the repertoire of molecules expressed both by that cell and its neighbors. PMID:20948304

Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier

PubMed Central

Curis, Céline; Percher, Florent; Jeannin, Patricia; Montange, Thomas; Chevalier, Sébastien A.; Seilhean, Danielle; Cartier, Luis; Couraud, Pierre-Olivier; Gout, Olivier; Gessain, Antoine; Ceccaldi, Pierre-Emmanuel

2016-01-01

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4+ T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. IMPORTANCE Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into

Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.

PubMed

Curis, Céline; Percher, Florent; Jeannin, Patricia; Montange, Thomas; Chevalier, Sébastien A; Seilhean, Danielle; Cartier, Luis; Couraud, Pierre-Olivier; Gout, Olivier; Gessain, Antoine; Ceccaldi, Pierre-Emmanuel; Afonso, Philippe V

2016-08-15

Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear

Impact of Intercellular Adhesion Molecule-1 Genetic Polymorphisms on Coronary Artery Disease Susceptibility in Taiwanese Subjects.

PubMed

Chou, Chi-Hung; Ueng, Kwo-Chang; Liu, Yu-Fan; Wu, Chih-Hsien; Yang, Shun-Fa; Wang, Po-Hui

2015-01-01

The principal pathogenesis of coronary artery disease (CAD) is coronary artery atherosclerosis, a chronic inflammatory disease of the vessel walls of the coronary artery. Intercellular adhesion molecule-1 (ICAM-1) displays an important role in the development of the inflammation reaction and atherosclerosis. Few studies report the association of ICAM-1 genetic polymorphisms with CAD in Taiwanese subjects. Therefore, we conducted a study to associate the single nucleotide polymorphisms (SNPs) of ICAM-1, rs5491, rs5498, rs281432 and rs3093030 with CAD. Five hundred and twenty-five male and female subjects, who received elective coronary angiography in Taiwan Chung Shan Medical University Hospital, were recruited to determine four ICAM-1 SNPs by real time-polymerase chain reaction and genotyping. The relationships among ICAM-1 SNPs, haplotypes, demographic and characteristics and CAD were analyzed. This study showed that rs281432 (C8823G) was the only ICAM-1 SNP which affect the development of CAD. Multivariate analysis revealed that ICAM-1 SNP rs281432 CC/CG [p=0.016; odds ratio (OR): 2.56, 95% confidence interval (CI): 1.19-5.56], male gender (p=0.018; OR: 1.66, 95% CI: 1.09-2.51), aspirin use in the past 7 days (p=0.001; OR: 2.05, 95% CI: 1.33-3.14), hypertension (p<0.001; OR: 2.15, 95% CI: 1.42-3.25), serum cardiac troponin I elevation (p<0.001; OR: 2.14, 95% CI: 1.47-3.24) and severe angina in recent 24 hours (p=0.001; OR: 1.97, 95% CI: 1.31- 2.95) increase the risk of CAD. In conclusion, ICAM-1 SNP rs281432 is an independent factor to predict the development of CAD. ICAM-1 SNP rs281432 homozygotic mutant GG can reduce the susceptibility to the CAD in Taiwanese subjects.

A Novel Nondevelopmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans

PubMed Central

Opperman, Karla; Moseley-Alldredge, Melinda; Yochem, John; Bell, Leslie; Kanayinkal, Tony; Chen, Lihsia

2015-01-01

The L1CAM family of cell adhesion molecules is a conserved set of single-pass transmembrane proteins that play diverse roles required for proper nervous system development and function. Mutations in L1CAMs can cause the neurological L1 syndrome and are associated with autism and neuropsychiatric disorders. L1CAM expression in the mature nervous system suggests additional functions besides the well-characterized developmental roles. In this study, we demonstrate that the gene encoding the Caenorhabditis elegans L1CAM, sax-7, genetically interacts with gtl-2, as well as with unc-13 and rab-3, genes that function in neurotransmission. These sax-7 genetic interactions result in synthetic phenotypes that are consistent with abnormal synaptic function. Using an inducible sax-7 expression system and pharmacological reagents that interfere with cholinergic transmission, we uncovered a previously uncharacterized nondevelopmental role for sax-7 that impinges on synaptic function. PMID:25488979

Molecules mediating adhesion of T and B cells, monocytes and granulocytes to vascular endothelial cells.

PubMed Central

Prieto, J; Beatty, P G; Clark, E A; Patarroyo, M

1988-01-01

Leucocytes interact with vascular endothelial cells (EC), and adhesion between these two cell types in vitro is modulated by phorbol ester. Monocytes were found to display the highest basal adhesion to EC, followed by Epstein-Barr virus-immortalized normal B cells (EBV-B), T cells and granulocytes. Phorbol ester treatment increased the adhesion of all types of leucocytes, except monocytes. In the presence of this compound, monoclonal antibody 60.3 to GP90 (CD18, a leucocyte-adhesion protein which is non-covalently associated to either GP160, GP155, or GP130) was found to inhibit the adhesion of the four types of leucocytes to a considerable extent, while anti-lymphocyte function-associated antigen-1 (LFA-1) antibody to GP160 (CD11a) inhibited the adhesion of T and B cells only. Antibody 60.1 to GP155 (CD11b) had a major inhibitory activity exclusively on granulocytes, while antibody LB-2, which recognizes a distinct adhesion molecule (GP84) and, in contrast to the previous antibodies, reacts with EC, mainly inhibited adhesion of EBV-B and did not increase the inhibition obtained with antibody 60.3 alone. Fab fragments of antibody 60.3 inhibited leucocyte adhesion more efficiently, in either the absence or presence of phorbol ester, than the intact antibody molecule. It is concluded the GP90, either alone or associated to the larger glycoproteins, mediates the adhesion in all types of leucocytes, while GP84 mediates the adhesion of the activated B cells. Images Figure 2 PMID:3259203

Withaferin A inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules by inactivation of Akt and NF-kappaB in human pulmonary epithelial cells.

PubMed

Oh, Jung Hwa; Kwon, Taeg Kyu

2009-05-01

We here investigated the functional effect of withaferin A on airway inflammation and its action mechanism. Withaferin A inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human lung epithelial A549 cells stimulated with tumor necrosis factor-alpha (TNF-alpha), resulting in the suppression of leukocyte adhesion to lung epithelial A549 cells. In addition, withaferin A inhibited TNF-alpha-induced expression of adhesion molecules (ICAM-1 and VCAM-1) protein and mRNA in a dose-dependent manner. Withaferin A prevented DNA binding activity of nuclear factor-kappaB (NF-kappaB) and nuclear translocation of NF-kappaB. It also inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK), which are upstream in the regulation of adhesion molecules by TNF-alpha. Furthermore, withaferin A inhibited U937 monocyte adhesion to A549 cells stimulated by TNF-alpha, suggesting that it may inhibit the binding of these cells by regulating the expression of critical adhesion molecules by TNF-alpha. Taken together, these results suggest that withaferin A inhibits cell adhesion through inhibition of ICAM-1 and VCAM-1 expression, at least in part, by blocking Akt and down-regulating NF-kappaB activity.

Genetics Home Reference: leukocyte adhesion deficiency type 1

MedlinePlus

... adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Leukocyte adhesion deficiency type 1 is a ...

Scaling from single molecule to macroscopic adhesion at polymer/metal interfaces.

PubMed

Utzig, Thomas; Raman, Sangeetha; Valtiner, Markus

2015-03-10

Understanding the evolution of macroscopic adhesion based on fundamental molecular interactions is crucial to designing strong and smart polymer/metal interfaces that play an important role in many industrial and biomedical applications. Here we show how macroscopic adhesion can be predicted on the basis of single molecular interactions. In particular, we carry out dynamic single molecule-force spectroscopy (SM-AFM) in the framework of Bell-Evans' theory to gain information about the energy barrier between the bound and unbound states of an amine/gold junction. Furthermore, we use Jarzynski's equality to obtain the equilibrium ground-state energy difference of the amine/gold bond from these nonequilibrium force measurements. In addition, we perform surface forces apparatus (SFA) experiments to measure macroscopic adhesion forces at contacts where approximately 10(7) amine/gold bonds are formed simultaneously. The SFA approach provides an amine/gold interaction energy (normalized by the number of interacting molecules) of (36 ± 1)k(B)T, which is in excellent agreement with the interaction free energy of (35 ± 3)k(B)T calculated using Jarzynski's equality and single-molecule AFM experiments. Our results validate Jarzynski's equality for the field of polymer/metal interactions by measuring both sides of the equation. Furthermore, the comparison of SFA and AFM shows how macroscopic interaction energies can be predicted on the basis of single molecular interactions, providing a new strategy to potentially predict adhesive properties of novel glues or coatings as well as bio- and wet adhesion.

High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria.

PubMed

Adukpo, Selorme; Kusi, Kwadwo A; Ofori, Michael F; Tetteh, John K A; Amoako-Sakyi, Daniel; Goka, Bamenla Q; Adjei, George O; Edoh, Dominic A; Akanmori, Bartholomew D; Gyan, Ben A; Dodoo, Daniel

2013-01-01

Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p<0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p>0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies

Clinical Significance of Soluble Intercellular Adhesion Molecule-1 and Interleukin-6 in Patients with Extrahepatic Cholangiocarcinoma.

PubMed

Shimura, Tatsuo; Shibata, Masahiko; Gonda, Kenji; Kofunato, Yasuhide; Okada, Ryo; Ishigame, Teruhide; Kimura, Takashi; Kenjo, Akira; Marubashi, Shigeru; Kono, Koji; Takenoshita, Seiichi

2017-09-19

Purpose/Aim: Although several prognostic factors for extrahepatic cholangiocarcinoma (EHC) have been reported, preoperative prognostic factors have yet to be established. We investigated the serum concentration of angiogenic, inflammatory, and nutritional parameters. Twenty-five patients with EHC were enrolled before starting treatment. Preoperative prognostic factors were identified using multivariate analyses. The serum soluble intercellular adhesion molecule-1 (sICAM-1) levels were significantly higher in the patients with EHC (436.0 ± 43.2 ng/ml) than in the healthy volunteers (228.6 ± 22.0 ng/ml) (p <.001). In addition, the serum IL-6 levels were significantly higher in the patients (18.0 ± 5.6 pg/ml) than in the healthy volunteers (5.7 ± 0.8 pg/ml) (p <.05). The serum IL-6 and sICAM-1 showed a strong correlation (r = 0.559) in the patients with EHC (p <.01). The serum IL-6 (area under the curve = 0.764, p =.030, cut-off level = 11.6) and sICAM-1 (area under the curve = 0.818, p =.007, cutoff level = 322.6) were revealed to be useful as prognostic factors by the receiver operating characteristic curves. The high IL-6 group and the high sICAM-1 group showed poorer DSS than those of the respective low groups. In the multivariate analysis, IL-6 (hazard ratio: 1.050, 95% confidence interval: 1.002-1.100, p =.043) and sICAM-1 (hazard ratio: 1.009, 95% confidence interval: 1.002-1.015, p =.009) were independent prognostic factors for DSS. IL-6 and sICAM-1 were independent preoperative prognostic factors in EHC patients, causing continuous inflammation and malnutrition in collaboration with other pro-angiogenic factors.

Phorbol esters alter alpha4 and alphad integrin usage during eosinophil adhesion to VCAM-1.

PubMed

Kikuchi, Matsuo; Tachimoto, Hiroshi; Nutku, Esra; Hudson, Sherry A; Bochner, Bruce S

2003-01-01

We examined the effect of the protein kinase C activator phorbol-12-myristate-13-acetate (PMA) on the human eosinophil adhesion molecule phenotype and attachment to VCAM-1 via alpha4 and alphad integrins under static and flow conditions. PMA increased surface expression of alphad integrins and decreased alpha4 integrin expression. Under static conditions, eosinophils bound well to VCAM-1, primarily via alpha4beta1 integrins, with a minor alphadbeta2 integrin component. Unexpectedly, PMA-stimulated eosinophils bound equally well to VCAM-1 and albumin in a temperature- and divalent cation-dependent manner, yet adhesion was independent of beta1 and beta2 integrins. Under flow conditions, eosinophils readily attached to VCAM-1, and adhesion was inhibited by both alpha4 and alphad mAbs (95 and 50% inhibition, respectively). Many fewer PMA-stimulated eosinophils bound to VCAM-1 under flow conditions, but both alpha4 and alphad mAbs inhibited adhesion equally. Thus, PMA alters eosinophil integrin expression and the relative contributions of alpha4 and alphad integrins during attachment to VCAM-1.

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

Inhibition of STAT3 phosphorylation by sulforaphane reduces adhesion molecule expression in vascular endothelial cell.

PubMed

Cho, Young S; Kim, Chan H; Ha, Tae S; Ahn, Hee Y

2015-11-18

Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) play key roles in the initiation of vascular inflammation. In this study, we explored whether sulforaphane, a dietary phytochemical, can inhibit the expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVEC) stimulated with lipopolysaccharide (LPS), and the mechanisms involved. Sulforaphane prevented the LPS-mediated increase in ICAM-1 and VCAM-1 expression, (P < 0.01) in HUVEC. Sulforaphane also prevented the LPS-mediated increase in the phosphorylation of signal transducer and activator of transcription 3 (STAT3) (P < 0.01). Stattic, a STAT3 inhibitor, reduced the LPS-induced expression of ICAM-1 and VCAM-1, and STAT3 phosphorylation (P < 0.01). STAT3 small interfering RNA treatment reduced the LPS-induced expression of ICAM-1, VCAM-1, and STAT3 (P < 0.01). Sulforaphane reduced LPS-mediated THP-1 monocyte adhesion to HUVEC (P < 0.01). In C57BL/6 mice, injection of LPS increased aortic ICAM-1 and VCAM-1 expression, and this effect was prevented by sulforaphane. These data provide insight into the mechanism through which sulforaphane partly reduces the expression of ICAM-1 and VCAM-1 on the vascular wall by inhibiting STAT3 phosphorylation.

L1 adhesion molecule on mouse leukocytes: regulation and involvement in endothelial cell binding.

PubMed

Hubbe, M; Kowitz, A; Schirrmacher, V; Schachner, M; Altevogt, P

1993-11-01

L1 is a cell surface glycoprotein of the immunoglobulin superfamily which was initially shown to mediate adhesion between neural cells. Recently we have reported that L1 is expressed by bone marrow cells and the majority of mature lymphocytes (Kowitz et al., Eur. J. Immunol. 1992. 22: 1199-1205). To analyze the function of L1 on leukocytes we studied its regulation following cell activation. In vitro activation of B lymphocytes with lipopolysaccharide or T lymphocytes with phorbol 12-myristate 13-acetate/Ca2+ ionophore, concanavalin A or anti-CD3 monoclonal antibody as well as in vivo activation of V beta 8+ T cells with staphylococcal enterotoxin B (SEB) revealed a down-regulation of L1 within 48 h. A rapid loss of L1 expression was seen when mouse neutrophils were activated with PMA alone. This rapid loss paralleled the shedding of L-selectin. We also studied a possible role of L1 in the binding of leukocytes to endothelial cells. ESb-MP lymphoma cells with a high expression of L1 (L1hi) could bind to bend3 endothelioma cells without prior activation with inflammatory cytokines. The interaction was inhibited by anti-L1 antibodies. In contrast, ESb-MP cells with low L1 expression (L1lo) were only marginally bound. Latex beads coated with affinity-isolated L1 antigen were also able to bind to the endothelioma cells in a specific fashion. The binding of ESb-MP lymphoma cells required Ca2+ and Mg2+ ions and was sensitive to cold temperature. Since the endothelioma cells did not express L1 the binding mechanism studied here is distinct from the established L1-L1 homotypic interaction. It is possible that the novel L1-mediated adhesion pathway involves an unidentified ligand and could play a role in leukocyte migration.

Prognostic implications of adhesion molecule expression in colorectal cancer.

PubMed

Seo, Kyung-Jin; Kim, Maru; Kim, Jeana

2015-01-01

Research on the expression of adhesion molecules, E-cadherin (ECAD), CD24, CD44 and osteopontin (OPN) in colorectal cancer (CRC) has been limited, even though CRC is one of the leading causes of cancer-related deaths. This study was conducted to evaluate the expression of adhesion molecules in CRC and to determine their relationships with clinicopathologic variables, and the prognostic significance. The expression of ECAD, CD24, CD44 and OPN was examined in 174 stage II and III CRC specimens by immunohistochemistry of TMA. Negative ECAD expression was significantly correlated with advanced nodal stage and poor tumor differentiation. Multivariate analysis showed that both negative expression of ECAD and positive expression of CD24 were independent prognostic factors for disease-free survival (DFS) in CRC patients (P<0.001, relative risk [RR] = 5.596, 95% CI = 2.712-11.549; P = 0.038, RR = 3.768, 95% CI = 1.077-13.185, respectively). However, for overall survival (OS), only ECAD negativity showed statistically significant results in multivariate analysis (P<0.001, RR = 4.819, 95% CI = 2.515-9.234). Positive expression of CD24 was associated with poor OS in univariate analysis but was of no prognostic value in multivariate analysis. In conclusion, our study suggests that among these four adhesion molecules, ECAD and CD24 expression can be considered independent prognostic factors. The role of CD44 and OPN may need further evaluation.

Prognostic implications of adhesion molecule expression in colorectal cancer

PubMed Central

Seo, Kyung-Jin; Kim, Maru; Kim, Jeana

2015-01-01

Research on the expression of adhesion molecules, E-cadherin (ECAD), CD24, CD44 and osteopontin (OPN) in colorectal cancer (CRC) has been limited, even though CRC is one of the leading causes of cancer-related deaths. This study was conducted to evaluate the expression of adhesion molecules in CRC and to determine their relationships with clinicopathologic variables, and the prognostic significance. The expression of ECAD, CD24, CD44 and OPN was examined in 174 stage II and III CRC specimens by immunohistochemistry of TMA. Negative ECAD expression was significantly correlated with advanced nodal stage and poor tumor differentiation. Multivariate analysis showed that both negative expression of ECAD and positive expression of CD24 were independent prognostic factors for disease-free survival (DFS) in CRC patients (P<0.001, relative risk [RR] = 5.596, 95% CI = 2.712-11.549; P = 0.038, RR = 3.768, 95% CI = 1.077-13.185, respectively). However, for overall survival (OS), only ECAD negativity showed statistically significant results in multivariate analysis (P<0.001, RR = 4.819, 95% CI = 2.515-9.234). Positive expression of CD24 was associated with poor OS in univariate analysis but was of no prognostic value in multivariate analysis. In conclusion, our study suggests that among these four adhesion molecules, ECAD and CD24 expression can be considered independent prognostic factors. The role of CD44 and OPN may need further evaluation. PMID:26097606

CHOLINE PARTIALLY PREVENTS THE IMPACT OF ETHANOL ON THE LIPID RAFT DEPENDENT FUNCTIONS OF L1 CELL ADHESION MOLECULE

PubMed Central

Tang, Ningfeng; Bamford, Penny; Jones, Jace; He, Min; Kane, Maureen A.; Mooney, Sandra M.; Bearer, Cynthia F.

2014-01-01

Background Fetal Alcohol Spectrum Disorder, the leading known cause of mental retardation, is caused by alcohol exposure during pregnancy. One mechanism of ethanol teratogenicity is the disruption of the function of L1 cell adhesion molecule (L1). These functions include enhancement of neurite outgrowth, trafficking through lipid rafts, and signal transduction. Recent data have shown that choline supplementation of rat pups reduces the effects of ethanol on neurobehavior. We sought to determine if choline could prevent the effect of ethanol on L1 function using a simple experimental system. Methods Cerebellar granule neurons (CGN) from postnatal day 6 rat pups were cultured with and without supplemental choline, and the effects on L1 signaling, lipid raft distribution and neurite outgrowth were measured in the presence or absence of ethanol. Results Choline significantly reduced the effect of ethanol on L1 signaling, the distribution of L1 in lipid rafts and L1 mediated neurite outgrowth. However, choline supplemented ethanol exposed cultures remained significantly different than controls. Conclusions Choline pretreatment of CGN significantly reduces the disruption of L1 function by ethanol, but does not completely return L1 function to baseline. This experimental system will enable discovery of the mechanism of the neuroprotective effect of choline. PMID:25421509

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, Xia, E-mail: zhongxia1977@126.com; Li, Xiaonan; Liu, Fuli

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 inhibitedmore » 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.« less

Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis.

PubMed

Panés, Julián; Aceituno, Montserrat; Gil, Fèlix; Miquel, Rosa; Piqué, Josep M; Salas, Azucena; McLean, Peter

2007-10-01

Modulation of adhesion molecule expression or function is regarded as a promising therapy for inflammatory conditions. This study evaluates the effects of an inhibitor of adhesion molecule expression (GI270384X) in two experimental models of colitis. Colitis of different severity was induced in C57BL/6J mice by administering 1, 2, or 3% dextran sulfate sodium (DSS). GI270384X (3, 10, or 25 mg.kg(-1).day(-1)) was administered as pretreatment or started 3 days after colitis induction. In IL-10-deficient mice, the highest dose was given for 2 wk. The clinical course of colitis, pathological changes, serum inflammatory biomarkers, expression of adhesion molecules, and leukocyte-endothelial cell interactions in colonic venules were measured in mice treated with vehicle or with active drug. In the most severe forms of colitis (2% and 3% DSS and IL-10-deficient mice), the magnitude of colonic inflammation was not modified by treatment with GI270384X. In a less severe form of colitis (1% DSS), GI270384X treatment dose dependently ameliorated the clinical signs of colitis, colonic pathological changes, and serum levels of biomarkers (IL-6 and serum amyloid A). Administration of 25 mg.kg(-1).day(-1) GI270384X abrogated upregulation of ICAM-1 in the inflamed colon but had no effect on VCAM-1 or E-selectin expression. This was associated with a significant reduction in number of rolling and firmly adherent leukocytes in colonic venules. These results indicate that GI270384X is effective in the treatment of experimental colitis of moderate severity. Reduced adhesion molecule expression and leukocyte recruitment to the inflamed intestine contribute to this beneficial effect.

Streptococcus pyogenes Phospholipase A2 Induces the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells and Aorta of Mice.

PubMed

Oda, Masataka; Domon, Hisanori; Kurosawa, Mie; Isono, Toshihito; Maekawa, Tomoki; Yamaguchi, Masaya; Kawabata, Shigetada; Terao, Yutaka

2017-01-01

The Streptococcus pyogenes phospholipase A 2 (SlaA) gene is highly conserved in the M3 serotype of group A S. pyogenes , which often involves hypervirulent clones. However, the role of SlaA in S. pyogenes pathogenesis is unclear. Herein, we report that SlaA induces the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) via the arachidonic acid signaling cascade. Notably, recombinant SlaA induced ICAM1 and VCAM1 expression in human umbilical vein endothelial cells (HUVECs), resulting in enhanced adhesion of human monocytic leukemia (THP-1) cells. However, C134A, a variant enzyme with no enzymatic activity, did not induce such events. In addition, culture supernatants from S. pyogenes SSI-1 enhanced the adhesion of THP-1 cells to HUVECs, but culture supernatants from the Δ slaA isogenic mutant strain had limited effects. Aspirin, a cyclooxygenase 2 inhibitor, prevented the adhesion of THP-1 cells to HUVECs and did not induce ICAM1 and VCAM1 expression in HUVECs treated with SlaA. However, zileuton, a 5-lipoxygenase inhibitor, did not exhibit such effects. Furthermore, pre-administration of aspirin in mice intravenously injected with SlaA attenuated the transcriptional abundance of ICAM1 and VCAM1 in the aorta. These results suggested that SlaA from S. pyogenes stimulates the expression of adhesion molecules in vascular endothelial cells. Thus, SlaA contributes to the inflammation of vascular endothelial cells upon S. pyogenes infection.

Adhesive interactions of human multiple myeloma cell lines with different extracellular matrix molecules.

PubMed

Kibler, C; Schermutzki, F; Waller, H D; Timpl, R; Müller, C A; Klein, G

1998-06-01

Multiple myeloma represents a human B cell malignancy which is characterized by a predominant localization of the malignant cell clone within the bone marrow. With the exception of the terminal stage of the disease the myeloma tumor cells do not circulate in the peripheral blood. The bone marrow microenvironment is believed to play an important role in homing, proliferation and terminal differentiation of myeloma cells. Here we have studied the expression of several extracellular matrix (ECM) molecules in the bone marrow of multiple myeloma patients and analyzed their adhesive capacities with four different human myeloma-derived cell lines. All ECM molecules analyzed (tenascin, laminin, fibronectin, collagen types I, III, V and VI) could be detected in bone marrow cryostat sections of multiple myeloma patients. Adhesion assays showed that only laminin, the microfibrillar collagen type VI and fibronectin were strong adhesive components for the myeloma cell lines U266, IM-9, OPM-2 and NCI-H929. Tenascin and collagen type I were only weak adhesive substrates for these myeloma cells. Adhesion to laminin and fibronectin was beta 1-integrin-mediated since addition of anti-beta 1-integrin antibodies could inhibit the binding of the four different cell types to both matrix molecules. In contrast, integrins do not seem to be involved in binding of the myeloma cells to collagen type VI. Instead, inhibition of binding by heparin suggested that membrane-bound heparan sulfate proteoglycans are responsible ligands for binding to collagen type VI. Adhesion assays with several B-cell lines resembling earlier differentiation stages revealed only weak interactions with tenascin and no interactions with collagen type VI, laminin or fibronectin. In summary, the interactions of human myeloma cells with the extracellular matrix may explain the specific retention of the plasma cells within the bone marrow.

Genetic Analysis of 13 Iranian Families With Leukocyte Adhesion Deficiency Type 1.

PubMed

Teimourian, Shahram; De Boer, Martin; Roos, Dirk; Isaian, Anna; Bemanian, Mohammad Hassan; Lashkary, Sharhzad; Nabavi, Mohammad; Arshi, Saba; Nateghian, Alireza; Sayyahfar, Shirin; Sazgara, Faezeh; Taheripak, Gholamreza; Alipour Fayez, Elham

2018-05-10

Leukocyte adhesion deficiency type 1 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene. This gene encodes the CD18 subunit of β2 integrin leukocyte adhesion cell molecules. Leukocyte adhesion deficiency type 1 is characterized by recurrent bacterial infections, impaired wound healing, inadequate pus formation, and delayed separation of the umbilical cord. Blood samples were taken from 13 patients after written consent had been obtained. Genomic DNA was extracted, and ITGB2 exons and exon-intron boundaries were amplified by polymerase chain reaction. The products were examined by Sanger sequencing. In this study, 8 different previously reported mutations (intron7+1G>A, c.715G>A, c.1777 C>T, c.843del C, c.1768T>C, c.1821C>A, Intron7+1G>A, c.1885G>A) and 2 novel mutations (c.1821C>A; p.Tyr607Ter and c.1822C>T; p.Gln608Ter) were found. c.1821C>A (p.Tyr607Ter) and c.1822C>T (p.Gln608Ter) mutations should be included in the panel of carrier detection and prenatal diagnosis.

Effects of anti-tumor necrosis factor-alpha and anti-intercellular adhesion molecule-1 antibodies on ischemia/reperfusion lung injury.

PubMed

Chiang, Chi-Huei

2006-10-31

Inhibition of neutrophil activation and adherence to endothelium by antibodies to tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecules (ICAM-1), respectively, might attenuate ischemia-reperfusion injury (I/R). I/R was conducted in an isolated rat lung model. Anti-TNF-alpha antibody and/or anti-ICAM-1 antibody were added before ischemia or after reperfusion. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficients (Kfc), and pathologic changes were assessed to evaluate the severity of I/R. The LWG, Kfc, pathological changes and lung injury score of treatment groups with anti-TNF-alpha antibody treatment, either pre-ischemia or during reperfusion, were less than those observed in control groups. Similar findings were found in group treated with anti-ICAM-1 antibody or combination therapy during reperfusion. In contrast, pre-I/R treatment with anti-ICAM-1 antibody induced severe lung edema and failure to complete the experimental procedure. No additional therapeutic effect was found in combination therapy. We conclude that TNF-alpha and ICAM-1 play important roles in I/R. Anti-TNF-alpha antibody has therapeutic and preventive effects on I/R. However, combined therapy with anti-TNF-alpha antibody and anti-ICAM-1 antibody may have no additive effect and need further investigation.

RP1 Is a Phosphorylation Target of CK2 and Is Involved in Cell Adhesion

PubMed Central

Göttig, Stephan; Henschler, Reinhard; Markuly, Norbert; Kleber, Sascha; Faust, Michael; Mischo, Axel; Bauer, Stefan; Zweifel, Martin; Knuth, Alexander; Renner, Christoph; Wadle, Andreas

2013-01-01

RP1 (synonym: MAPRE2, EB2) is a member of the microtubule binding EB1 protein family, which interacts with APC, a key regulatory molecule in the Wnt signalling pathway. While the other EB1 proteins are well characterized the cellular function and regulation of RP1 remain speculative to date. However, recently RP1 has been implicated in pancreatic cancerogenesis. CK2 is a pleiotropic kinase involved in adhesion, proliferation and anti-apoptosis. Overexpression of protein kinase CK2 is a hallmark of many cancers and supports the malignant phenotype of tumor cells. In this study we investigate the interaction of protein kinase CK2 with RP1 and demonstrate that CK2 phosphorylates RP1 at Ser236 in vitro. Stable RP1 expression in cell lines leads to a significant cleavage and down-regulation of N-cadherin and impaired adhesion. Cells expressing a Phospho-mimicking point mutant RP1-ASP236 show a marked decrease of adhesion to endothelial cells under shear stress. Inversely, we found that the cells under shear stress downregulate endogenous RP1, most likely to improve cellular adhesion. Accordingly, when RP1 expression is suppressed by shRNA, cells lacking RP1 display significantly increased cell adherence to surfaces. In summary, RP1 phosphorylation at Ser236 by CK2 seems to play a significant role in cell adhesion and might initiate new insights in the CK2 and EB1 family protein association. PMID:23844040

RP1 is a phosphorylation target of CK2 and is involved in cell adhesion.

PubMed

Stenner, Frank; Liewen, Heike; Göttig, Stephan; Henschler, Reinhard; Markuly, Norbert; Kleber, Sascha; Faust, Michael; Mischo, Axel; Bauer, Stefan; Zweifel, Martin; Knuth, Alexander; Renner, Christoph; Wadle, Andreas

2013-01-01

RP1 (synonym: MAPRE2, EB2) is a member of the microtubule binding EB1 protein family, which interacts with APC, a key regulatory molecule in the Wnt signalling pathway. While the other EB1 proteins are well characterized the cellular function and regulation of RP1 remain speculative to date. However, recently RP1 has been implicated in pancreatic cancerogenesis. CK2 is a pleiotropic kinase involved in adhesion, proliferation and anti-apoptosis. Overexpression of protein kinase CK2 is a hallmark of many cancers and supports the malignant phenotype of tumor cells. In this study we investigate the interaction of protein kinase CK2 with RP1 and demonstrate that CK2 phosphorylates RP1 at Ser(236) in vitro. Stable RP1 expression in cell lines leads to a significant cleavage and down-regulation of N-cadherin and impaired adhesion. Cells expressing a Phospho-mimicking point mutant RP1-ASP(236) show a marked decrease of adhesion to endothelial cells under shear stress. Inversely, we found that the cells under shear stress downregulate endogenous RP1, most likely to improve cellular adhesion. Accordingly, when RP1 expression is suppressed by shRNA, cells lacking RP1 display significantly increased cell adherence to surfaces. In summary, RP1 phosphorylation at Ser(236) by CK2 seems to play a significant role in cell adhesion and might initiate new insights in the CK2 and EB1 family protein association.

Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors.

PubMed

Wiltshire, Rachael; Nelson, Vicky; Kho, Dan Ting; Angel, Catherine E; O'Carroll, Simon J; Graham, E Scott

2016-01-27

Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1β. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors.

Multiple cell adhesion molecules shaping a complex nicotinic synapse on neurons.

PubMed

Triana-Baltzer, Gallen B; Liu, Zhaoping; Gounko, Natalia V; Berg, Darwin K

2008-09-01

Neuroligin, SynCAM, and L1-CAM are cell adhesion molecules with synaptogenic roles in glutamatergic pathways. We show here that SynCAM is expressed in the chick ciliary ganglion, embedded in a nicotinic pathway, and, as shown previously for neuroligin and L1-CAM, acts transcellularly to promote synaptic maturation on the neurons in culture. Moreover, we show that electroporation of chick embryos with dominant negative constructs disrupting any of the three molecules in vivo reduces the total amount of presynaptic SV2 overlaying the neurons expressing the constructs. Only disruption of L1-CAM and neuroligin, however, reduces the number of SV2 puncta specifically overlaying nicotinic receptor clusters. Disrupting L1-CAM and neuroligin together produces no additional decrement, indicating that they act on the same subset of synapses. SynCAM may affect synaptic maturation rather than synapse formation. The results indicate that individual neurons can express multiple synaptogenic molecules with different effects on the same class of nicotinic synapses.

Choline partially prevents the impact of ethanol on the lipid raft dependent functions of l1 cell adhesion molecule.

PubMed

Tang, Ningfeng; Bamford, Penny; Jones, Jace; He, Min; Kane, Maureen A; Mooney, Sandra M; Bearer, Cynthia F

2014-11-01

Fetal alcohol spectrum disorder, the leading known cause of mental retardation, is caused by alcohol exposure during pregnancy. One mechanism of ethanol (EtOH) teratogenicity is the disruption of the functions of L1 cell adhesion molecule (L1). These functions include enhancement of neurite outgrowth, trafficking through lipid rafts, and signal transduction. Recent data have shown that choline supplementation of rat pups reduces the effects of EtOH on neurobehavior. We sought to determine whether choline could prevent the effect of EtOH on L1 function using a simple experimental system. Cerebellar granule neurons (CGN) from postnatal day 6 rat pups were cultured with and without supplemental choline, and the effects on L1 signaling, lipid raft distribution, and neurite outgrowth were measured in the presence or absence of EtOH. Choline significantly reduced the effect of EtOH on L1 signaling, the distribution of L1 in lipid rafts and L1-mediated neurite outgrowth. However, choline supplemented EtOH-exposed cultures remained significantly different than controls. Choline pretreatment of CGN significantly reduces the disruption of L1 function by EtOH, but does not completely return L1 function to baseline. This experimental system will enable discovery of the mechanism of the neuroprotective effect of choline. Copyright © 2014 by the Research Society on Alcoholism.

Cytokines, chemokines and soluble adhesion molecules in aqueous humor of children with uveitis.

PubMed

Sijssens, Karen M; Rijkers, Ger T; Rothova, Aniki; Stilma, Jan S; Schellekens, Peter A W J F; de Boer, Joke H

2007-10-01

Uveitis in childhood is a visual threatening disease with a complication rate of more than 75%. Despite extensive research, the etiology of uveitis is still unclear although the general opinion is now that uveitis is a T-cell mediated disease. The purpose of this study was to investigate the profile of cytokines, chemotactic cytokines (chemokines) and soluble adhesion molecules in the aqueous humor (AqH) of children with uveitis in order to identify the factors that control the immune response in the eye. In this clinical laboratory investigation we analyzed, with a multiplex immunoassay, 16 immune mediators in the AqH of 25 children with uveitis and 6 children without uveitis. Increased levels of interleukin-2 (IL-2), IL-6, IL-10, IL-13, IL-18, interferon-gamma, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, RANTES, IL-8 and interferon-inducible 10-kDa protein were found in the AqH of children with uveitis compared with controls. No significant differences were found for IL-1 beta, IL-4, IL-12 p-70, soluble vascular cell adhesion molecule 1 and Eotaxin. Lower levels of IL-10 and IL-8 were found in quiet stage uveitis (surgical) samples compared with active uveitis (diagnostic) samples and in samples of patients treated with methotrexate (MTX) compared with samples of patients not treated with MTX. Lower levels of IL-10 were as well found in samples taken during the first 3 months after the diagnosis of uveitis than samples taken later during the disease process. No significant differences were found between patients treated with or without topical or systemic (perioperative and long term) corticosteroids. In conclusion, in children with uveitis, multiple intraocular cytokines, chemokines and soluble adhesion molecules are increased in the AqH regardless of active or inactive inflammation. Whether the IL-8 and IL-10 levels in AqH of children with uveitis are correlated with uveitis activity, early or late phase of the course of the disease

Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect

PubMed Central

Greineder, Colin F.; Brenza, Jacob B.; Carnemolla, Ronald; Zaitsev, Sergei; Hood, Elizabeth D.; Pan, Daniel C.; Ding, Bi-Sen; Esmon, Charles T.; Chacko, Ann Marie; Muzykantov, Vladimir R.

2015-01-01

Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood–tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to partner enzymatically to generate enhanced biologic effect. Based on the recent discovery that paired antibodies directed to adjacent epitopes of platelet endothelial cell adhesion molecule (PECAM)-1 stimulate each other’s binding, we fused single-chain fragments (scFv) of paired anti-mouse PECAM-1 antibodies to recombinant murine thrombomodulin (TM) and endothelial protein C receptor (EPCR), endothelial membrane proteins that partner in activation of protein C (PC). scFv/TM and scFv/EPCR bound to mouse endothelial PECAM-1 with high affinity (EC50 1.5 and 3.8 nM, respectively), and codelivery induced a 5-fold increase in PC activation not seen when TM and EPCR are anchored to distinct cell adhesion molecules. In a mouse model of acute lung injury, dual targeting reduces both the expression of lung inflammatory markers and trans-endothelial protein leak by as much as 40%, as compared to either agent alone. These findings provide proof of principle for endothelial dual targeting, an approach with numerous potential biomedical applications.—Greineder, C. F., Brenza, J. B., Carnemolla, R., Zaitsev, S., Hood, E. D., Pan, D. C., Ding, B.-S., Esmon, C. T., Chacko, A. M., Muzykantov, V. R. Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect. PMID:25953848

Sarcoptes scabiei (Acari: Sarcoptidae) Mite Extract Modulates Expression of Cytokines and Adhesion Molecules by Human Dermal Microvascular Endothelial Cells.

PubMed Central

Elder, B. Laurel; Arlian, Larry G.; Morgan, Marjorie S.

2007-01-01

The inflammatory and immune responses seen with the worldwide disease scabies (caused by the mite Sarcoptes scabiei) are complex. Clinical symptoms are delayed for weeks in patients when they are infested with scabies for the first time. This study was undertaken to elucidate the role of the human dermal microvascular endothelial cell (HMVEC-D) in modulating the inflammatory and immune responses in the skin to S. scabiei. Extracts of S. scabiei were incubated with HMVEC-D and the expression of adhesion molecules and chemokine receptors on the cells and the secretion of selected cytokines were determined by ELISA. S. scabiei extract was found to inhibit HMVEC-D expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) although not intercellular adhesion molecule-1 (ICAM-1). The secretion of interleukin-8 (IL-8) was also inhibited by S. scabiei extract. S. scabiei extract increased expression of the chemokine receptor CXCR-1, and both down-regulated and up-regulated expression of CXCR-2 depending on the concentration tested. These findings help explain the delayed inflammatory reaction to infestation with S. scabiei. PMID:17017228

The fibroblast growth factor receptor (FGFR) agonist FGF1 and the neural cell adhesion molecule-derived peptide FGL activate FGFR substrate 2alpha differently.

PubMed

Chen, Yongshuo; Li, Shizhong; Berezin, Vladimir; Bock, Elisabeth

2010-07-01

Activation of fibroblast growth factor (FGF) receptors (FGFRs) both by FGFs and by the neural cell adhesion molecule (NCAM) is crucial in the development and function of the nervous system. We found that FGFR substrate 2alpha (FRS2alpha), Src homologous and collagen A (ShcA), and phospholipase-Cgamma (PLCgamma) were all required for neurite outgrowth from cerebellar granule neurons (CGNs) induced by FGF1 and FGL (an NCAM-derived peptide agonist of FGFR1). Like FGF1, FGL induced tyrosine phosphorylation of FGFR1, FRS2alpha, ShcA, and PLCgamma in a time- and dose-dependent manner. However, the activation of FRS2alpha by FGL was significantly lower than the activation by FGF1, indicating a differential signaling profile induced by NCAM compared with the cognate growth factor.

Elevated expression in situ of selectin and immunoglobulin superfamily type adhesion molecules in retroocular connective tissues from patients with Graves' ophthalmopathy.

PubMed Central

Heufelder, A E; Bahn, R S

1993-01-01

Activation of certain adhesion molecules within vascular endothelium and the surrounding extravascular space is a critical event in the recruitment and targeting of an inflammatory response or autoimmune attack to a particular tissue site. We have recently demonstrated that the adhesion of lymphocytes to cultured retroocular fibroblasts obtained from patients with Graves' ophthalmopathy (GO) is mediated predominantly by the interaction of lymphocyte function-associated antigen-1 (LFA-1), expressed on lymphocytes, with intercellular adhesion molecule-1 (ICAM-1), expressed by these cells following exposure to interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), IL-1 alpha or purified thyroid-stimulating immunoglobulins. We now report the expression and localization in situ of several adhesion molecules, ICAM-1, endothelial leucocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and LFA-3 in retroocular tissues derived from patients with severe GO (n = 4) and normal individuals (n = 3). Serial cryostat sections of tissue specimens were processed for immunoperoxidase staining using various MoAbs against ICAM-1, ELAM-1, VCAM-1 and LFA-3. In addition, consecutive sections were stained with MoAbs against LFA-1, CD45RO (UCHL-1)DR-human leucocyte antigen (HLA-DR), CD11b/CD18 (Mac-1), and CD11c/CD18 (p150,95). In GO-retroocular tissues, strong immunoreactivity for ICAM-1 and LFA-3 was detected in blood vessels (> 90%), in perimysial fibroblasts surrounding extraocular muscle fibres, and in connective tissue distinct from extraocular muscle. No ICAM-1 or LFA-3 immunoreactivity was present in extraocular muscle cells themselves. ICAM-1 and LFA-3 immunoreactivity in normal tissues was minimal or absent both in connective and muscle tissues. Vascular endothelium was strongly positive for ELAM-1 and VCAM-1 in GO-retroocular tissues, while VCAM-1 immunoreactivity was minimal (< 5% of blood vessels) and ELAM-1 immunoreactivity was

Overactivation of Hedgehog Signaling Alters Development of the Ovarian Vasculature in Mice1

PubMed Central

Ren, Yi; Cowan, Robert G.; Migone, Fernando F.; Quirk, Susan M.

2012-01-01

ABSTRACT The hedgehog (HH) signaling pathway is critical for ovarian function in Drosophila, but its role in the mammalian ovary has not been defined. Previously, expression of a dominant active allele of the HH signal transducer protein smoothened (SMO) in Amhr2cre/+SmoM2 mice caused anovulation in association with a lack of smooth muscle in the theca of developing follicles. The current study examined events during the first 2 wk of life in Amhr2cre/+SmoM2 mice to gain insight into the cause of anovulation. Expression of transcriptional targets of HH signaling, Gli1, Ptch1, and Hhip, which are used as measures of pathway activity, were elevated during the first several days of life in Amhr2cre/+SmoM2 mice compared to controls but were similar to controls in older mice. Microarray analysis showed that genes with increased expression in 2-day-old mutants compared to controls were enriched for the processes of vascular and tube development and steroidogenesis. The density of platelet endothelial cell adhesion molecule (PECAM)-labeled endothelial tubes was increased in the cortex of newborn ovaries of mutant mice. Costaining of preovulatory follicles for PECAM and smooth muscle actin showed that muscle-type vascular support cells are deficient in theca of mutant mice. Expression of genes for steroidogenic enzymes that are normally expressed in the fetal adrenal gland were elevated in newborn ovaries of mutant mice. In summary, overactivation of HH signaling during early life alters gene expression and vascular development and this is associated with the lifelong development of anovulatory follicles in which the thecal vasculature fails to mature appropriately. PMID:22402963

Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway.

PubMed

Li, Yingzhu; Clough, Nancy; Sun, Xiaolin; Yu, Weidong; Abbott, Brian L; Hogan, Christopher J; Dai, Zonghan

2007-04-15

Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as beta1-integrin, paxillin and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of the phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function.

Active and inactive β1 integrins segregate into distinct nanoclusters in focal adhesions.

PubMed

Spiess, Matthias; Hernandez-Varas, Pablo; Oddone, Anna; Olofsson, Helene; Blom, Hans; Waithe, Dominic; Lock, John G; Lakadamyali, Melike; Strömblad, Staffan

2018-06-04

Integrins are the core constituents of cell-matrix adhesion complexes such as focal adhesions (FAs) and play key roles in physiology and disease. Integrins fluctuate between active and inactive conformations, yet whether the activity state influences the spatial organization of integrins within FAs has remained unclear. In this study, we address this question and also ask whether integrin activity may be regulated either independently for each integrin molecule or through locally coordinated mechanisms. We used two distinct superresolution microscopy techniques, stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion microscopy (STED), to visualize active versus inactive β1 integrins. We first reveal a spatial hierarchy of integrin organization with integrin molecules arranged in nanoclusters, which align to form linear substructures that in turn build FAs. Remarkably, within FAs, active and inactive β1 integrins segregate into distinct nanoclusters, with active integrin nanoclusters being more organized. This unexpected segregation indicates synchronization of integrin activities within nanoclusters, implying the existence of a coordinate mechanism of integrin activity regulation. © 2018 Spiess et al.

Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection.

PubMed

Kulkarni, Manjusha; Bowman, Emily; Gabriel, Janelle; Amburgy, Taylor; Mayne, Elizabeth; Zidar, David A; Maierhofer, Courtney; Turner, Abigail Norris; Bazan, Jose A; Koletar, Susan L; Lederman, Michael M; Sieg, Scott F; Funderburg, Nicholas T

2016-10-01

Human immunodeficiency virus (HIV)-infected individuals have increased risk for vascular thrombosis, potentially driven by interactions between activated leukocytes and the endothelium. Monocyte subsets (CD14 + CD16 - , CD14 + CD16 + , CD14 Dim CD16 + ) from HIV negative (HIV - ) and antiretroviral therapy-treated HIV positive (HIV + ) participants (N = 19 and 49) were analyzed by flow cytometry for adhesion molecule expression (lymphocyte function-associated antigen 1 [LFA-1], macrophage-1 antigen [Mac-1], CD11c/CD18, very late antigen [VLA]-4) and the fractalkine receptor (CX3CR1); these receptors recognize ligands (intercellular adhesion molecules [ICAMs], vascular cell adhesion molecule [VCAM]-1, fractalkine) on activated endothelial cells (ECs) and promote vascular migration. Plasma markers of monocyte (soluble [s]CD14, sCD163) and EC (VCAM-1, ICAM-1,2, fractalkine) activation and systemic (tumor necrosis factor receptor [TNFR-I], TNFR-II) and vascular (lipoprotein-associated phospholipase A 2 [Lp-PLA 2 ]) inflammation were measured by enzyme-linked immunosorbent assay. Proportions of CD16 + monocyte subsets were increased in HIV + participants. Among all monocyte subsets, levels of LFA-1 were increased and CX3CR1 levels were decreased in HIV + participants ( P < .01). Levels of sCD163, sCD14, fractalkine, ICAM-1, VCAM-1, TNFR-II, and Lp-PLA 2 were also increased in HIV + participants ( P < .05), and levels of sCD14, TNFR-I, and TNFR-II were directly related to ICAM-1 and VCAM-1 levels in HIV + participants. Expression of CX3CR1 on monocyte subsets was inversely related to plasma Lp-PLA 2 ( P < .05 for all). Increased proportions of CD16 + monocytes, cells with altered adhesion molecule expression, combined with elevated levels of their ligands, may promote vascular inflammation in HIV infection. © The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Association of adipokines and adhesion molecules with indicators of obesity in women undergoing mammography screening

PubMed Central

2012-01-01

Background The soluble cell adhesion molecules and adipokines are elevated in patients with obesity, hypertension, type 2 diabetes mellitus, breast cancer and atherosclerosis. Objective To investigate the relationship between anthropometric profile, dietary intake, lipid profile and fasting glycemia with serum levels of adipokines (adiponectin and PAI-1) and adhesion molecules (ICAM-1 and VCAM-1) in women without breast cancer undergoing routine mammographic screening. Design Transversal study. Subjects One hundred and forty-five women over 40-years old participated in this study. Results In 39.3% of cases the BMI was above 30 kg/m2; 46.9% had hypertension, 14.5% had type 2 Diabetes Mellitus, 31.7% had dyslipidemia and 88.3% presented a waist-to-hip ratio ≥ 0.8. A linear correlation was found between serum levels of PAI-1 and triglycerides, between serum levels of PAI-1 and WHR and between serum levels of VCAM-1 and BMI. Conclusion We found a high prevalence of obesity and metabolic syndrome. PAI-1 and VCAM-1 levels were correlated with clinical indicators of obesity and overweight. PMID:23113882

Cyclosporin A inhibits CD11a/CD18 adhesion molecules due to inhibition of TNFα and IL-1β levels in the mouse model of pleurisy induced by carrageenan

PubMed Central

Dalmarco, Eduardo Monguilhott; Medeiros, Yara Santos

2008-01-01

The mouse model of pleurisy induced by carrageenan is characterized by a significant enhancement of cell migration due to neutrophils 4 h after pleurisy induction. Forty-eight hours after pleurisy induction, a significant increase in cell migration due to mononuclear cells occurs. Recently, studies in our laboratory have demonstrated that cyclosporine A (CsA) inhibits leukocyte migration in the pleural cavity and lungs in the mouse model of pleurisy induced by carrageenan. In the present work we evaluated whether CsA was able to downregulate CD11a/CD18 adhesion molecule in the lungs, as well as TNFα and IL-1β levels in the fluid leakage of the pleural cavity in this model. Our results showed that CsA significantly decreased CD11a/CD18 in the lungs, as well as TNFα and IL-1β levels in the fluid leakage of the pleural cavity 4 h and 48 h after pleurisy induction. It is our hypothesis that the inhibitory effect elicited by CsA upon these adhesion molecules may be also be attributed to the downregulation of TNFα and IL-1β cytokines. PMID:19262158

Reduced immunohistochemical expression of adhesion molecules in vitiligo skin biopsies.

PubMed

Reichert Faria, Adriane; Jung, Juliana Elizabeth; Silva de Castro, Caio César; de Noronha, Lucia

2017-03-01

Because defects in adhesion impairment seem to be involved in the etiopathogenesis of vitiligo, this study aimed to compare the immunohistochemical expression of several adhesion molecules in the epidermis of vitiligo and non lesional vitiligo skin. Sixty-six specimens of lesional and non lesional skin from 33 volunteers with vitiligo were evaluated by immunohistochemistry using anti-beta-catenin, anti-E-cadherin, anti-laminin, anti-beta1 integrin, anti-collagen IV, anti-ICAM-1 and anti-VCAM-1 antibodies. Biopsies of vitiligo skin demonstrated a significant reduction in the expression of laminin and integrin. The average value of the immunohistochemically positive reaction area of the vitiligo specimens was 3053.2μm 2 , compared with the observed value of 3431.8μm 2 in non vitiligo skin (p=0.003) for laminin. The immuno-positive area was 7174.6μm 2 (vitiligo) and 8966.7μm 2 (non lesional skin) for integrin (p=0.042). A reduction in ICAM-1 and VCAM-1 expression in the basal layer of the epidermis in vitiligo samples was also observed (p=0.001 and p<0.001, respectively). However, no significant differences were observed with respect to the expression of beta-catenin, E-cadherin, and collagen IV between vitiligo and non lesional skin. Our results suggest that an impairment in adhesion exists in vitiligo skin, which is supported by the diminished immunohistochemical expression of laminin, beta1 integrin, ICAM-1 and VCAM-1. Copyright © 2017 Elsevier GmbH. All rights reserved.

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

Chrysin Attenuates VCAM-1 Expression and Monocyte Adhesion in Lipopolysaccharide-Stimulated Brain Endothelial Cells by Preventing NF-κB Signaling.

PubMed

Lee, Bo Kyung; Lee, Won Jae; Jung, Yi-Sook

2017-07-03

Adhesion of leukocytes to endothelial cells plays an important role in neuroinflammation. Therefore, suppression of the expression of adhesion molecules in brain endothelial cells may inhibit neuroinflammation. Chrysin (5,7-dihydroxyflavone) is a flavonoid component of propolis, blue passion flowers, and fruits. In the present study, we examined the effects of chrysin on lipopolysaccharide (LPS)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in mouse cerebral vascular endothelial (bEnd.3) cells. In bEnd.3 cells, LPS increased mRNA expression of VCAM-1 in a time-dependent manner, and chrysin significantly decreased LPS-induced mRNA expression of VCAM-1. Chrysin also reduced VCAM-1 protein expression in a concentration-dependent manner. Furthermore, chrysin blocked adhesion of monocytes to bEnd.3 cells exposed to LPS. Nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, which are all activated by LPS, were significantly inhibited by chrysin. These results indicate that chrysin inhibits the expression of VCAM-1 in brain endothelial cells by inhibiting NF-κB translocation and MAPK signaling, resulting in the attenuation of leukocyte adhesion to endothelial cells. The anti-inflammatory effects of chrysin suggest a possible therapeutic application of this agent to neurodegenerative diseases, such as multiple sclerosis, septic encephalopathy, and allergic encephalomyelitis.

Adhesion molecules, chemokines and matrix metallo-proteinases response after albendazole and albendazole plus steroid therapy in swine neurocysticercosis.

PubMed

Singh, Satyendra K; Prasad, Kashi N; Singh, Aloukick K; Gupta, Kamlesh K; Singh, Amrita; Tripathi, Mukesh; Gupta, Rakesh K

2017-11-01

The treatment of neurocysticercosis (NCC) varies with location, number and stage of the Taenia solium cysticerci (cysts). Albendazole (ABZ) effectively kills cysticerci, and subsequently induces neuro-inflammation facilitated by leukocyte infiltration. We hypothesize that immune response varies around drug responder (degenerating/dying) and non-responder (viable) cysts after ABZ and ABZ plus steroid (ABZS) therapy, which may determine the disease pathogenesis. Twenty cysticercotic swine were treated with ABZ (n = 10; group1) and ABZS (n = 10; group2). Expression of adhesion molecules, chemokines and matrix metallo-proteinases (MMPs) was measured by qRT-PCR (quantitative reverse transcriptase-polymerase chain reaction) and ELISA. Gelatin gel zymography was performed to detect the activity of MMP-2 and -9. In group1, ABZ therapy induced higher expressions of ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), E-selectin, MCP-1 (monocyte chemotactic protein-1), Eotaxin-1, MIP-1α (macrophage inflammatory protein-1α), RANTES (regulated on activation, normal T cell expressed and secreted), MMP-2 and MMP-9 around ABZ responder (AR) cysts. Three pigs with cyst burdens ≥10 died following ABZ therapy. However, in group2, moderate expressions of ICAM-1, VCAM-1, E-selectin, RANTES and MMP-9 were associated with ABZS responder (ASR), whereas low expressions of these molecules were associated with ABZS non-responder (ASNR) cysts. In conclusion, ABZ alone therapy is not safe since it causes death of pigs due to higher inflammatory immune response around dying cysts. However, combination therapy is an effective treatment regimen even with the high cyst burden. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin.

PubMed

Calvo, Alfonso; Yokoyama, Yumi; Smith, Lois E; Ali, Iqbal; Shih, Shu-Ching; Feldman, Andrew L; Libutti, Steven K; Sundaram, Ramakrishnan; Green, Jeffrey E

2002-09-20

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model. Copyright 2002 Wiley-Liss, Inc.

Effect of 10-Week Supervised Moderate-Intensity Intermittent vs. Continuous Aerobic Exercise Programs on Vascular Adhesion Molecules in Patients with Heart Failure.

PubMed

Aksoy, Sibel; Findikoglu, Gulin; Ardic, Fusun; Rota, Simin; Dursunoglu, Dursun

2015-10-01

Abnormal expression of cellular adhesion molecules may be related to endothelial dysfunction, a key feature in chronic heart failure. This study compares the effects of 10-wk supervised moderate-intensity continuous aerobic exercise (CAE) and intermittent aerobic exercise (IAE) programs on markers of endothelial damage, disease severity, functional and metabolic status, and quality-of-life in chronic heart failure patients. Fifty-seven patients between 41 and 81 yrs with New York Heart Association class II-III chronic heart failure and with a left ventricular ejection fraction of 35%-55% were randomized into three groups: nonexercising control, CAE, and IAE, which exercised three times a week for 10 wks. Endothelial damage was assessed by serum markers of vascular cell adhesion molecule-1, serum intercellular adhesion molecule-1, and nitric oxide; disease severity was measured by left ventricular ejection fraction and N-terminal probrain natriuretic peptide; metabolic status was evaluated by body composition analysis and lipid profile levels; functional status was evaluated by cardiorespiratory exercise stress test and 6-min walking distance; quality-of-life was assessed with Left Ventricular Dysfunction-36 and Short-Form 36 questionnaires at the baseline and at the end of the 10th week. Significant decreases in serum vascular cell adhesion molecule-1 or serum intercellular adhesion molecule-1 in IAE and CAE groups after training were found, respectively. Resting systolic and diastolic blood pressure, peak systolic and diastolic blood pressure, 6-min walking distance, and the mental health and vitality components of Short-Form 36 improved in the CAE group, whereas left ventricular ejection fraction and 6-min walking distance improved in the IAE group compared with the control group. Both moderate-intensity CAE and IAE programs significantly reduced serum markers of adhesion molecules and prevented the change in VO2 in patients with chronic heart failure.

Female receptivity phenotype of icebox mutants caused by a mutation in the L1-type cell adhesion molecule neuroglian.

PubMed

Carhan, A; Allen, F; Armstrong, J D; Hortsch, M; Goodwin, S F; O'Dell, K M C

2005-11-01

Relatively little is known about the genes and brain structures that enable virgin female Drosophila to make the decision to mate or not. Classical genetic approaches have identified several mutant females that have a reluctance-to-mate phenotype, but most of these have additional behavioral defects. However, the icebox (ibx) mutation was previously reported to lower the sexual receptivity of females, without apparently affecting any other aspect of female behavior. We have shown that the ibx mutation maps to the 7F region of the Drosophila X chromosome to form a complex complementation group with both lethal and viable alleles of neuroglian (nrg). The L1-type cell adhesion molecule encoded by nrg consists of six immunoglobulin-like domains, five fibronectin-like domains, one transmembrane domain and one alternatively spliced intracellular domain. The ibx strain has a missense mutation causing a glycine-to-arginine change at amino acid 92 in the first immunoglobulin domain of nrg. Defects in the central brain of ibx mutants are similar to those observed in another nrg mutant, central brain deranged(1) (ceb(1)). However, both ceb(1) homozygous and ceb(1)/ibx heterozygous females are receptive. The expression of a transgene containing the non-neural isoform of nrg rescues both the receptivity and the brain structure phenotypes of ibx females.

Timing is everything: Rac1 controls Net1A localization to regulate cell adhesion.

PubMed

Carr, Heather S; Frost, Jeffrey A

2013-01-01

Cell adhesion to the extracellular matrix elicits a temporal reorganization of the actin cytoskeleton that is regulated first by Rac1 and later by RhoA. The signaling mechanisms controlling late stage RhoA activation are incompletely understood. Net1A is a RhoA/RhoB-specific guanine nucleotide exchange factor that is required for cancer cell motility. The ability of Net1A to stimulate RhoA activation is negatively regulated by nuclear sequestration. However, mechanisms controlling the plasma membrane localization of Net1A had not previously been reported. Recently we have shown that Rac1 activation stimulates plasma membrane relocalization and activation of Net1A. Net1A relocalization is independent of its catalytic activity and does not require its C-terminal pleckstrin homology or PDZ interacting domains. Rac1 activation during cell adhesion stimulates a transient relocalization of Net1A that is terminated by proteasomal degradation of Net1A. Importantly, plasma membrane localization of Net1A is required for efficient myosin light chain phosphorylation, focal adhesion maturation, and cell spreading. These data show for the first time a physiological mechanism controlling Net1A relocalization from the nucleus. They also demonstrate a previously unrecognized role for Net1A in controlling actomyosin contractility and focal adhesion dynamics during cell adhesion.

Plasma concentration of soluble intercellular adhesion molecule-1 (sICAM-1) is elevated in type 2 diabetic patients, and sICAM-1 synthesis is associated with leptin-induced activation of the mitogen-activated protein kinase (MAPK) pathway.

PubMed

Cha, Jin Joo; Hyun, Young Youl; Jee, Yi Hwa; Lee, Mi Jin; Han, Kum Hyun; Kang, Young Sun; Han, Sang Youb; Cha, Dae Ryong

2013-08-01

The intercellular adhesion molecule-1 (ICAM-1) and leptin are important inflammatory biomarkers. We investigated whether plasma-soluble ICAM-1 levels were related to the diabetic nephropathy and systemic inflammation. One hundred forty-seven type 2 diabetic patients and 46 healthy control subjects were studied. Plasma sICAM-1 concentrations were significantly higher in the diabetic groups than controls and increased significantly as diabetic nephropathy advanced. Plasma sICAM-1 levels were positively correlated with body mass index, fasting and postprandial blood glucose, urinary albumin excretion, and negatively correlated with creatinine clearance. Multiple regression analysis showed that plasma leptin levels were associated with a significant increase in plasma sICAM-1 levels. In cultured HUVECs, leptin increased ICAM-1 production in a dose-dependent manner, and this stimulating effect of leptin on ICAM-1 expression was reversed by MEK inhibitor, PD98059. Overall, these findings suggest that activation of leptin synthesis in a diabetic environment promotes ICAM-1 activation via mitogen-activated protein kinase pathway in type 2 diabetic patients.

The analysis of genomic structures in the L1 family of cell adhesion molecules provides no evidence for exon shuffling events after the separation of arthropod and chordate lineages.

PubMed

Zhao, G; Hortsch, M

1998-07-17

Members of the L1 family of neural cell adhesion molecules consist of multiple extracellular immunoglobulin and fibronectin type III domains that mediate the adhesive properties of this group of transmembrane proteins. In vertebrate genomes, these protein domains are separated by introns, and it has been suggested that L1-type genes might have been subject to exon-shuffling events during evolution. However, comparison of the human L1-CAM and the chicken neurofascin gene with the genomic structure of their Drosophila homologue, neuroglian, indicates that no major rearrangement of protein domains has taken place subsequent to the split of the arthropod and chordate phyla. The Drosophila neuroglian gene appears to have lost most of the introns that have been conserved in the human L1-CAM and the chicken neurofascin gene. Nevertheless, exon shuffling or the generation of new exons by mutational changes might have been responsible for the generation of additional, alternatively spliced exons in L1-type genes.

Secreted Frizzled-related protein 1 (sFRP1) regulates spermatid adhesion in the testis via dephosphorylation of focal adhesion kinase and the nectin-3 adhesion protein complex

PubMed Central

Wong, Elissa W. P.; Lee, Will M.; Cheng, C. Yan

2013-01-01

Development of spermatozoa in adult mammalian testis during spermatogenesis involves extensive cell migration and differentiation. Spermatogonia that reside at the basal compartment of the seminiferous epithelium differentiate into more advanced germ cell types that migrate toward the apical compartment until elongated spermatids are released into the tubule lumen during spermiation. Apical ectoplasmic specialization (ES; a testis-specific anchoring junction) is the only cell junction that anchors and maintains the polarity of elongating/elongated spermatids (step 8–19 spermatids) in the epithelium. Little is known regarding the signaling pathways that trigger the disassembly of the apical ES at spermiation. Here, we show that secreted Frizzled-related protein 1 (sFRP1), a putative tumor suppressor gene that is frequently down-regulated in multiple carcinomas, is a crucial regulatory protein for spermiation. The expression of sFRP1 is tightly regulated in adult rat testis to control spermatid adhesion and sperm release at spermiation. Down-regulation of sFRP1 during testicular development was found to coincide with the onset of the first wave of spermiation at approximately age 45 d postpartum, implying that sFRP1 might be correlated with elongated spermatid adhesion conferred by the apical ES before spermiation. Indeed, administration of sFRP1 recombinant protein to the testis in vivo delayed spermiation, which was accompanied by down-regulation of phosphorylated (p)-focal adhesion kinase (FAK)-Tyr397 and retention of nectin-3 adhesion protein at the apical ES. To further investigate the functional relationship between p-FAK-Tyr397 and localization of nectin-3, we overexpressed sFRP1 using lentiviral vectors in the Sertoli-germ cell coculture system. Consistent with the in vivo findings, overexpression of sFRP1 induced down-regulation of p-FAK-Tyr397, leading to a decline in phosphorylation of nectin-3. In summary, this report highlights the critical role of s

Regulation of the epithelial adhesion molecule CEACAM1 is important for palate formation.

PubMed

Mima, Junko; Koshino, Aya; Oka, Kyoko; Uchida, Hitoshi; Hieda, Yohki; Nohara, Kanji; Kogo, Mikihiko; Chai, Yang; Sakai, Takayoshi

2013-01-01

Cleft palate results from a mixture of genetic and environmental factors and occurs when the bilateral palatal shelves fail to fuse. The objective of this study was to search for new genes involved in mouse palate formation. Gene expression of murine embryonic palatal tissue was analyzed at various developmental stages before, during, and after palate fusion using GeneChip® microarrays. Ceacam1 was one of the highly up-regulated genes during palate formation, and this was confirmed by quantitative real-time PCR. Immunohistochemical staining showed that CEACAM1 was present in prefusion palatal epithelium and was degraded during fusion. To investigate the developmental role of CEACAM1, function-blocking antibody was added to embryonic mouse palate in organ culture. Palatal fusion was inhibited by this function-blocking antibody. To investigate the subsequent developmental role of CEACAM1, we characterized Ceacam1-deficient (Ceacam1(-/-)) mice. Epithelial cells persisted abnormally at the midline of the embryonic palate even on day E16.0, and palatal fusion was delayed in Ceacam1(-/-) mice. TGFβ3 expression, apoptosis, and cell proliferation in palatal epithelium were not affected in the palate of Ceacam1(-/-)mice. However, CEACAM1 expression was retained in the remaining MEE of TGFβ-deficient mice. These results suggest that CEACAM1 has roles in the initiation of palatal fusion via epithelial cell adhesion.

In vivo imaging of endothelial cell adhesion molecule expression after radiosurgery in an animal model of arteriovenous malformation.

PubMed

Raoufi-Rad, Newsha; McRobb, Lucinda S; Lee, Vivienne S; Bervini, David; Grace, Michael; Ukath, Jaysree; Mchattan, Joshua; Sreenivasan, Varun K A; Duong, T T Hong; Zhao, Zhenjun; Stoodley, Marcus A

2017-01-01

Focussed radiosurgery may provide a means of inducing molecular changes on the luminal surface of diseased endothelium to allow targeted delivery of novel therapeutic compounds. We investigated the potential of ionizing radiation to induce surface expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells (EC) in vitro and in vivo, to assess their suitability as vascular targets in irradiated arteriovenous malformations (AVMs). Cultured brain microvascular EC were irradiated by linear accelerator at single doses of 0, 5, 15 or 25 Gy and expression of ICAM-1 and VCAM-1 measured by qRT-PCR, Western, ELISA and immunocytochemistry. In vivo, near-infrared (NIR) fluorescence optical imaging using Xenolight 750-conjugated ICAM-1 or VCAM-1 antibodies examined luminal biodistribution over 84 days in a rat AVM model after Gamma Knife surgery at a single 15 Gy dose. ICAM-1 and VCAM-1 were minimally expressed on untreated EC in vitro. Doses of 15 and 25 Gy stimulated expression equally; 5 Gy was not different from the unirradiated. In vivo, normal vessels did not bind or retain the fluorescent probes, however binding was significant in AVM vessels. No additive increases in probe binding were found in response to radiosurgery at a dose of 15 Gy. In summary, radiation induces adhesion molecule expression in vitro but elevated baseline levels in AVM vessels precludes further induction in vivo. These molecules may be suitable targets in irradiated vessels without hemodynamic derangement, but not AVMs. These findings demonstrate the importance of using flow-modulated, pre-clinical animal models for validating candidate proteins for vascular targeting in irradiated AVMs.

Endothelium adhesion molecules ICAM-1, ICAM-2, VCAM-1 and VLA-4 expression in leprosy.

PubMed

de Sousa, Juarez; Sousa Aarão, Tinara Leila; Rodrigues de Sousa, Jorge; Hirai, Kelly Emi; Silva, Luciana Mota; Dias, Leonidas Braga; Oliveira Carneiro, Francisca Regina; Fuzii, Hellen Thais; Quaresma, Juarez Antonio Simões

2017-03-01

Leprosy triggers a complex relationship between the pathogen and host immune response. Endothelium plays an important role in this immune response by directly influencing cell migration to infected tissues. The objective of this work is to investigate the possible role of endothelium in M. leprae infection, correlating the characteristics of endothelial markers with the expression pattern of cytokines. Thirty-six skin biopsy samples were cut into 5-μm thick sections and stained with hematoxylin-eosin and Ziehl-Neelsen for morphological analysis and then submitted to immunohistochemical analysis using monoclonal antibodies against ICAM-1, ICAM-2, VCAM-1, and VLA-4. Immunostaining for ICAM-1 showed a significantly larger number of stained endothelial cells in the tuberculoid leprosy (9.92 ± 1.11 cells/mm 2 ) when compared to lepromatous samples (5.87 ± 1.01 cells/mm 2 ) and ICAM-2 revealed no significant difference in the number of endothelial cells expressing this marker between the tuberculoid (13.21 ± 1.27 cells/mm 2 ) and lepromatous leprosy (14.3 ± 1.02 cells/mm 2 ). VCAM-1-immunostained showed 18.28 ± 1.46/mm 2 cells in tuberculoid leprosy and 10.67 ± 1.25 cells/mm 2 in the lepromatous leprosy. VLA-4 exhibited 22.46 ± 1.38 cells/mm 2 in the tuberculoid leprosy 16.04 ± 1.56 cells/mm 2 in the lepromatous leprosy. Samples with characteristics of the tuberculoid leprosy exhibited a larger number of cells stained with ICAM-1, VCAM-1 and VLA-4, demonstrating the importance of these molecules in the migration and selection of cells that reach the inflamed tissue. Copyright © 2017 Elsevier Ltd. All rights reserved.

Phosphorylation of tyrosine 285 of PAK1 facilitates βPIX/GIT1 binding and adhesion turnover

PubMed Central

Hammer, Alan; Oladimeji, Peter; De Las Casas, Luis E.; Diakonova, Maria

2015-01-01

The p21-activated serine-threonine kinase (PAK1) regulates cell motility and adhesion. We have previously shown that the prolactin (PRL)-activated tyrosine kinase JAK2 phosphorylates PAK1 in vivo and in vitro and identified tyrosines 153, 201, and 285 in PAK1 as sites of JAK2 tyrosyl phosphorylation. Here, we further investigate the role of the tyrosyl phosphorylated PAK1 (pTyr-PAK1) in regulation of cell adhesion. We use human breast cancer T47D cell lines that stably overexpress PAK1 wild type or PAK1 Y3F mutant in which these 3 JAK2 phosphorylation sites were mutated to phenylalanine. We demonstrate that PRL/JAK2-dependent phosphorylation of these tyrosines promotes a motile phenotype in the cells upon adhesion, participates in regulation of cell adhesion on collagen IV, and is required for maximal PAK1 kinase activity. Down-regulation of PAK1 abolishes the effect of PAK1 on cell adhesion. We show that the tyrosyl phosphorylation of PAK1 promotes PAK1 binding to β-PAK1-interacting guanine-nucleotide exchange factor (βPIX) and G protein-coupled receptor kinase-interacting target 1 (GIT1), phosphorylation of paxillin on Ser273, and formation and distribution of adhesion complexes. Using phosphospecific antibodies (Abs) directed to single phosphorylated tyrosines on PAK1, we identified Tyr285 as a site of PRL-dependent phosphorylation of PAK1 by JAK2. Furthermore, using PAK1 Y285F mutant, we provide evidence for a role of pTyr285 in cell adhesion, enhanced βPIX/GIT1 binding, and adhesion turnover. Our immunohistochemistry analysis demonstrates that pTyr285- PAK1 may modulate PAK1 signaling during tumor progression.—Hammer, A., Oladimeji, P., De La Casas, L. E., Diakonova, M. Phosphorylation of tyrosine 285 of PAK1 facilitates bPIX/GIT1 binding and adhesion turnover. PMID:25466889

Drospirenone and levonorgestrel in combination with either 30 or 20 mcg ethinylestradiol reduce soluble adhesion molecules in Brazilian women; cross-sectional study.

PubMed

Stocco, Bianca; Fumagalli, Helen Figueiredo; Franceschini, Silvio Antônio; Martinez, Edson Zangiacomi; Marzocchi-Machado, Cleni Mara; Toloi, Maria Regina Torqueti

2012-11-01

The objective of this study was to evaluate the effect of three contraceptive pills containing ethinylestradiol (EE) (20 or 30 mcg) in combination with drospirenone (DRSP) and levonorgestrel (LNG) on plasma concentration of adhesion molecules vascular cell adhesion molecule -1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. A cross-sectional study was conducted with 72 participants (18-30 years old) distributed into three groups that used oral contraceptives containing EE 20 or 30 mcg combined with DRSP 3 mg or EE 30 mcg/LNG 150 mcg for at least 6 months. The control group was comprised of nonusers of contraceptives. Soluble VCAM-1, soluble ICAM-1 and soluble E-selectin were evaluated by enzyme-linked immunosorbent assay. Compared to the control group, a significant decrease was found in VCAM-1 and ICAM-1 concentrations with use of DRSP/20 EE and LNG/30 EE. DRSP/20 EE and LNG/30 EE induce favorable changes in endothelial function. Copyright © 2012 Elsevier Inc. All rights reserved.

[Value of adhesion molecules for evaluating the efficiency of therapy for ulcerative colitis and Crohn's disease].

PubMed

Parfenov, A I; Boldyreva, O N; Ruchkina, I N; Knyazev, O V; Sagynbaeva, V E; Shcherbakov, P L; Khomeriki, S G; Lazebnik, L B; Konoplyannikov, A G

2014-01-01

To define the value of adhesion molecules (sVCAM-1 integrin, P-selectin, E-selectin, and L-selectin) for the prediction and evaluation of the efficiency of treatment in patients with ulcerative colitis (UC) and Crohn's disease. Twenty-six patients with UC and 14 patients with CD were examined. Of them, 16 patients took infliximab (INF) in a dose of 5 mg/kg of body weight according to the standard scheme; 14 patients received cultured mesenchymal stem stromal cells (MSSCs) in a quantity of 150 x 10(8) cells, and 10 had azathioprine (AZA) 2 mg/kg and glucocorticosteroids (GCS) 1 mg/kg of body weight. Enzyme immunoassay was used to determine the serum concentration of the adhesion molecules (L-selectin, E-selectin, P-selectin, and sVCAM-1 integrin) before and 2 months after treatment. The signs of bowel inflammatory disease activity and the elevated levels of adhesion molecules whose synthesis did not occur under normal conditions remained in the patients receiving GCS and AZA. INF treatment caused a decrease in P-selectin, E-selectin, and sVCAM-1 levels to 8.9 +/- 1.0, 5.5 +/- 1.7, and 9.5 +/- 4.4 ng/ml, respectively (p < 0.001). Incorporation of MSSCs was followed by a reduction of the concentrations of P-selectin and E-selectin to 6.9 +/- 1.1 and 5.7 +/- 1.3 ng/ml, respectively (p < 0.001). The level of integrin (cVCAM-1) fell to 12.2 +/- 2.2 ng/ml (p > 0.1); that of L-selectin did not drop after MSSC administration and INF induction therapy. P-selectin, E-selectin, L-selectin, and sVCAM-1 integrin are current inflammatory markers and may be used to evaluate the efficiency of standard and biological therapies for inflammatory bowel diseases and to predict disease course.

Endothelial NOS is required for SDF-1alpha/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells.

PubMed

Kaminski, Alexander; Ma, Nan; Donndorf, Peter; Lindenblatt, Nicole; Feldmeier, Gregor; Ong, Lee-Lee; Furlani, Dario; Skrabal, Christian A; Liebold, Andreas; Vollmar, Brigitte; Steinhoff, Gustav

2008-01-01

In the era of intravascular approaches for regenerative cell therapy, the underlying mechanisms of stem cell migration to non-marrow tissue have not been clarified. We hypothesized that next to a local inflammatory response implying adhesion molecule expression, endothelial nitric oxide synthase (eNOS)-dependent signaling is required for stromal- cell-derived factor-1 alpha (SDF-1alpha)-induced adhesion of c-kit+ cells to the vascular endothelium. SDF-1alpha/tumor necrosis factor-alpha (TNF-alpha)-induced c-kit+-cell shape change and migration capacity was studied in vitro using immunohistochemistry and Boyden chamber assays. In vivo interaction of c-kit+ cells from bone marrow with the endothelium in response to SDF-1alpha/TNF-alpha stimulation was visualized in the cremaster muscle microcirculation of wild-type (WT) and eNOS (-/-) mice using intravital fluorescence microscopy. In addition, NOS activity was inhibited with N-nitro-L-arginine-methylester-hydrochloride in WT mice. To reveal c-kit+-specific adhesion behavior, endogenous leukocytes (EL) and c-kit+ cells from peripheral blood served as control. Moreover, intercellular adhesion molecule-1 (ICAM-1) and CXCR4 were blocked systemically to determine their role in inflammation-related c-kit+-cell adhesion. In vitro, SDF-1alpha enhanced c-kit+-cell migration. In vivo, SDF-1alpha alone triggered endothelial rolling-not firm adherence-of c-kit+ cells in WT mice. While TNF-alpha alone had little effect on adhesion of c-kit+ cells, it induced maximum endothelial EL adherence. However, after combined treatment with SDF-1alpha+TNF-alpha, endothelial adhesion of c-kit+ cells increased independent of their origin, while EL adhesion was not further incremented. Systemic treatment with anti-ICAM-1 and anti-CXCR4-monoclonal antibody completely abolished endothelial c-kit+-cell adhesion. In N-nitro-L-arginine-methylester-hydrochloride-treated WT mice as well as in eNOS (-/-) mice, firm endothelial adhesion of c-kit+ cells

Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.

PubMed

Garnacho, Carmen; Dhami, Rajwinder; Simone, Eric; Dziubla, Thomas; Leferovich, John; Schuchman, Edward H; Muzykantov, Vladimir; Muro, Silvia

2008-05-01

Type B Niemann-Pick disease (NPD) is a multiorgan system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lung is an important and challenging therapeutic target. In this study, we designed and evaluated new delivery vehicles for enzyme replacement therapy of type B NPD, consisting of polystyrene and poly(lactic-coglycolic) acid polymer nanocarriers targeted to intercellular adhesion molecule (ICAM)-1, an endothelial surface protein up-regulated in many pathologies, including type B NPD. Real-time vascular imaging using intravital microscopy and postmortem imaging of mouse organs showed rapid, uniform, and efficient binding of fluorescently labeled ICAM-1-targeted ASM nanocarriers (anti-ICAM/ASM nanocarriers) to endothelium after i.v. injection in mice. Fluorescence microscopy of lung alveoli actin, tissue histology, and 125I-albumin blood-to-lung transport showed that anti-ICAM nanocarriers cause neither detectable lung injury, nor abnormal vascular permeability in animals. Radioisotope tracing showed rapid disappearance from the circulation and enhanced accumulation of anti-ICAM/125I-ASM nanocarriers over the nontargeted naked enzyme in kidney, heart, liver, spleen, and primarily lung, both in wild-type and ASM knockout mice. These data demonstrate that ICAM-1-targeted nanocarriers may enhance enzyme replacement therapy for type B NPD and perhaps other lysosomal storage disorders.

Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells.

PubMed

Park, Eun Hye; Kim, Seokho; Jo, Ji Yoon; Kim, Su Jin; Hwang, Yeonsil; Kim, Jin-Man; Song, Si Young; Lee, Dong-Ki; Koh, Sang Seok

2013-03-01

Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein involved in vascular remodeling, bone formation and developmental morphogenesis. CTHRC1 has recently been shown to be expressed in human cancers such as breast cancer and melanoma. In this study, we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease. CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models. Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness, whereas these cellular activities were diminished by down-regulation of the protein. CTHRC1 activated several key signaling molecules, including Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase and Rac1. Treatment with chemical inhibitors of Src, MEK or Rac1 and expression of dominant-negative Rac1 attenuated CTHRC1-induced cell migration and adhesion. Collectively, our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells.

Erythrocyte plasma membrane-bound ERK1/2 activation promotes ICAM-4-mediated sickle red cell adhesion to endothelium.

PubMed

Zennadi, Rahima; Whalen, Erin J; Soderblom, Erik J; Alexander, Susan C; Thompson, J Will; Dubois, Laura G; Moseley, M Arthur; Telen, Marilyn J

2012-02-02

The core pathology of sickle cell disease (SCD) starts with the erythrocyte (RBC). Aberration in MAPK/ERK1/2 signaling, which can regulate cell adhesion, occurs in diverse pathologies. Because RBCs contain abundant ERK1/2, we predicted that ERK1/2 is functional in sickle (SS) RBCs and promotes adherence, a hallmark of SCD. ERK1/2 remained active in SS but not normal RBCs. β(2)-adrenergic receptor stimulation by epinephrine can enhance ERK1/2 activity only in SS RBCs via PKA- and tyrosine kinase p72(syk)-dependent pathways. ERK signaling is implicated in RBC ICAM-4 phosphorylation, promoting SS RBC adhesion to the endothelium. SS RBC adhesion and phosphorylation of both ERK and ICAM-4 all decreased with continued cell exposure to epinephrine, implying that activation of ICAM-4-mediated SS RBC adhesion is temporally associated with ERK1/2 activation. Furthermore, recombinant ERK2 phosphorylated α- and β-adducins and dematin at the ERK consensus motif. Cytoskeletal protein 4.1 also showed dynamic phosphorylation but not at the ERK consensus motif. These results demonstrate that ERK activation induces phosphorylation of cytoskeletal proteins and the adhesion molecule ICAM-4, promoting SS RBC adhesion to the endothelium. Thus, blocking RBC ERK1/2 activation, such as that promoted by catecholamine stress hormones, could ameliorate SCD pathophysiology.

Curcumin inhibits activation induced by urban particulate material or titanium dioxide nanoparticles in primary human endothelial cells

PubMed Central

Montiel-Dávalos, Angélica; Silva Sánchez, Guadalupe Jazmin; Huerta-García, Elizabeth; Rueda-Romero, Cristhiam; Soca Chafre, Giovanny; Mitre-Aguilar, Irma B.; Alfaro-Moreno, Ernesto; Pedraza-Chaverri, José

2017-01-01

Curcumin has protective effects against toxic agents and shows preventive properties for various diseases. Particulate material with an aerodynamic diameter of ≤10 μm (PM10) and titanium dioxide nanoparticles (TiO2-NPs) induce endothelial dysfunction and activation. We explored whether curcumin is able to attenuate different events related to endothelial activation. This includes adhesion, expression of adhesion molecules and oxidative stress induced by PM10 and TiO2-NPs. Human umbilical vein endothelial cells (HUVEC) were treated with 1, 10 and 100 μM curcumin for 1 h and then exposed to PM10 at 3 μg/cm2 or TiO2-NPs at 10 μg/cm2. Cell adhesion was evaluated by co-culture with U937 human myelomonocytic cells. Adhesion molecules expression was measured by flow cytometry after 3 or 24 h of exposure. Oxidative stress was determined by 2,7-dichlorodihydrofluorescein (H2DCF) oxidation. PM10 and TiO2-NPs induced the adhesion of U937 cells and the expression of E- and P-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1). The expression of E- and P-selectins matched the adhesion of monocytes to HUVEC after 3 h. In HUVEC treated with 1 or 10 μM curcumin, the expression of adhesion molecules and monocytes adhesion was significantly diminished. Curcumin also partially reduced the H2DCF oxidation induced by PM10 and TiO2-NPs. Our results suggest an anti-inflammatory and antioxidant role by curcumin attenuating the activation caused on endothelial cells by exposure to particles. Therefore, curcumin could be useful in the treatment of diseases where an inflammatory process and endothelial activation are involved. PMID:29244817

Glucosamine Treatment-mediated O-GlcNAc Modification of Paxillin Depends on Adhesion State of Rat Insulinoma INS-1 Cells*

PubMed Central

Kwak, Tae Kyoung; Kim, Hyeonjung; Jung, Oisun; Lee, Sin-Ae; Kang, Minkyung; Kim, Hyun Jeong; Park, Ji-Min; Kim, Sung-Hoon; Lee, Jung Weon

2010-01-01

Protein-protein interactions and/or signaling activities at focal adhesions, where integrin-mediated adhesion to extracellular matrix occurs, are critical for the regulation of adhesion-dependent cellular functions. Although the phosphorylation and activities of focal adhesion molecules have been intensively studied, the effects of the O-GlcNAc modification of their Ser/Thr residues on cellular functions have been largely unexplored. We investigated the effects of O-GlcNAc modification on actin reorganization and morphology of rat insulinoma INS-1 cells after glucosamine (GlcN) treatment. We found that paxillin, a key adaptor molecule in focal adhesions, could be modified by O-GlcNAc in INS-1 cells treated with GlcN and in pancreatic islets from mice treated with streptozotocin. Ser-84/85 in human paxillin appeared to be modified by O-GlcNAc, which was inversely correlated to Ser-85 phosphorylation (Ser-83 in rat paxillin). Integrin-mediated adhesion signaling inhibited the GlcN treatment-enhanced O-GlcNAc modification of paxillin. Adherent INS-1 cells treated with GlcN showed restricted protrusions, whereas untreated cells showed active protrusions for multiple-elongated morphologies. Upon GlcN treatment, expression of a triple mutation (S83A/S84A/S85A) resulted in no further restriction of protrusions. Together these observations suggest that murine pancreatic β cells may have restricted actin organization upon GlcN treatment by virtue of the O-GlcNAc modification of paxillin, which can be antagonized by a persistent cell adhesion process. PMID:20829364

Protective effect of co-administration of rosuvastatin and probucol on atherosclerosis in rats.

PubMed

Chen, Zuoyuan; Li, Shan; Zhao, Wenna; Chen, Xiuhua; Wang, Xiaxia

2014-10-01

This study aimed to study the combined effect of rosuvastatin and probucol on atherosclerosis (AS) in rats. In total, 95 male Wistar rats were divided into 5 groups: 25 in the control group (A), 25 in the model group (B), 15 in the rosuvastatin group (C), 15 in the probucol group (D), and 15 in the rosuvastatin combined probucol group (E). A high-lipid diet and vitamin D3 were administered to establish AS rat model. Groups C, D, and E received corresponding drugs. Blood lipids, oxidized low-density lipoprotein (OX-LDL), malonaldehyde (MDA), superoxide dismutase (SOD), adiponectin (APN), and vascular endothelial cadherin (VE-cadherin) were measured. Platelet endothelial cell adhesion molecule-1 (PECAM-1) was detected by immune histochemistry. In groups B-E, AS rat models were successfully constructed. In groups C-E, blood lipids, OX-LDL, VE-cadherin, MDA, PECAM-1, and intimal thickness were decreased (p < 0.01), while SOD and APN were increased (p < 0.05), compared with that in group B. Furthermore, group E had lower levels of OX-LDL, MDA, and PECAM-1 but higher levels of SOD and APN and attenuated intimal thickening compared with groups C or D (p < 0.05). Administering rosuvastatin and probucol could attenuate AS lesions through modulation of oxidative stress, PECAM-1, and APN. Both drugs might help slow the progression of AS.

Bio-active molecules modified surfaces enhanced mesenchymal stem cell adhesion and proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mobasseri, Rezvan; Center for Nanofibers & Nanotechnology, Department of Mechanical Engineering, National University of Singapore, 117576; Tian, Lingling

Surface modification of the substrate as a component of in vitro cell culture and tissue engineering, using bio-active molecules including extracellular matrix (ECM) proteins or peptides derived ECM proteins can modulate the surface properties and thereby induce the desired signaling pathways in cells. The aim of this study was to evaluate the behavior of human bone marrow mesenchymal stem cells (hBM-MSCs) on glass substrates modified with fibronectin (Fn), collagen (Coll), RGD peptides (RGD) and designed peptide (R-pept) as bio-active molecules. The glass coverslips were coated with fibronectin, collagen, RGD peptide and R-peptide. Bone marrow mesenchymal stem cells were cultured on differentmore » substrates and the adhesion behavior in early incubation times was investigated using scanning electron microscopy (SEM) and confocal microscopy. The MTT assay was performed to evaluate the effect of different bio-active molecules on MSCs proliferation rate during 24 and 72 h. Formation of filopodia and focal adhesion (FA) complexes, two steps of cell adhesion process, were observed in MSCs cultured on bio-active molecules modified coverslips, specifically in Fn coated and R-pept coated groups. SEM image showed well adhesion pattern for MSCs cultured on Fn and R-pept after 2 h incubation, while the shape of cells cultured on Coll and RGD substrates indicated that they might experience stress condition in early hours of culture. Investigation of adhesion behavior, as well as proliferation pattern, suggests R-peptide as a promising bio-active molecule to be used for surface modification of substrate in supporting and inducing cell adhesion and proliferation. - Highlights: • Bioactive molecules modified surface is a strategy to design biomimicry scaffold. • Bi-functional Tat-derived peptide (R-pept) enhanced MSCs adhesion and proliferation. • R-pept showed similar influences to fibronectin on FA formation and attachment.« less

Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1.

PubMed

Parmo-Cabañas, Marisa; García-Bernal, David; García-Verdugo, Rosa; Kremer, Leonor; Márquez, Gabriel; Teixidó, Joaquin

2007-08-01

The alpha4beta1 integrin is expressed on thymocytes and mediates cell attachment to its ligands CS-1/fibronectin (CS-1/FN) and VCAM-1 in the thymus. The chemokine CCL25 is highly expressed in the thymus, where it binds to its receptor CCR9 on thymocytes promoting migration and activation. We show here that alpha4beta1 and CCR9 are coexpressed mainly on double- and single-positive thymocytes and that CCL25 strongly stimulates CD4(+)CD8(+) and CD4(+)CD8(-) adhesion to CS-1/FN and VCAM-1. CCL25 rapidly activated the GTPases Rac and Rap1 on thymocytes, and this activation was required for stimulation of adhesion, as detected using the CCR9(+)/alpha4beta1(+) human T cell line Molt-4. To study the role on CCL25-stimulated adhesion of the Rac downstream effector Wiskott-Aldrich syndrome protein family verproline-homologous protein 2 (WAVE2) as well as of Rap1-GTP-interacting proteins, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP-interacting adapter molecule (RIAM), we knocked down their expression and tested transfectant attachment to alpha4beta1 ligands. We found that WAVE2 and RAPL but not RIAM were required for efficient triggering by CCL25 of T cell adhesion to CS-1/FN and VCAM-1. Although Rac and Rap1 activation was required during early steps of T cell adhesion stimulated by CCL25, WAVE2 was needed for the development of actin-dependent T cell spreading subsequent to adhesion strengthening but not during initial alpha4beta1-ligand interactions. These results suggest that regulation by CCL25 of adhesion of thymocyte subpopulations mediated by alpha4beta1 could contribute to control their trafficking in the thymus during maturation, and identify Rac-WAVE2 and Rap1-RAPL as pathways whose activation is required in inside-out signaling, leading to stimulated adhesion.

Inhibition of tumor necrosis factor-{alpha}-induced expression of adhesion molecules in human endothelial cells by the saponins derived from roots of Platycodon grandiflorum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Ji Young; Kim, Dong Hee; Kim, Hyung Gyun

2006-01-15

Adhesion molecules play an important role in the development of atherogenesis and are produced by endothelial cells after being stimulated with various inflammatory cytokines. This study examined the effect of saponins that were isolated from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil saponins (CKS), on the cytokine-induced monocyte/human endothelial cell interaction, which is a crucial early event in atherogenesis. CKS significantly inhibited the TNF{alpha}-induced increase in monocyte adhesion to endothelial cells as well as decreased the protein and mRNA expression levels of vascular adhesion molecule-1 and intercellular cell adhesion molecule-1 on endothelial cells. Furthermore, CKS significantly inhibited themore » TNF{alpha}-induced production of intracellular reactive oxygen species (ROS) and activation of NF-{kappa}B by preventing I{kappa}B degradation and inhibiting I{kappa}B kinase activity. Overall, CKS has anti-atherosclerotic and anti-inflammatory activity, which is least in part the result of it reducing the cytokine-induced endothelial adhesion to monocytes by inhibiting intracellular ROS production, NF-{kappa}B activation, and cell adhesion molecule expression in endothelial cells.« less

Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction.

PubMed

Yan, Meiping; Zhang, Xinhua; Chen, Ao; Gu, Wei; Liu, Jie; Ren, Xiaojiao; Zhang, Jianping; Wu, Xiaoxiong; Place, Aaron T; Minshall, Richard D; Liu, Guoquan

2017-11-01

Intercellular adhesion molecule-1 (ICAM-1) mediates the firm adhesion of leukocytes to endothelial cells and initiates subsequent signaling that promotes their transendothelial migration (TEM). Vascular endothelial (VE)-cadherin plays a critical role in endothelial cell-cell adhesion, thereby controlling endothelial permeability and leukocyte transmigration. This study aimed to determine the molecular signaling events that originate from the ICAM-1-mediated firm adhesion of neutrophils that regulate VE-cadherin's role as a negative regulator of leukocyte transmigration. We observed that ICAM-1 interacts with Src homology domain 2-containing phosphatase-2 (SHP-2), and SHP-2 down-regulation via silencing of small interfering RNA in endothelial cells enhanced neutrophil adhesion to endothelial cells but inhibited neutrophil transmigration. We also found that VE-cadherin associated with the ICAM-1-SHP-2 complex. Moreover, whereas the activation of ICAM-1 leads to VE-cadherin dissociation from ICAM-1 and VE-cadherin association with actin, SHP-2 down-regulation prevented ICAM-1-VE-cadherin association and promoted VE-cadherin-actin association. Furthermore, SHP-2 down-regulation in vivo promoted LPS-induced neutrophil recruitment in mouse lung but delayed neutrophil extravasation. These results suggest that SHP-2- via association with ICAM-1-mediates ICAM-1-induced Src activation and modulates VE-cadherin switching association with ICAM-1 or actin, thereby negatively regulating neutrophil adhesion to endothelial cells and enhancing their TEM.-Yan, M., Zhang, X., Chen, A., Gu, W., Liu, J., Ren, X., Zhang, J., Wu, X., Place, A. T., Minshall, R. D., Liu, G. Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction. © FASEB.

E-selectin ligand-1 (ESL-1) is a novel adiponectin binding protein on cell adhesion.

PubMed

Yamamoto, Hiroyasu; Kuroda, Nana; Uekita, Hiromi; Kochi, Ikoi; Matsumoto, Akane; Niinaga, Ryu; Funahashi, Tohru; Shimomura, Iichiro; Kihara, Shinji

2016-02-05

Adiponectin (APN) is an adipocyte-derived bioactive molecule with anti-diabetic and anti-atherogenic properties. Although anti-diabetic effects are mostly mediated by the adiponectin receptors AdipoR1 and AdipoR2, the anti-atherogenic mechanisms have not been fully elucidated. In this study, we identified E-selectin ligand (ESL)-1 as a novel APN-binding protein by mass spectrometry analysis of HepG2 cell-derived immunoprecipitant with an anti-APN antibody. Cell adhesion assays using fluorescence-labelled monocyte cell line THP-1 cells and human umbilical vein endothelial cells (HUVECs) revealed that APN-pre-treated THP-1 cells had reduced binding ability to HUVECs. This APN-mediated suppressive effect on monocyte binding to endothelial cells was partially abrogated by targeting ESL-1 with shRNA in THP-1 cells. In addition, serial mutagenesis analysis disclosed that five extracellular amino acids close to the N-terminus of ESL-1 were essential for binding with APN. Our results highlight the fact that interaction between APN and ESL-1 could provide a fundamental mechanism underlying the anti-atherogenic properties of APN. Copyright © 2016 Elsevier Inc. All rights reserved.