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At least 307 records · Page 17Linked to original sources
PubMed2003

Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin.

Although the alpha 2 beta 1 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that alpha 2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes- and zymosan-induced peritonitis. Since exudative neutrophils of wild-type mice expressed little alpha 2 beta 1 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive alpha 2 beta 1 integrin expression on peritoneal mast cells. Although alpha 2-null mice contain normal numbers of peritoneal mast cells, these alpha 2-null cells do not support in vivo mast cell-dependent inflammatory responses. We conclude that alpha 2 beta 1 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection.

Animals↗
PubMed2001

Rac, a small guanosine triphosphate-binding protein, and p21-activated kinase are activated during platelet spreading on collagen-coated surfaces: roles of integrin alpha(2)beta(1).

In this study, the receptors and signals involved in collagen-induced platelet spreading were examined. It was found that platelet spreading on collagen (presenting a polygon shape with a number of filopodialike projections) was inhibited by the anti-integrin alpha(2) antibody, suggesting the involvement of integrin alpha(2)beta(1) in this process. Studies with a glutathione-S-transferase fusion protein that binds specifically to activated Rac and in vitro p21-activated kinase (PAK) kinase assays revealed that Rac and PAK were activated during this collagen-activated process. Platelet spreading on collagen-coated surfaces was inhibited strongly by PP1 (a Src family kinase inhibitor) or weakly by wortmannin (a phosphatidylinositol 3-kinase [PI3-kinase] inhibitor) but not at all by Y-27632 (a Rho kinase inhibitor). The surfaces coated with anti-integrin alpha(2)beta(1) antibodies also induced platelet spreading (presenting an almost complete round shape) and activation of Rac and PAK, although more slowly than collagen-coated surfaces. The antibody-induced responses were strongly inhibited by PP1 or wortmannin but not by Y-27632. The same concentration of Y-27632 inhibited collagen-induced shape change of platelets in suspension. These findings suggest that Rac and/or PAK activation, but not Rho, may play certain roles in platelet spreading via integrin alpha(2)beta(1) and that Src family kinases and PI3-kinase participate in these processes. Furthermore, the difference between spreading on collagen and the anti-integrin antibody suggests the involvement of other receptor(s) (in addition to the integrin alpha(2)beta(1)) for collagen-induced spreading, the most likely candidate being glycoprotein VI.

Amides↗
PubMed2005

Epidermal growth factor mediates detachment from and invasion through collagen I and Matrigel in Capan-1 pancreatic cancer cells.

BACKGROUND: Pancreatic adenocarcinoma is a highly invasive neoplasm. Epidermal growth factor (EGF) and its receptor are over expressed in pancreatic cancer, and expression correlates with invasion and metastasis. We hypothesized that EGF receptor and integrin signalling pathways interact in mediating cellular adhesion and invasion in pancreatic cancer, and that invasiveness correlates temporally with detachment from extracellular matrix. METHODS: We tested this hypothesis by investigating the role of EGF in mediating adhesion to and invasion through collagen I and Matrigel in the metastatic pancreatic adenocarcinoma cell line Capan-1. Adhesion and invasion were measured using in vitro assays of fluorescently-labeled cells. Adhesion and invasion assays were also performed in the primary pancreatic adenocarcinoma cell line MIA PaCa-2. RESULTS: EGF inhibited adhesion to collagen I and Matrigel in Capan-1 cells. The loss of adhesion was reversed by AG825, an inhibitor of erbB2 receptor signalling and by wortmannin, a PI3K inhibitor, but not by the protein synthesis inhibitor cycloheximide. EGF stimulated invasion through collagen I and Matrigel at concentrations and time courses similar to those mediating detachment from these extracellular matrix components. Adhesion to collagen I was different in MIA PaCa-2 cells, with no significant change elicited following EGF treatment, whereas treatment with the EGF family member heregulin-alpha elicited a marked increase in adhesion. Invasion through Matrigel in response to EGF, however, was similar to that observed in Capan-1 cells. CONCLUSION: An inverse relationship exists between adhesion and invasion capabilities in Capan-1 cells but not in MIA PaCa-2 cells. EGF receptor signalling involving the erbB2 and PI3K pathways plays a role in mediating these events in Capan-1 cells.

Biocompatible Materials↗
PubMed2003

Systematic identification of regulatory proteins critical for T-cell activation.

BACKGROUND: The activation of T cells, mediated by the T-cell receptor (TCR), activates a battery of specific membrane-associated, cytosolic and nuclear proteins. Identifying the signaling proteins downstream of TCR activation will help us to understand the regulation of immune responses and will contribute to developing therapeutic agents that target immune regulation. RESULTS: In an effort to identify novel signaling molecules specific for T-cell activation we undertook a large-scale dominant effector genetic screen using retroviral technology. We cloned and characterized 33 distinct genes from over 2,800 clones obtained in a screen of 7 x 108 Jurkat T cells on the basis of a reduction in TCR-activation-induced CD69 expression after expressing retrovirally derived cDNA libraries. We identified known signaling molecules such as Lck, ZAP70, Syk, PLC gamma 1 and SHP-1 (PTP1C) as truncation mutants with dominant-negative or constitutively active functions. We also discovered molecules not previously known to have functions in this pathway, including a novel protein with a RING domain (found in a class of ubiquitin ligases; we call this protein TRAC-1), transmembrane molecules (EDG1, IL-10R alpha and integrin alpha2), cytoplasmic enzymes and adaptors (PAK2, A-Raf-1, TCPTP, Grb7, SH2-B and GG2-1), and cytoskeletal molecules (moesin and vimentin). Furthermore, using truncated Lck, PLC gamma 1, EDG1 and PAK2 mutants as examples, we showed that these dominant immune-regulatory molecules interfere with IL-2 production in human primary lymphocytes. CONCLUSIONS: This study identified important signal regulators in T-cell activation. It also demonstrated a highly efficient strategy for discovering many components of signal transduction pathways and validating them in physiological settings.

Antigens, CD↗
PubMed1996

Expression of beta 1 integrins in human endometrial stromal and decidual cells.

The present study was undertaken to investigate the expression of beta1 integrins in human endometrium and decidua using flow cytometry, immunohistochemistry, and immunoprecipitation. Fluorescence-activated flow cytometry demonstrated the greater expression of the beta 1, alpha 1, alpha 2, and alpha 5 subunits of the beta1 integrin family in cultured stromal cells from the midsecretory phase, than in those of the early proliferative phase. The addition of estradiol (E2) and progesterone (P) to cultured stromal cells in the early proliferative phase increased the expression of beta1 integrins in vitro. The immunohistochemical distribution of beta1 integrins demonstrated predominantly glandular epithelial staining in the proliferative phase, and mesenchymal and glandular staining in the midsecretory phase. Flow cytometry also demonstrated the expression of the beta 1, alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of beta 1 integrin family in cultured decidual cells, and the enriched-fraction of prolactin (PRL)-producing decidual cells isolated by Percoll gradients showed high levels of beta 1, integrins expression. Immunohistochemistry confirmed the beta 1 integrin cell surface phenotypes in cultured decidual cells observed by flow cytometry. Autoradiography of immunoprecipitate subjects to SDS-PAGE revealed three major polypeptides with molecular weights of 130 kDa (beta 1 subunit), 165 kDa (alpha 2 subunit), and 210 kDa (alpha 1 subunit) under reducing conditions. In summary, the present study demonstrated that endometrial stromal and decidual cells expressed beta1 integrin subunits at their surfaces. The expression exhibited a variability throughout the menstrual cycles, being predominantly detected in the secretory phase, and was maintained highly in the decidua. Thus, beta 1 integrins in human endometrium and decidua may be important in mediating the organization of extracellular matrix proteins derived from embryos during the early stage of implantation.

Abortion, Therapeutic↗
PubMed2005

Tumour necrosis factor alpha confers an invasive, transformed phenotype on mammary epithelial cells.

Although loss of cell-cell adhesion and gain of invasive properties play a crucial role in the malignant progression of epithelial tumours, the molecular signals that trigger these processes have not been fully elucidated. In light of the well-established relationship between chronic inflammation and cancer, we hypothesized that pro-inflammatory cytokines disrupt epithelial-cell adhesion and promote cell migration. To test this hypothesis, we used an in vitro model in which 31EG4-2A4 mouse mammary epithelial cells grown in a collagen gel form compact spheroidal colonies. Among the several cytokines examined, tumour necrosis factor alpha (TNF-alpha) caused a pronounced 3D scattering of preformed epithelial-cell colonies and induced 31EG4-2A4 cells grown on top of a collagen gel to invade the underlying matrix. In addition, TNF-alpha abolished contact-mediated inhibition of cell proliferation and stimulated cell growth both in the absence of exogenous mitogens and under anchorage-independent conditions. TNF-alpha induced the expression of matrix metalloproteinase 9 (MMP-9). Addition of the MMP inhibitor BB-94 abrogated TNF-alpha-induced 3D scattering. TNF-alpha also enhanced the attachment of 31EG4-2A4 cells to type-I collagen and markedly increased the expression of the alpha2 integrin subunit. Addition of a blocking antibody to beta1-integrin or of rhodocetin (a specific alpha2beta1 antagonist) to collagen-gel cultures abrogated 3D scattering. Collectively, these results demonstrate an essential role for MMPs and alpha2beta1 integrin in the invasive response of 31EG4-2A4 cells to TNF-alpha. We propose that the biological activities described in this study contribute to the ability of TNF-alpha to promote tumour progression and cancer-cell dissemination.

Animals↗
PubMed1995

Integrin alpha 2 I-domain is a binding site for collagens.

Integrins alpha 1 beta 1 and alpha 2 beta 1 are major cellular receptors for collagens. The alpha 1 and alpha 2 subunits contain a approximately 200 amino acid inserted domain (I-domain) in their N-terminal region and, because of the homology between the I-domains and the collagen-binding A-domains of von Willebrand factor, it has been suggested that the I-domains might mediate the collagen-binding functions of alpha 1 beta 1 and alpha 2 beta 1. In order to fully investigate this hypothesis, we have generated recombinant human alpha 2 I-domain (r alpha 2I) by reverse transcriptase-polymerase chain reaction/bacterial expression and tested its ability to mediate the collagen-binding functions of alpha 2 beta 1. R alpha 2 I binds specifically to type I collagen in a concentration-dependent manner: binding is cation dependent and, like the complete receptor, is supported by magnesium and manganese ions but not by calcium ions. R alpha 2I is recognised by anti-functional anti-alpha 2 monoclonal antibodies 6F1, 5E8 and P1E6 in capture ELISAs, and anti-functional antibodies inhibited r alpha 2I-collagen binding. In addition, r alpha 2I inhibits cell spreading on collagen. R alpha 2I is therefore a collagen-binding domain and can account for many of the collagen-binding functions of integrin alpha 2 beta 1. We have also determined the collagen specificity of r alpha 2I and found that it binds types I, II and XI collagen.

Animals↗
PubMed2000

Collagen degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells.

Cell migration is a key event in many biological processes and depends on signals from both extracellular matrix and soluble motogenic factors. During atherosclerotic plaque development, vascular smooth muscle cells migrate from the tunica media to the intima through a basement membrane and interstitial collagenous matrix and proliferate to form a neointima. Matrix metalloproteinases have previously been implicated in neointimal formation and in this study smooth muscle cell adhesion and migration on degraded collagen have been evaluated. Vascular smooth muscle cells adhered to native intact collagen type I and to its first degradation by-product, 3/4 fragment (generated by collagenase-3 cleavage), unwound at 35 degrees C to mimic physiological conditions. PDGF-BB pre-treatment induced a fourfold stimulation of smooth muscle cell motility on the collagen 3/4 fragment whereas no increase in smooth muscle cell motility on collagen type I was observed. Cell migration on collagen type I was mediated by alpha2 integrin, whereas PDGF-BB-stimulated migration on the 3/4 collagen fragment was dependent on alphavbeta3 integrin. alphavbeta3 integrin was organised in clusters concentrated at the leading and trailing edges of the cells and was only expressed when cells were exposed to the 3/4 collagen fragment. Tyrphostin A9, an inhibitor of PDGF receptor-beta tyrosine kinase activity, resulted in complete abolition of migration of PDGF-BB treated cells on collagen type I and 3/4 fragment. These results strongly support the hypothesis that the cellular migratory response to soluble motogens can be regulated by proteolytic modification of the extracellular matrix.

Anticoagulants↗
PubMed2006

Differential expression of platelet glycoprotein Ia/IIa in Taiwan Chinese corresponds to glycoprotein ia gene polymorphisms.

Glycoprotein (GP) Ia/IIa plays a key role in platelet function by acting as a primary receptor for subendothelial collagen, thereby contributing to arterial thrombosis. In this study, we found that the expression level of platelet GPIa/IIa among Taiwan Chinese varies over sixfold and this difference relates either to the GPIa gene 807 C/T dimorphisms or the appearance of BglII restriction sequence within intron G. This is the first study to demonstrate the wide variation of platelet GPIa/IIa density in an Oriental population and its correlation to the GPIa gene polymorphisms. These results provide useful tools for predicting platelet GPIa/IIa density of Chinese.

Adult↗
PubMed2002

Platelet dysfunction in Chediak-Higashi syndrome-affected cattle.

A serious symptom of cattle affected with Chediak-Higashi syndrome (CHS) is a bleeding tendency. This diathesis is characterized by insufficient platelet aggregation as a result of depressed response to collagen. One possible cause for the depression is a decrease in contribution of endogenous agonists such as ADP or thromboxane A(2), which are released following collagen stimulation. However, these endogenous agonists play only a minor role in collagen-induced aggregation of bovine platelets. More importantly, activation of phospholipase C as a result of a direct action of collagen is depressed, leading to a depression of Ca(2+) mobilization, in platelets from CHS-affected cattle. Several types of collagen receptor are proposed to work in concert to induce aggregation. Among them, glycoprotein VI (GPVI) and GPIa/IIa (integrin alpha2 beta1) have been supposed to play dominant roles in collagen-induced aggregation. However, there are arguments about the role of each receptor, especially the role of GPIa/IIa, and the crosstalk between receptors. Recently, we reported that the Ca(2+) signaling produced by rhodocytin, which had been first reported to be an agonist for the collagen receptor GPIa/IIa, produced much less Ca(2+) signaling in CHS platelets than in normal ones, whereas that produced by GPVI activators was normal. These suggest that GPIa/IIa or the rhodocytin-associated pathway is impaired in CHS platelets. CHS platelets are valuable to reassess the mechanism of collagen-dependent signal transduction system and to delineate the inter-relationship among collagen receptors.

Animals↗
PubMed1999

B1 integrin activation inhibits in vitro tube formation: effects on cell migration, vacuole coalescence and lumen formation.

Human endothelial cells (EC), when plated onto gels of extracellular matrix proteins such as Matrigel or collagen form capillary tubes in a process thought to mimic angiogenesis. We have shown previously that the extent of tube formation and the phenotype of the lumen are regulated by integrins (Gamble et al 1993) and lumen formation occurs through a process of vacuolization, coalescence and ultimate directional fusion of these vacuoles with the plasma membrane (Meyer 1997 et al). We now show here that activation of beta1 integrins on endothelial cells inhibits tube formation. On collagen gels, endothelial cells treated with 31 activating antibody 8A2 failed to migrate into the gel and tube formation was inhibited. Although several integrins mediate EC attachment to collagen alpha2beta1 is the chief determinant of EC behaviour since a blocking antibody to (alpha2beta1 reversed the effect of 8A2. On Matrigel tube formation was also inhibited by 8A2 treatment although cell alignment and sprout formation was still evident. Electron microscopy revealed the organisation of normal numbers of cells into solid sprouts and the formation of small intracellular vacuoles suggesting that initial stages of tube formation including cell migration were unaffected. However, beta1 integrin activation inhibited the coalescence of these small vacuoles into larger vacuoles, the recruitment of more cells into the sprout and the subsequent formation of mature lumen. The inhibition of capillary tube formation by beta1 activation was time dependent and long lasting. The critical time for activation of the beta1 integrin was the initial 1-2h after plating in order to inhibit tube formation although once activated, the beta1 mediated inhibition on Matrigel was still evident 4 days later. Our results suggest that beta1 integrins are critical in capillary tube formation in at least two phases. beta1 integrins are essential for migration of EC through collagen gels. Independently, beta1 integrins, although not involved in initial vacuole formation, are involved in the process of vacuole coalescence and subsequent lumen formation since beta1 integrin activation inhibits these processes.

Antibodies, Monoclonal↗
PubMed1996

Alpha 2 beta 1 integrin is required for the collagen and FGF-1 induced cell dispersion in a rat bladder carcinoma cell line.

We have investigated the role of integrins in the epithelial to mesenchymal transition (EMT) induced by either collagen or fibroblast growth factor-1 (FGF-1) in the rat bladder carcinoma cell line NBT-II. The major collagen-binding receptor is the alpha 2 beta 1 integrin. An increase in expression of alpha 2 beta 1 integrin coincided with EMT induced by either collagen or FGF-1. When both inducers were present, a further increase in alpha 2 expression was observed which correlated with an enhancement in the speed of locomotion. Overexpression of human alpha 2 in NBT-II cells did not trigger EMT but rendered cells more sensitive to the dispersing effect of collagen and FGF-1. Anti-human alpha 2 blocking antibodies affected cell scattering and motility induced by either collagen or FGF-1. These data demonstrate that alpha 2 beta 1 integrin is the mediator of the cell scattering effect induced by collagen. They also indicate that a functional alpha 2 integrin is essential for the motile behavior of NBT-II cells during the FGF-1 induced EMT.

Animals↗
PubMed1999

Keratinocyte growth factor (KGF) promotes keratinocyte cell attachment and migration on collagen and fibronectin.

Keratinocyte growth factor (KGF) induction of keratinocyte attachment and migration on provisional and basement membrane proteins was examined. KGF-treated keratinocytes showed increased attachment to collagen types I and IV and fibronectin, but, not to laminin-1, vitronectin, or tenascin. This increase was time- and dose-dependent. Increase in attachment occurred with 2 10 microg/ml of ECM proteins. This KGF-stimulated cell attachment was beta1 integrin-dependent but was not associated with stimulation of the cell surface expression nor affinity (activity) of the collagen integrin receptor (alpha2beta1) nor the fibronectin integrin receptors (alpha5beta1 or alphav). At the basal layer of KGF-treated cells significant accumulation of beta1 integrins was found at the leading edges, and actin stress fibers colocalized with beta1. KGF also induced migratory phenotype and stimulated keratinocyte migration on both fibronectin and collagen types I and IV but not on laminin-1, vitronectin nor tenascin. The results suggest that in addition to its proliferation promoting activity. KGF is able to modulate keratinocyte adhesion and migration on collagen and fibronectin. Our data suggest that KGF induced integrin avidity (clustering), a signaling event, which is not dependent on the alteration of cell surface integrin numbers.

Antigens, CD↗
PubMed2004

Association of the gene polymorphisms of platelet glycoprotein Ia and IIb/IIIa with myocardial infarction and extent of coronary artery disease in the Korean population.

Platelet membrane receptor glycoproteins (GP) are essential for the platelet activation process, and the genetic polymorphisms in the genes that encode platelet glycoproteins have been proposed to influence the risk of acute coronary syndrome and atherosclerosis. In this study, we investigated the role of GPIa, HPA-1 and HPA-3 polymorphisms as putative risk factors for myocardial infarction (MI) and the extent of coronary artery disease. We selected 1,073 subjects who underwent coronary angiography; 242 had normal or minimal coronary atherosclerosis, and 831 patients had significant coronary artery disease (CAD). The genotype was determined by the methods of single base extension for C807T/G873A polymorphisms of GPIa, and restriction fragment length polymorphism for HPA-1 and HPA-3. The C807T and G873A polymorphisms of GPIa showed complete linkage in the Korean population. For HPA-1 gene polymorphism, only the HPA-1a/a (PlA1/A1) genotype was observed in 192 selected subjects from our study population. The distribution of GPIa (C807T/G873A) and HPA-3 genotypes did not differ significantly between normal subjects and CAD subjects. No significant association between MI and both gene polymorphisms was present. However, for the subgroup analysis of young male patients whose age was less than 56 years, the genotype frequency of HPA-3b/b was significantly lower in patients with MI compared to patients without a history of MI (7.5% vs. 20.0%, p=0.04). The odds ratio for HPA-3 b homozygosity versus the HPA-3a carrier was 0.32 (95% CI, 0.10- 0.99, p=0.04). Conclusively, HPA-3 polymorphism was associated with MI in Korean individuals younger than 56 years of age, but other polymorphisms of GP, which we studied, were not associated with both the extent of coronary atherosclerosis or MI.

Aged↗
PubMed2000

Potent costimulation of effector T lymphocytes by human collagen type I.

Purified, resting peripheral blood T lymphocytes were previously reported to undergo beta(1) integrin-dependent activation when cultured with anti-CD3 mAb coimmobilized with fibronectin, but not type I collagen. However, the extravascular T cells that encounter immobilized extracellular matrix proteins and are involved in disease pathogenesis have different properties from resting peripheral blood cells. In this study, we confirm that resting CD4(+) and CD8(+) T cells from peripheral blood are costimulated by immobilized fibronectin, but not type I collagen. In contrast, Ag- or mitogen-stimulated CD4(+) and CD8(+) T cell lines, used as models of the effector cells involved in disease, are more potently costimulated by type I collagen than fibronectin. The collagen-induced effects are similar in assays with serum-free medium and in more physiological assays in which anti-CD3 mAb is replaced by a threshold concentration of Ag and irradiated autologous PBMC as APC. The responses are beta(1) integrin dependent and mediated largely by very late Ag (VLA) 1 and 2, as shown by their up-regulation on the T cell lines as compared with freshly purified resting PBL, and by the effects of blocking mAb. Reversed phase HPLC located the major costimulatory sequence(s) in the alpha1 chain of type I collagen, the structure of which was confirmed by amino acid sequencing. The results demonstrate the potential importance of type I collagen, an abundant extracellular matrix protein, in enhancing the activation of extravascular effector T cells in inflammatory disease, and point to a new immunotherapeutic target.

Adjuvants, Immunologic↗
PubMed2004

The alpha 1 beta 1 and alpha E beta 7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties.

Dendritic cells (DCs) are a heterogeneous population of APCs with critical roles in T cell activation and immune regulation. We report in this study the identification and characterization of a novel subset of DCs resident in skin-draining peripheral lymph nodes of normal mice. This subset of CD11c(high)CD40(high)CD8alpha(intermediate (int)) DCs expresses the collagen-binding integrin, alpha1beta1, and the E-cadherin-binding integrin, alphaEbeta7. Although alpha1beta1 and alphaEbeta7 are also expressed on CD11c(high)CD40(int)CD8alpha(high) lymphoid DCs, CD11c(high)CD40(high)CD8alpha(int) DCs demonstrate preferential integrin-mediated adhesion to collagen and fibronectin. This DC subset most likely acquires expression of these integrins in peripheral lymph node, as this subset is not found in the spleen or mesenteric lymph node, and recent DC migrants from the skin lack expression of alpha1beta1 and alphaEbeta7 integrins. Resident CD40(high) DCs express alpha1beta1 integrin and colocalize with collagen in lymph nodes. When compared with CD11c(high)CD40(high)CD8alpha(int) DCs lacking expression of these integrins, the alpha1beta1+alphaEbeta7+DC subset exhibits more efficient formation of Ag-independent conjugates with T cells, and a decreased ability to acquire soluble Ag. Thus, the alpha1beta1 and alphaEbeta7 integrins define a unique population of peripheral lymph node-derived DCs with altered functional properties and adhesive potential that localizes these cells to sites in lymph nodes where Ag presentation to T cells occurs.

Animals↗