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PubMed1997

NKRP1A molecule is involved in transendothelial migration of CD4+ human T lymphocytes.

Among human CD4+ T lymphocytes, 5-20% express the C-type lectin molecule NKRP1A. Interestingly, CD4+ NKRP1A+ T lymphocytes express high levels of beta 1 and beta 2 integrins, thus representing a T lymphocyte subset that can possibly adhere and migrate through vascular endothelium. Indeed, resting CD4+ NKRP1A+ lymphocytes, differently from the CD4+ NKRP1A- subset, migrated across endothelial cell monolayers in a Transwell chamber system. This transendothelial migration was strongly reduced after pre-treatment with an anti-NKRP1A monoclonal antibody (mAb). In addition, the NKRP1A negative Jurkatt CD4+ T-cell line that had been stably transfected with NKRP1A cDNA, migrated more rapidly and efficiently than untransfected Jurkatt cells. Finally, mAb-mediated cross-linking of NKRP1A molecule in CD4+ T lymphocytes induced the upregulation of the LFA1 Mg2+ binding site as well as beta 1 and beta 2 integrin chains. Altogether, these findings indicate that NKRP1A molecule is involved in transendothelial migration of resting CD4+ T lymphocytes.

Antigens, Surface↗
PubMedDate not supplied

Quantification of cell adhesion force with AFM: distribution of vitronectin receptors on a living MC3T3-E1 cell.

Distribution of vitronectin (VN) receptors on a living murine osteoblastic cell was successfully measured by atomic force microscopy (AFM). First, the distribution of the integrin beta(5) subunit which constitutes a part of the VN receptor on the cell was confirmed by conventional immunohistochemistry after fixing the cell. To visualize the distribution of the receptor on a living cell by an independent and potentially a more quantitative method, the AFM was used with a microbead attached to the cantilever tip to increase the area of contact and VN was immobilized on the microbead. Force measurements were then performed over a large area of a living murine osteoblastic cell using the microbead covered with VN.

Animals↗
PubMed2003

Investigation of mechanisms involved in phagocytosis of Legionella pneumophila by human cells.

Legionella pneumophila, the causative agent of Legionnaires' disease, is able to survive and multiply efficiently in a variety of mammalian cells. By using in vitro assays, the uptake of L. pneumophila into monocytes has shown to be mediated, at least in part, through attachment of complement-coated bacteria to complement receptors, but complement-independent phagocytosis could also be demonstrated. Since complement levels in the human lung are normally low, the role of complement-dependent phagocytosis in the pathogenesis of Legionnaires' disease is doubtful. However, the contribution of other potential phagocytosis-related host cell surface molecules to the phagocytosis of L. pneumophila has never been investigated. We therefore analyzed the role of complement receptors 1 (CD35) and 3 (CD11b/18), the lipopolysaccharide (LPS) receptor (CD14), the beta(1)-integrin chain of the fibronectin receptor (CD29), the intercellular adhesion molecule 1 (ICAM-1, CD54) and the transferrin receptor (CD71) in the complement-independent uptake of L. pneumophila. To exclude any influence of culture conditions onto phagocytosis rates, we compared a fresh clinical isolate with an agar-adapted isolate of L. pneumophila. In addition, we used three different host cell types (MM6, HeLa and Jurkat cells) expressing different rates of complement receptors. We could show that both strains of L. pneumophila were phagocytized by the three host cell lines to the same extent, but intracellular multiplication was only found in MM6 and, although to a much lesser degree, in Jurkat cells. Preincubation of MM6 cells with monoclonal antibodies directed against the above cited phagocytosis-related receptors did not result in inhibition of L. pneumophila uptake. We therefore conclude that typical phagocytosis-related cell surface receptors are not involved in the complement-independent phagocytosis of L. pneumophila.

Antibodies, Monoclonal↗
PubMed2003

Modulation of adhesion, spreading and cytoskeleton organization of 3T3 fibroblasts by sulfonic groups present on polymer surfaces.

The early phase of 3T3 fibroblast interaction with sulfonated styrene copolymer surfaces, of two sulfonic group densities and thus of differing wettability, was studied. The sulfonic groups present on copolymer surfaces affected the behaviour of cells, i.e. they stimulated cell adhesion, activated cell spreading and influenced cytoskeleton reorganization. The relative number of adhering cells correlated, while the number of spreading cells inversely correlated, with the surface density of sulfonic groups. Cell shape and the pattern of distribution of F-actin, alpha-actinin and vinculin in the interacting cells also depend on the surface density of sulfonic groups. On surfaces of high sulfonic group density, highly polarized cells were observed with F-actin bundles. On surfaces of low sulfonic group density, the cells spread with a square-like morphology with F-actin organized in stress fibres. In contrast, the cells spread poorly on nonsulfonated surfaces and cell adhesion was unaffected by surface wettability. The contribution of alpha(5)beta(1), alpha(4), and beta(5)integrins to the cell interaction with fibronectin (FN) and vitronectin (VN) adsorbed from serum-containing medium on polymer surfaces was examined. Our results suggest that surface sulfonic groups influence the conformation of FN and VN adsorbed on polymer surfaces and, in turn, determine the integrins that are involved in cell adhesion.

3T3 Cells↗
PubMed2004

Leukotriene D4 and eosinophil transendothelial migration, superoxide generation, and degranulation via beta2 integrin.

BACKGROUND: Evidence indicates that cysteinyl leukotriene (cysLT) 1 receptor antagonists possess anti-inflammatory properties in asthmatic patients in vivo. Although the exact mechanisms of these actions remain unknown, cysLTs regulate the locomotion and functions of eosinophils. We previously reported that leukotriene D4 augments the expression of eosinophil beta2 integrin and the adhesion of eosinophils to rh intercellular adhesion molecule 1 via beta2 integrin. OBJECTIVE: To examine whether leukotriene D4 modifies the transendothelial migration (TEM) and effector functions of eosinophils. METHODS: We evaluated the effects of leukotriene D4 on (1) eosinophil TEM across human umbilical vein endothelial cells, (2) superoxide anion (O2-) generation, and (3) eosinophil-derived neurotoxin release in eosinophils isolated from the blood of healthy individuals. RESULTS: Leukotriene D4 (0.1-1 microM) significantly induced eosinophil TEM, O2- generation, and eosinophil-derived neurotoxin release. Pranlukast, a cysLT1 receptor antagonist, significantly inhibited all of these parameters, although the inhibitory effect on O2- generation was partial. All of these responses were significantly inhibited by anti-beta2 integrin but not by anti-alpha4 integrin antibodies. CONCLUSIONS: Leukotriene D4 directly up-regulates the TEM and effector functions of eosinophils mainly via the cysLT1 receptor and beta2 integrin. These effects of leukotriene D4 probably contribute to the manifestation of eosinophil inflammation in asthmatic airways.

Adult↗
PubMed2001

Chlamydia pneumoniae-infected monocytes exhibit increased adherence to human aortic endothelial cells.

Interactions between monocytes and endothelial cells play an important role in the pathogenesis of atherosclerosis, and monocyte adhesion to arterial endothelium is one of the earliest events in atherogenesis. Work presented in this study examined human monocyte adherence to primary human aortic endothelial cells following monocyte infection with Chlamydia pneumoniae, an intracellular pathogen associated with atherosclerosis by a variety of sero-epidemiological, pathological and functional studies. Infected monocytes exhibited enhanced adhesion to aortic endothelial cells in a time- and dose-dependent manner. Pre-treatment of C. pneumoniae with heat did not effect the organism's capacity to enhance monocyte adhesion, suggesting that heat-stable chlamydial antigens such as chlamydial lipopolysaccharide (cLPS) mediated monocyte adherence. Indeed, treatment of monocytes with cLPS was sufficient to increase monocyte adherence to endothelial cells, and increased adherence of infected or cLPS-treated monocytes could be inhibited by the LPS antagonist lipid X. Moreover, C. pneumoniae-induced adherence could be inhibited by incubating monocytes with a mAb specific to the human beta 2-integrin chain, suggesting that enhanced adherence resulted from increased expression of these adhesion molecules. These data show that C. pneumoniae can enhance the capacity of monocytes to adhere to primary human aortic endothelial cells. The enhanced adherence exhibited by infected monocytes may increase monocyte residence time in vascular sites with reduced wall shear stress and promote entry of infected cells into lesion-prone locations.

Antibodies, Monoclonal↗
PubMed2004

Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma.

The oncogene c-maf is translocated in approximately 5%-10% of multiple myelomas. Unexpectedly, we observed c-maf expression in myeloma cell lines lacking c-maf translocations and in 50% of multiple myeloma bone marrow samples. By gene expression profiling, we identified three c-maf target genes: cyclin D2, integrin beta7, and CCR1. c-maf transactivated the cyclin D2 promoter and enhanced myeloma proliferation, whereas dominant inhibition of c-maf blocked tumor formation in immunodeficient mice. c-maf-driven expression of integrin beta7 enhanced myeloma adhesion to bone marrow stroma and increased production of VEGF. We propose that c-maf transforms plasma cells by stimulating cell cycle progression and by altering bone marrow stromal interactions. The frequent overexpression of c-maf in myeloma makes it an attractive target for therapeutic intervention.

Animals↗
PubMed2004

c-maf in multiple myeloma: an oncogene enhancing tumor-stroma interactions.

Gene expression profiling studies reported by Hurt et al. in this issue of Cancer Cell reveal an unexpectedly frequent overexpression of c-maf in multiple myeloma and identify molecular targets of c-maf transactivation. The results define c-maf as a prototype of a class of oncogenes that not only stimulate cell cycle progression, but also promote pathological interactions between tumor and stroma cells.

Cadherins↗
PubMed2005

A controlled study of colonic immune activity and beta7+ blood T lymphocytes in patients with irritable bowel syndrome.

BACKGROUND & AIMS: The mechanisms behind irritable bowel syndrome (IBS) are incompletely understood. Recently several studies have suggested a low-grade colonic inflammation as initiator of the gut dysfunctions recorded in this patient group. The aim of this study was to characterize the phenotype and homing properties of colonic and peripheral blood lymphocytes in patients with IBS. METHODS: Patients with IBS (n=33), defined by the Rome II criteria, were compared with UC patients (n=23) and control subjects (n=15) without gastrointestinal symptoms. Colonic and peripheral blood lymphocytes were analyzed by flow cytometry. Secretion of IFN-gamma from intestinal biopsies was determined by enzyme-linked immunosorbent assay, and immunohistochemical staining of colonic biopsies was performed. RESULTS: IBS patients displayed an increased frequency of peripheral blood CD4+ and CD8+ T cells expressing the gut homing integrin beta7. Accordingly, IBS and UC patients had an augmented frequency of lamina propria CD8+ T cells in the ascending colon as compared with control subjects. The frequency of intestinal T cells expressing integrin beta7+ was unaltered in IBS and UC patients, although the expression of mucosal addressin cell adhesion molecule-1+ endothelium, the ligand for integrin beta7, was increased in the ascending colon of IBS and UC patients as compared with control subjects. CONCLUSIONS: Patients with IBS exhibit an enhanced immune activity in the gut and an increased frequency of integrin beta7+ T lymphocytes in the peripheral blood. Our data further support the hypothesis of IBS being at least partially an inflammatory disorder.

Adult↗
PubMed2006

Importance of force linkage in mechanochemistry of adhesion receptors.

The alpha subunit-inserted (I) domain of integrin alphaLbeta2 [lymphocyte function-associated antigen-1 (LFA-1)] binds to intercellular adhesion molecule-1 (ICAM-1). The C- and N-termini of the alpha I domain are near one another on the "lower" face, opposite the metal ion-dependent adhesion site (MIDAS) on the "upper face". In conversion to the open alpha I domain conformation, a 7 A downward, axial displacement of C-terminal helix alpha7 is allosterically linked to rearrangement of the MIDAS into its high-affinity conformation. Here, we test the hypothesis that when an applied force is appropriately linked to conformational change, the conformational change can stabilize adhesive interactions that resist the applied force. Integrin alpha I domains were anchored to the cell surface through their C- or N-termini using type I or II transmembrane domains, respectively. C-terminal but not N-terminal anchorage robustly supported cell rolling on ICAM-1 substrates in shear flow. In contrast, when the alphaL I domain was mutationally stabilized in the open conformation with a disulfide bond, it mediated comparable levels of firm adhesion with type I and type II membrane anchors. To exclude other effects as the source of differential adhesion, these results were replicated using alpha I domains conjugated through the N- or C-terminus to polystyrene microspheres. Our results demonstrate a mechanical feedback system for regulating the strength of an adhesive bond. A review of crystal structures of integrin alpha and beta subunit I domains and selectins in high- and low-affinity conformations demonstrates a common mechanochemical design in which biologically applied tensile force stabilizes the more extended, high-affinity conformation.

Cell Adhesion↗
PubMedDate not supplied

Targeting Beta-3 integrin using a linear hexapeptide labeled with a near-infrared fluorescent molecular probe.

Biomolecules containing the RGD peptide sequence are known to bind integrins with high affinity. Studies of hexa-and hepta-peptides labeled with a near-infrared fluorescent probe (cypate) showed that rearranging the glycine in a linear RGD peptide sequence to form the GRD analogue favored the uptake of the GRD compound by alphavbeta3 integrin receptor (ABIR)-positive A549 tumor cells and tissue. The internalization of the GRD compound in A549 cells and tumor uptake in mice were inhibited by ABIR-avid peptides, suggesting its recognition by this receptor. Further studies with functional blocking antibodies and beta3 knockout cells revealed that beta3 integrin mediates the internalization of the cypate-GRD peptide. Molecular modeling studies supported preferential interaction of the probe with the beta3 subunit of integrins relative to the alphav subunit. The results demonstrate that the cypate-GRD peptide targets beta3 integrin, thereby providing a strategy to monitor drug delivery and efficacy, and physiopathologic processes mediated by this protein.

Animals↗
PubMed2002

Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions.

The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.

Actins↗
PubMed2003

Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1.

Leukocyte functional antigen 1 (LFA-1), with intercellular adhesion molecule ligands, mediates T cell adhesion, but the signaling pathways and functional effects imparted by LFA-1 are unclear. Here, intracellular phosphoprotein staining with 13-dimensional flow cytometry showed that LFA-1 activation induced phosphorylation of the beta(2) integrin chain and release of Jun-activating binding protein 1 (JAB-1), and mediated signaling of kinase Erk1/2 through cytohesin-1. Dominant negatives of both JAB-1 and cytohesin-1 inhibited interleukin 2 production and impaired T helper type 1 differentiation. LFA-1 stimulation lowered the threshold of T cell activation. Thus, LFA-1 signaling contributes to T cell activation and effects T cell differentiation.

Antigens, CD↗
PubMed2005

Flexible, actin-based ridges colocalise with the beta1 integrin on the surface of melanoma cells.

Using a combination of laser-scanning confocal microscopy and atomic force microscopy, we have identified flexible, actin-based structures on the surface of cells derived from the vertical growth phase of melanoma progression. These flexible structures, lacking on the surface of mature melanocytes, were observed on the surface of all four melanoma cell lines tested. Further investigation revealed that the beta1 integrin colocalises with these actin-based ridges on the cell surface, whereas beta1 integrin distribution in melanocytes did not correlate with actin-based structures. Fibronectin staining on the surface of melanoma cells was partially codistributed with the ridges. The combination of structural information derived from atomic force microscopy images and fluorescent imaging of the distribution of labelled proteins involved in invasion and metastasis has allowed us to identify a common feature that may be involved in disease progression, at the surface of vertical growth phase melanoma cells, despite the known variation in genetic composition of melanoma.

Actins↗
PubMed2004

A critical 'threshold' of beta 2-integrin engagement regulates augmentation of cytokine-mediated superoxide anion release.

1. Neutrophil adhesion regulates a number of processes involved in the pathogenesis of inflammatory diseases including rheumatoid arthritis. Neutrophil destructive potential can be modulated by adhesion, allowing alteration of inflammatory cell behaviour while preserving antimicrobial defences. beta(2)-Integrin-mediated neutrophil adhesion to albumin-coated latex beads (ACLB) allows modulation of integrin clustering and ligation and analysis of the effects of adhesion on neutrophil responses. Tumour necrosis factor-alpha (TNF alpha) enhanced neutrophil binding of different diameter ACLB equally, by almost four-fold, and independently of bead size. Adhesion of neutrophils to ACLB caused a size-dependent generation and release of O(2)(-) and also potentiated TNF alpha-induced O(2)(-) release. 2. Binding of ACLB was not affected by disruption of cytoskeletal integrity with nocodazole or cytochalasin D or following blockade of tyrosine kinase activity. In contrast, tyrosine phosphorylation and an intact cytoskeleton were essential for adhesion- and cytokine-induced O(2)(-) release from neutrophils. Inhibition of adhesion- and cytokine-induced O(2)(-) release by 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazol[3,4-d]pyrimidine (PP2) indicated that a Src-family tyrosine kinase was the principal regulatory pathway mediating this response in neutrophils, a distal role for p38 MAPK was revealed by use of SB203580. 3. Tyrosine phosphorylation of c-Fgr, a Src-family tyrosine kinase, occurred following ACLB adhesion and exposure to TNF alpha, and was susceptible to inhibition by PP2. We suggest that activation of the key regulatory enzyme c-Fgr is achieved following ligation of a critical threshold of integrins following binding of large (>3 microM) ACLB.

Binding Sites↗
PubMed2005

Glycoprotein-specific ubiquitin ligases recognize N-glycans in unfolded substrates.

Misfolded or unassembled polypeptides in the endoplasmic reticulum (ER) are retro-translocated into the cytosol and degraded by the ubiquitin-proteasome system. We reported previously that the SCF(Fbs1,2) ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway. Here we investigated how the SCF(Fbs1,2) complexes interact with unfolded glycoproteins. The SCF(Fbs1) complex was associated with p97/VCP AAA ATPase and bound to integrin-beta1, one of the SCF(Fbs1) substrates, in the cytosol in a manner dependent on p97 ATPase activity. Both Fbs1 and Fbs2 proteins interacted with denatured glycoproteins, which were modified with not only high-mannose but also complex-type oligosaccharides, more efficiently than native proteins. Given that Fbs proteins interact with innermost chitobiose in N-glycans, we propose that Fbs proteins distinguish native from unfolded glycoproteins by sensing the exposed chitobiose structure.

Adenosine Triphosphatases↗
PubMed2006

Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects.

We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68+/CD11c+ (myeloid-derived) dermal leukocytes. Because this contrasted with earlier reports of a keratinocyte source, we assessed IL-20 mRNA expression in a variety of cells in vitro, and confirmed a myeloid-derived cellular source (monocytes). Plastic adhesion, activation of beta2 integrins, and incubation with tumor necrosis factor-alpha stimulated expression in these cells. IL-20 receptor (IL-20R)alpha and IL-20Rbeta mRNA was decreased in LS versus NL skin, which also contrasted with earlier findings. To investigate the relationship between IL-20 and disease activity, we examined psoriasis patients treated with the CD2-targeted agent alefacept. In therapeutic responders, lesional IL-20 mRNA decreased to NL levels, suggesting that CD2+ leukocytes may proximally regulate IL-20. Finally, to assess IL-20 function, we used microarrays to screen IL-20-treated keratinocytes, which demonstrated upregulation of disease-related and IFN-gamma-induced genes. Hence, IL-20 may influence inflammation through IFN-like effects. Together, these data indicate that IL-20 may be an important effector cytokine in psoriasis, and that its inhibition may represent a potential therapeutic target.

Adult↗
PubMed2003

The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3.

The integrins alpha(v)beta(1), alpha(v)beta(5), alpha(v)beta(6) and alpha(v)beta(8) have all recently been shown to interact with the RGD motif of the latency-associated peptide (LAPbeta(1)) of transforming growth factor beta(1) (TGFbeta(1)), with binding to alpha(v)beta(6) and alpha(v)beta(8) leading to TGFbeta(1) activation. Previously it has been suggested that the remaining alpha(v) integrin, alpha(v)beta(3,) does not interact with LAPbeta(1). However, here we show clearly that alpha(v)beta(3) does indeed interact with the LAPbeta(1) RGD motif. This interaction is similar to other alpha(v)beta(3) ligands in terms of the cations required for adhesion, the concentrations of LAPbeta(1) required for binding and the ability of a small-molecule inhibitor of alpha(v)beta(3), SB223245, to block the interaction. Using glutathione S-transferase fusion proteins we have mapped a minimal integrin-binding loop in LAPbeta(1) and then used this approach to probe the integrin-binding properties of the equivalent loops in LAPbeta(2) and LAPbeta(3). We show that the RGD motif of LAPbeta(3) also interacts with alpha(v)beta(3), in addition to alpha(v)beta(6), alpha(v)beta(1) and alpha(v)beta(5), whereas the corresponding loop in LAPbeta(2) does not interact with these integrins. These observations therefore correct a previously reported inaccuracy in the literature. Furthermore, they are important as they link alpha(v)beta(3) and TGFbeta, which may have implications in cancer and a number of inflammatory and fibrotic diseases where expression of both proteins has been documented.

Acetates↗