Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion molecules and chemokines contribute to selective eosinophil recruitment in allergic inflammation. In this study, we examined the effects of eotaxin-2, a CCR3-specific chemokine, on integrin-mediated eosinophil adhesion to vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), or both using a parallel plate flow system. Tissue culture plates were coated with various combinations of VCAM-1, ICAM-1, and/or eotaxin-2. Human eosinophils were infused at physiologic shear stress (0.5 dyn/cm(2)) for 10 min, and the numbers of attached eosinophils were monitored using video microscopy. Cells accumulated efficiently on VCAM-1 and even better on surfaces co-coated with VCAM-1 and ICAM-1, but poorly on surfaces coated with ICAM-1 or bovine serum albumin alone. When eotaxin-2 was co-immobilized with adhesion proteins, fewer cells adhered to VCAM-1 and more adhered to ICAM-1, whereas levels of attachment to VCAM-1 plus ICAM-1 showed no net change. However, experiments with adhesion molecule blocking monoclonal antibody showed that the contribution of ICAM-1-mediated adhesion was always greater if eotaxin-2 was present. Pretreatment of cells with a CCR3-blocking mAb, or PD98059, a MAP-kinase inhibitor, prevented the eotaxin-2-induced changes in eosinophil attachment. These data suggest that eotaxin-2, acting via MAP kinases, may facilitate eosinophil recruitment at sites of allergic inflammation by shifting their adhesion molecule usage away from VCAM-1-dominated to ICAM-1-dominated pathways.
Am J Respir Cell Mol Biol 2002 Jun
PMID:Eotaxin-2 alters eosinophil integrin function via mitogen-activated protein kinases. 1203 62

The object of our study was the question about the relevance of the tumor surrounding inflammatory cells with respect to the metastatic potential of the tumor cells. To imitate the role of inflammatory cells, three colon carcinoma (HT-29, HRT-18, and SW-620), one breast carcinoma (MCF-7), and one melanoma (ST-ML-12) cell lines were treated with pro-inflammatory stimuli, LPS, TNF-alpha, or IL-1beta. HUVEC monolayers were then stimulated by the collected supernatants (SN) of the tumor cells, following washing out of the applied stimuli. Analysis of CAM expression on HUVEC was performed using cell enzyme immunoassay. E-selectin, VCAM-1, and, in part, ICAM-1 were significantly up-regulated on HUVEC by exposure to SN of all LPS-stimulated tumor cells. This was especially the case for the colon carcinoma cell lines. A minimal increase of expression of VCAM-1 was observed after exposure to SN from TNF-alpha-stimulated HT-29 and MCF-7 cells. IL-1beta stimulation had no effect on endothelial CAM expression. These observations indicate that LPS could play a crucial role in tumor metastasis by inducing the release of soluble factors from different tumor cell lines capable of up-regulating CAM expression. This might be of special significance in colon carcinomas, where a large source of bacterial LPS is available in the intestinal lumen.
Exp Mol Pathol 2002 Aug
PMID:Effect of pro-inflammatory stimuli on tumor cell-mediated induction of endothelial cell adhesion molecules in vitro. 1212 53

Tranilast [N-(3,4-dimethoxycinnamoyl)anthranilic acid] inhibits vascular inflammation. However, the relevant anti-inflammatory mechanisms are not completely understood. We studied the effects of tranilast on nuclear factor-kappaB (NF-kappaB)-dependent endothelial cell adhesion molecule expression and transcriptional regulation. Cultured human umbilical vein endothelial cells were preincubated with 12.5 to 100 microg/ml tranilast. Tumor necrosis factor-alpha (TNF-alpha)-induced endothelial VCAM-1, ICAM-1, and E-selectin surface expression was inhibited dose dependently. Maximal inhibition achieved with 100 microg/ml tranilast was 38 +/- 6.9, 31.8 +/- 1.5, and 31.9 +/- 1.9%, respectively (mean +/- S.E.M., p < 0.001, n = 5). Secretion of interleukin 6, which is also NF-kappaB-sensitive, was significantly inhibited by tranilast. Endothelial MHC-I expression, which is independent of NF-kappaB, was not inhibited. Although cytokine-induced degradation of NF-kappaB inhibitor proteins (IkappaB-alpha, -beta, and -epsilon), nuclear translocation of NF-kappaB, and binding of NF-kappaB to kappaB cis-acting elements in the adhesion molecule promoters were not affected by tranilast, ICAM-1-kappaB and E-selectin-kappaB reporter gene activity was inhibited by 53% (n = 5, p < 0.01) and 51% (n = 5, p < 0.001), respectively. In contrast, using SP-1 and C/EBP constructs, reporter gene activity was not altered. Expression of the transcriptional coactivator cAMP response element binding protein binding protein (CBP) was inhibited by tranilast, resulting in a loss of interaction between NF-kappaB and CBP. Therefore, in therapeutically relevant concentrations (50 microg/ml), tranilast inhibits NF-kappaB-dependent transcriptional activation by interfering with the NF-kappaB/CBP association. We propose that inhibition of NF-kappaB dependent gene transcription contributes to the anti-inflammatory effects of tranilast.
Mol Pharmacol 2002 Oct
PMID:Tranilast inhibits cytokine-induced nuclear factor kappaB activation in vascular endothelial cells. 1223 32

The integrin VLA-4 (alpha4,beta1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CV of 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.
J Comput Aided Mol Des 2002 Mar
PMID:3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists. 1236 18

Staphylococcal scalded skin syndrome (SSSS) results from the effect of exfoliative-toxins produced by staphylococcal strains. The disease affects predominantly children, and is rare in adults. We report two cases of the adult type of SSSS. Corticotherapy, chronic alcohol abuse and epilepsy-related immune changes might have been predisposing factors in these patients. The immunopathological characteristics of the inflammatory cell infiltrate in adults SSSS have not been thoroughly explored so far in the literature. Biopsies from 2 patients with bullous SSSS skin were studied by means of immunochemistry using a panel of 10 antibodies directed to FXIIIa, CD15, CD31, CD45R0, CD50, CD54, CD62E, CD95, CD106, and L1-protein, respectively. Cutaneous biopsies from related blistering diseases were compared. They included drug-induced toxic epidermal necrolysis (TEN), bullous impetigo and superficial pemphigus. A dense cell infiltrate composed of granulocytes (CD15+), macrophages (L1 protein+) and memory T cells (CD45R0+) and a strong expression of ICAM-3 (CD50) were present in the epidermis. CD95+ keratinocytes were lining the intraepidermal blisters. Type I dermal dendrocytes (Factor XIIIa+) were numerous and plump in the dermis. Bullous impetigo exhibited the same pattern of inflammatory cells, but with a lower density in type I dermal dendrocytes. TEN differed from SSSS by both the absence of CD15+ granulocytes and a stronger expression of the pro-apoptotic CD95 antigen in the epidermis. In superficial pemphigus, CD95 antigen was not expressed, and CD15+ granulocytes, CD45R0+ lymphocytes and L1 protein+ monocytes were much less numerous. It is concluded that the specific binding of SSSS-induced exotoxins to the desmosomes alters the keratinocyte metabolism leading to an inflammatory reaction followed by focal apoptosis. Our findings are in line with the concept that SSSS exotoxins might be superantigens. A common pathomechanism leading to epidermal destruction is likely operative in SSSS and bullous impetigo. The inflammatory cell composition in TEN and superficial pemphigus markedly differs from that in SSSS.
Int J Mol Med 2002 Dec
PMID:Differential pathomechanisms of epidermal necrolytic blistering diseases. 1242 94

The alpha4 integrins (alpha4beta1 and alpha4beta7) are cell surface heterodimers expressed mostly on leukocytes that mediate cell-cell and cell-extracellular matrix adhesion. A characteristic feature of alpha4 integrins is that their adhesive activity can be subjected to rapid modulation during the process of cell migration. Herein, we show that transforming growth factor-beta1 (TGF-beta1) rapidly (0.5-5 min) and transiently up-regulated alpha4 integrin-dependent adhesion of different human leukocyte cell lines and human peripheral blood lymphocytes (PBLs) to their ligands vascular cell adhesion molecule-1 (VCAM-1) and connecting segment-1/fibronectin. In addition, TGF-beta1 enhanced the alpha4 integrin-mediated adhesion of PBLs to tumor necrosis factor-alpha-treated human umbilical vein endothelial cells, indicating the stimulation of alpha4beta1/VCAM-1 interaction. Although TGF-beta1 rapidly activated the small GTPase RhoA and the p38 mitogen-activated protein kinase, enhanced adhesion did not require activation of both signaling molecules. Instead, polymerization of actin cytoskeleton triggered by TGF-beta1 was necessary for alpha4 integrin-dependent up-regulated adhesion, and elevation of intracellular cAMP opposed this up-regulation. Moreover, TGF-beta1 further increased cell adhesion mediated by alpha4 integrins in response to the chemokine stromal cell-derived factor-1alpha. These data suggest that TGF-beta1 can potentially contribute to cell migration by dynamically regulating cell adhesion mediated by alpha4 integrins.
Mol Biol Cell 2003 Jan
PMID:Rapid up-regulation of alpha4 integrin-mediated leukocyte adhesion by transforming growth factor-beta1. 1252 26

Mononuclear cell infiltration of the thyroid is a prominent feature of chronic lymphocytic thyroiditis. Adhesion molecules play a major role in determining the localization of inflammatory mononuclear cells in the thyroid. Previous reports from animal models and human studies have described the thyroidal expression of adhesion molecules only late in clinical disease. In this study, we examined the distribution and kinetics of expression of E-selectin, VCAM-1, LFA-1, and ICAM-1 in the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by dietary iodine. Mice were fed 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin-biotin-peroxidase assay. We found a dramatic increase in E-selectin and VCAM-1 expression on intrathyroidal endothelial cells after 16 weeks of iodine treatment. In addition, we describe for the first time that thyrocytes from the NOD-H2h4 mouse, and the parental NOD, constitutively express ICAM-1 independent of iodine treatment and prior to mononuclear cell infiltration of the thyroid gland. ICAM-1 was not detected on the thyrocytes of other untreated strains of mice, implicating expression of this adhesion molecule as a critical event in the recruitment of inflammatory mononuclear cells to the thyroid.
Exp Mol Pathol 2002 Dec
PMID:Adhesion molecules as susceptibility factors in spontaneous autoimmune thyroiditis in the NOD-H2h4 mouse. 1256 90

With an own histological classification of rheumatoid arthritis (RA) in synovial membranes (SM) of two main types: type I (B-lymphocytic and plasma cellular, local non-destructive, better prognosis); type II (T-lymphocytic, macrophacytic, local destructive, worse prognosis) and type III as a mixed one we examined whether there is a relation between special adhesion molecules and any of this histological types. 32 fresh cryo-conserved RA-SM (type I, II, III; n = 9, 11, 12, respectively) were investigated immunohistochemically using the APAAP method in order to obtain the expression of LFA-1, VCAM-1, CD44 and E-selectin. Positive cells were counted morphometrically within six histological areas: lining layer, subintimal, perivascular, lymphatic follicles, perifollicular and interstitial. Type II showed a significant higher expression than type I for LFA-1 in lining layer and subintimal II (65%; 53% vs 0%; 32%); for VCAM-1 in subintimal, perifollicular, perivascular and interstitial areas (61%, 54%, 58%, 61% vs 6%, 8%, 5%, 6%). In lining layer and lymphatic follicles no significant difference between both types was detected. CD44 and E-selectin: No statistical differences could be found. RA-SM type II shows high expression of LFA-1 and VCAM-1, this is related to a higher destructive process.
Cell Mol Biol (Noisy-le-grand) 2002
PMID:Strong LFA-1 and VCAM-1 expression in histological type II of rheumatoid arthritis. 1264 40

Microvascular complications in sickle cell disease occur as a result of obstruction of small vessels by deoxygenated sickle cells. Cerebrovascular complications are also common and result from obstruction of large blood vessels by thrombosis with changes in vessels that have some similarity to those found in arteriosclerotic vascular disease. Endothelial damage and activation from sickle cell-endothelial interactions may contribute to both. We find that endothelial cells have increased expression of VCAM-1, E-selectin, and ICAM-1 when exposed to sickle blood cells. The concentration-dependent, sickle-induced, adhesion molecule expression is significantly greater than that promoted by normal cells. The time course of Cell Adhesion Molecule (CAM) expression is similar to that induced by TNF-alpha and IL1. Studies after white cell enrichment and reduction suggest leukocytes are the primary mediators. CAM expression by endothelial cells appears stimulated by soluble factors. Antibody inhibition studies support TNF-alpha and IL-1, produced by sickle leukocytes, as the primary soluble factors responsible for the observed CAM expression. Both the induction of endothelial CAM expression and subsequent endothelial adherence of sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
Pediatr Pathol Mol Med
PMID:Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. 1267 44

Eosinophil localization to cholinergic nerves occurs in a variety of inflammatory conditions, including asthma. This localization is mediated by interactions between eosinophil integrins and neuronal vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Eosinophil-nerve cell interactions lead to generation of neuronal reactive oxygen species and release of eosinophil proteins. The effects of eosinophil adhesion on neuronal intracellular signaling pathways were investigated. Eosinophil adhesion to IMR32 cholinergic nerves led to a rapid and sustained activation of the nuclear transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 in the nerve cells. Eosinophil binding to neuronal ICAM-1 led to a rapid activation of ERK1/2 in nerve cells. Inhibition of ERK1/2 prevented NF-kappaB activation. Eosinophil adhesion to VCAM-1 resulted in AP-1 activation, mediated partially by rapid activation of the p38 mitogen-activated protein kinase. These data show that adhesion of eosinophils induces mitogen-activated protein kinase-dependent activation of the transcription factors NF-kappaB and AP-1 in nerve cells, indicating that eosinophil adhesion may control nerve growth and phenotype.
Am J Respir Cell Mol Biol 2004 Mar
PMID:Effect of eosinophil adhesion on intracellular signaling in cholinergic nerve cells. 1285 9


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