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PubMed2003

Integrin alpha4beta1 (VLA-4) expression and activity in retinal and peripheral neurons.

The integrin alpha4beta1 fulfills important roles in inflammation and hematopoesis, but its functions in neurons are not well understood. Here we show that the alpha4 subunit is expressed on mouse retinal ganglion cells (RGCs) and undifferentiated retinal neuroblasts during the period of axon extension and migration. To determine if alpha4 integrins expressed by retinal neurons were active, neurons were cultured on known alpha4 ligands in vitro. Recombinant soluble vascular cell adhesion molecule 1 (rsVCAM-1), fibronectin, and osteopontin (OPN) induced neurite outgrowth that was diminished by function blocking antibodies specific for alpha4. Neurite outgrowth on OPN was also blocked by antibodies to the integrin beta1 subunit, implicating the alpha4beta1 heterodimer as one integrin receptor mediating outgrowth on OPN. OPN immunoreactivity was detected in the RGC fiber layer and optic nerve, suggesting that it may act as an alpha4 ligand in vivo. Neurons from chick lumbar sympathetic ganglia, chick dorsal root ganglia, and mouse superior cervical ganglia also extended neurites on rsVCAM-1, suggesting that integrin alpha4beta1 may play a role in the development of multiple neuronal cell types.

Animals↗
PubMed2005

Cooperation of the metalloprotease, disintegrin, and cysteine-rich domains of ADAM12 during inhibition of myogenic differentiation.

The extracellular domain of the mature form of ADAM12 consists of the metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor (EGF)-like domains. The disintegrin, cysteine-rich, and EGF-like fragments have been shown previously to support cell adhesion via activated integrins or proteoglycans. In this study, we report that the entire extracellular domain of mouse ADAM12 produced in Drosophila S2 cells supported efficient adhesion and spreading of C2C12 myoblasts even in the absence of exogenous integrin activators. This adhesion was not mediated by beta1 integrins or proteoglycans, was myoblast-specific, and required the presence of both the metalloprotease and disintegrin/cysteine-rich domains of ADAM12. Analysis of the recombinant proteins by far-UV circular dichroism suggested that the secondary structures of the autonomously expressed metalloprotease domain and the disintegrin/cysteine-rich/EGF-like domains differ from the structures present in the intact extracellular domain. Furthermore, the intact extracellular domain (but not the metalloprotease domain or the disintegrin/cysteine-rich/EGF-like fragment alone) decreased the expression of the cell cycle inhibitor p21 and myogenin, two markers of differentiation, and inhibited C2C12 myoblast fusion. Thus, the novel protein-protein interaction reported here involving the extracellular domain of ADAM12 may have important biological consequences during myoblast differentiation.

3T3 Cells↗
PubMedDate not supplied

NOV/CCN3 induces adhesion of muscle skeletal cells and cooperates with FGF2 and IGF-1 to promote proliferation and survival.

During mammalian development, expression of the Nephroblastoma overexpressed gene (NOV/CCN3) is tightly regulated in skeletal muscles. Ex vivo, ectopic expression of NOV blocks myogenic differentiation. NOV also supports endothelial cell adhesion and angiogenesis through interactions with integrins. Integrins play fundamental roles during myogenesis. In this study, we show that NOV mediates adhesion and spreading of myoblasts. Myoblasts adhesion to NOV does not require proteoglycans and is dependent on integrin beta1, whereas spreading involves another RGD-sensitive integrin. The C-Terminal part of NOV as well as full-length is able to support adhesion of myoblasts; in addition, both increase focal-adhesion kinase (FAK) phosphorylation. Furthermore, NOV is an adhesive substrate that, combined with FGF2 or IGF-1, promotes cell specific proliferation and survival, respectively, in a better way than fibronectin. Taken together, these results identify NOV as an adhesion substrate for myoblasts which, in concert with growth factors, could play a role in the physiology of muscle cells.

Animals↗
PubMed1998

Osteopontin is a ligand for the alpha4beta1 integrin.

Recent work has shown that osteopontin expression is upregulated at sites of cardiovascular injury. It has been hypothesized that osteopontin provides an adhesive matrix for endothelial and smooth muscle cells during remodeling of the vascular wall following injury. Osteopontin has also been found to be synthesized by monocytes and macrophages within injury sites. Here, we present data showing that osteopontin can promote leukocyte adhesion through the alpha4beta1 integrin. In the presence of physiologic concentrations of Mg2+ and Ca2+, osteopontin purified from bovine milk promoted cell-substrate adhesion of HL-60 and Ramos cells, two model leukocyte cell lines. As with other adhesive ligands, adhesion to osteopontin required leukocyte activation. Under these conditions, no adhesion to control substrates such as bovine serum albumin was observed. Leukocyte adhesion was inhibited by anti-integrin antibodies directed at either the alpha4 or beta1 integrin subunits but not by control antibodies directed to other integrins. Further adhesion experiments revealed that leukocyte binding to osteopontin was completely inhibited by an alpha4beta1-binding peptide containing the leucine-aspartate-valine (LDV) sequence, while a control, non-binding peptide containing leucine-glutamate-valine (LEV) had minimal effects. Affinity chromatography using either surface labeled HL-60 or Ramos cell extracts revealed that the alpha4beta1 integrin specifically bound to osteopontin. Immunoprecipitation of eluted fractions from these columns positively identified the alpha4beta1 integrin. In order to localize potential alpha4beta1-binding sites within osteopontin, the protein was proteolytically cleaved with thrombin. A 30 kDa N-terminal osteopontin fragment purified using fast protein liquid chromatography promoted alpha4beta1 dependent leukocyte adhesion in a manner similar to that of the intact protein. These data collectively demonstrate that the alpha4beta1 integrin is a new adhesion receptor for osteopontin and that an alpha4beta1 binding site exists in the NH2-terminal thrombin fragment of osteopontin.

Animals↗
PubMed2000

Role of phosphoinositide 3-kinase and the Cbl adaptor protein in coupling the alpha4beta1 integrin to mitogen-activated protein kinase signalling.

Cell adhesion mediated by beta1 integrin receptors leads to the initiation of intracellular signals that affect cell differentiation and survival. Here we have analysed the mechanism by which the alpha4beta1 integrin activates the mitogen-activated protein kinase pathway in HL60 cells, a myelomonocytic cell line that lacks the expression of focal adhesion kinase. A role for phosphoinositide 3-kinase (PI-3K) in alpha4 integrin-mediated activation of extracellular signal-regulated protein kinase 2 (ERK2) is suggested by the ability of PI-3K inhibitors and a dominant-negative form of the p85 subunit of PI-3K to block the activation of ERK2 by integrin. Stimulation of alpha4beta1 integrins on HL60 cells also leads to increased tyrosine phosphorylation of the 120 kDa adaptor protein Cbl. PI-3K activity associated with Cbl also increases on the stimulation of alpha4beta1 integrins, although immunodepletion experiments suggest that Cbl-associated PI-3K does not account for all of the PI-3K activity induced on the stimulation of integrins in these cells. The expression of wild-type Cbl or the 70Z/3 Cbl mutant enhances basal ERK2 activity in transfectants with a minimal effect on alpha4 integrin-mediated ERK2 activity. In contrast, overexpression of the Hut Cbl truncation mutant, which does not associate with p85, has no effect on the ERK2 pathway. These results suggest that PI-3K has a major role in coupling alpha4beta1 integrins to ERK2 activation in myeloid cells and that the Cbl adaptor protein has a role in basal, but not alpha4beta1 integrin-mediated, activation of ERK2.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Integrin alpha(v)beta1 is an adenovirus coreceptor.

The human embryonic kidney (HEK293) cell line, commonly used for recombinant adenovirus (Ad) propagation, does not express the Ad coreceptor alpha(v)beta3 or alpha(v)beta5 integrins, yet these cells are efficiently infected by Ad vectors. Here we demonstrate that Ad binds to HEK293 cells via the fiber receptor CAR and is subsequently internalized via interaction with integrin alpha(v)beta1. Function-blocking antibodies directed against alpha(v) or beta1, but not beta3, beta5, or alpha5, integrin subunits block Ad infection and viral endocytosis. Therefore, alpha(v)beta1 serves as a coreceptor for Ad infection, and the lack of beta3 and/or beta5 but the relatively high expression of alpha(v)beta1 integrins on certain tumor cell types may explain why these cells are readily transduced by Ad vectors.

Adenoviridae↗
PubMed2003

Reduced expression of the regulatory A subunit of serine/threonine protein phosphatase 2A in human breast cancer MCF-7 cells.

The beta1 subunit of integrin is serine/threonine phosphorylated in growth arrested human breast cancer MCF-7 cells, while it is not in quiescent normal human breast epithelial (HBE) cells. Using the affinity-purified antibodies PB788-9 against the synthetic oligopeptide that contained phosphothreonines corresponding to threonines 788 and 789 on beta1 integrin, beta1 integrin in MCF-7 cells, but not in HBE cells, was found to react with PB788-9. The beta1 integrin immunoprecipitates from HBE cells co-immunoprecipitated the core enzyme of serine/threonine protein phosphatase (PP) 2A, consisting of the regulatory A (PP2A-A) and the catalytic C (PP2A-C) subunits, with the protein phosphatase activity susceptible to okadaic acid (OA), an inhibitor of PP2A and PP1, but not to a PP1 inhibitor. In contrast, beta1 integrin from MCF-7 cells co-immunoprecipitated PP2A-C, but not PP2A-A, with no protein phosphatase activity. Immunoblotting of whole cell lysates revealed that a comparable amount of PP2A-C was present in either HBE or MCF-7 cells, but the amount of PP2A-A was significantly reduced in MCF-7 cells compared to that in HBE cells. The results suggest that the failure of beta1 integrin dephosphorylation at threonines 788 and 789 may be due to a significant reduction in the PP2A-A expression in MCF-7 cells.

Actins↗
PubMed2000

Integrin-like proteins in the pollen tube: detection, localization and function.

The distribution of integrin-like proteins in the pollen tube was examined by immunofluorescent labeling and western blotting techniques using antibodies against human placenta integrin vitronectin receptor (VnR), and alpha(v), beta3 and beta1 integrin subunits. Pseudocolor-coded confocal images showed intense immunostaining within 10 and 5 microm of the tip of the pollen tube in Lilium davidii and Nicotiana tabacum respectively. In both segments the site near the plasma membrane was labeled. Western blotting analyses revealed cross-reaction of anti-beta3, anti-alpha(v) and anti-VnR with the proteins in the plasma membrane preparation of L. davidii and Hemerocallis citrina pollen tube. These studies provide evidence for the first time that the integrin-like protein is present in pollen tubes, and it may be mainly composed of alpha(v) and beta3 subunits in lily pollen tubes. In a functional assay, neither anti-VnR antibody nor the Arg-Gly-Asp-Ser tetrapeptide inhibited pollen tube growth of N. tabacum in vitro, but both of them depressed tube growth on the stigma and in style under quasi in vivo culture conditions. The integrin-like proteins localized in the tip and periphery of the pollen tube appeared to play roles in growth of the pollen tube tip and interaction with the extracellular matrix of the style.

Antibodies, Monoclonal↗
PubMed2006

Regulation of cell-matrix adhesion dynamics and Rac-1 by integrin linked kinase.

Extracellular matrix (ECM) receptors of the integrin family initiate changes in cell shape and motility by recruiting signaling components that coordinate these events. Integrin-linked kinase (ILK) is one such partner of beta1 integrins that participates in dynamic rearrangement of cell-matrix adhesions and cell spreading by mechanisms that are not well understood. To further elucidate the role of ILK in these events, we engineered a chimeric molecule comprising ILK fused to a membrane-targeted green fluorescent protein (ILK-GFP-F). ILK-GFP-F is highly enriched in cell-matrix adhesions, and its expression in fibroblasts leads to an accumulation of focal adhesions (2-5 microm) and elongated adhesions (>5 microm). ILK-GFP-F enhances cell spreading on fibronectin and induces a constitutive increase in the levels of GTP-bound Rac-1. Conversely, ILK knock-down by siRNA transfection decreases active Rac-1. Endogenous ILK was found to associate with PKL (paxillin kinase linker) and the Rac/Cdc42 guanine nucleotide exchange factor betaPIX. Further, expression of a dominant negative betaPIX mutant reversed the increase in active Rac-1 levels of ILK-GFP-F-expressing cells, thus placing betaPIX in the pathway leading from ILK to Rac-1 activation. However, expression of constitutively active Rac only partially restores the spreading defects of ILK-depleted cells, suggesting that an additional ILK-dependent signal is required for cell spreading.

Animals↗
PubMed2001

Increased neutrophil motility by beta-glucan in the absence of chemoattractant.

Systemic candidasis is a life-threatening complication of antibiotic and immunosuppressive therapies and can alter host defense mechanisms through pathways that are poorly understood. Promotion of polymorphonuclear leukocyte (PMN) chemotaxis by beta-glucan towards fMLP or IL-8 gradients demonstrates a fundamental effect on host defenses by pathogenic fungi. The aim of the present study was to determine whether recognition of beta-glucan is sufficient to alter PMN motility in the absence of agonists of G-coupled protein chemotactic receptors. Present findings demonstrate a profound increase in PMN motility by beta-glucan supplementation of a fibronectin substratum in an underagarose migration assay. Motility on beta-glucan included a 3-fold increase in distance of migration, as well as a 5-fold increase in the number of PMNs recruited into the motile phase as compared to motility on fibronectin alone. This promotion of motility is determined by the beta2 integrin complement receptor 3 (CR3) (CD11b/CD18) rather than the beta1 integrin very late antigen 3 (VLA-3), which mediates chemotaxis on beta-glucan-supplemented matrix towards fMLP. PMN motility on beta-glucan-supplemented fibronectin was selectively decreased by inhibitors of pp60 src and ras, whereas motility was promoted by inhibition of p38-MAPK. No effect of these inhibitors was seen on PMNs migrating on fibronectin alone. Migration on beta-glucan-supplemented fibronectin, but not on fibronectin alone, was negatively regulated by protein kinase C (PKC) or cAMP activation. These findings indicate that beta-glucan is sufficient to alter the migratory capacity of PMN in the absence of costimulation by fMLP. Enhanced PMN migration on beta-glucan is mediated through specific integrins and second messenger pathways that are distinct from those utilized by PMNs migrating in the absence of beta-glucan.

CD18 Antigens↗
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↗
PubMed2006

[The role of integrins in the physiologic and pathogenic processes].

Cell adhesion molecules (CAM) are a numerous, diverse group of cell surface proteins, which are both receptors and ligands for receptors. Their functions include adhesion, recognition, cell-cell interaction, and communication between mediate cells and extracellular matrix. The following groups of CAM can be distinguished: seletins, integrins, cadherins and other isoforms, including CD 44. Integrins are heterodimers formed from the alpha and beta chains. The a subclass is responsible for a specific bond with ligands. It defines the specificity of integrins. The 8 chain participates in the integration with cytoskeleton ptoteins. It determines the functions of the integrin receptor. The best recognized integrins include: integrin beta1, beta2 and beta3. The expression and activity of integrins have been found to be affected by a variety of factors being either activators or inhibitors. Adhesion molecules (including integrins) play a significant role in both physiological processes (embryogenesis, organogenesis, the normal growth and tissue development) and pathogenic ones. In the latter case, they are particularly involved in inflammatory, allergic and neoplastic diseases. The role of integrins is also emphasized in organ response to trauma and in skin lesion redevelopment. The knowlegde of the integrin molecular basis and that of other adhesion molecules can contribute significantly to the creation of new diagnostic and therapeutic perspectives. An adequate modification of cellular adhesion constitutes a promising way of the pathogenic processes control.

Animals↗
PubMed2003

Nitric oxide has a role in regulating VLA-4-integrin expression on the human neutrophil cell surface.

Recent research demonstrates that the beta1 integrins may be involved in neutrophil migration. Here, we investigate the role of nitric oxide in the expression and function of the very late antigen-4 (VLA-4) and Mac-1 integrins on human neutrophils. Human blood neutrophils were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) and their adhesion to fibronectin (FN) and serum observed. Adhesion of neutrophils to FN and serum increased significantly following incubation with 0.1mM L-NAME by 65.5 and 44.6%, respectively. Increased adhesions to FN and serum were abolished by a VLA-4-specific monoclonal antibody, HP2/1, and a Mac-1-specific monoclonal antibody, ICRF 44, respectively. The microfilament- and microtubule-depolymerizing agents, dihydrochalasin B and nocodazole, were also able to reverse L-NAME-induced adhesion to both FN and serum. L-NAME induced a discrete increase in the expression of CD49d (VLA-4, 25.3+/-4.8%), but not CD11b, on the neutrophil cell surface, as detected by flow cytometry. Results indicate that NO has a role in regulating VLA-4 and Mac-1 function on the human neutrophil cell surface and that this modulation in integrin function is accompanied by cytoskeletal rearrangements and changes in the ability of the neutrophil to adhere to the extracellular matrix.

Antibodies, Monoclonal↗
PubMed1999

Irradiation induces increase of adhesion molecules and accumulation of beta2-integrin-expressing cells in humans.

PURPOSE: The purpose of our investigation was to describe the dose- and time-dependent histomorphologic alterations of the irradiated tissue, the composition of the infiltrate, and the expression patterns of various adhesion molecules. METHODS AND MATERIALS: We analyzed immunohistochemically alterations in oral mucosa in 13 head and neck cancer patients before radiotherapy and with 30 Gy and 60 Gy. All had oral mucosa irradiation, with a final dose of 60 Gy using conventional fractionation. Snap-frozen specimens were stained using the indirect immunperoxidase technique. Histomorphology was studied in paraffin-embedded sections. In addition, we determined the clinical degree of oral mucositis. RESULTS: Histomorphologic evaluation showed no vascular damage. Irradiation caused a steep increase of beta2-integrin-bearing cells (p < 0.01), whereas the percentage of beta1-integrin-positive cells remained at low levels. Additionally we found an increase in the expression of endothelial intercellular adhesion molecule-1 (ICAM-1) (p < 0.01) and E-selectin (p < 0.05), while endothelial vascular cell adhesion molecule-1 (VCAM-1) expression remained at very low levels. CONCLUSION: Our findings indicate that in radiation-induced oral mucositis there is no marked vascular damage until the end of radiotherapy. For recruitment of leukocytes, beta2 is more involved than beta1. Pharmaceuticals that block leukocyte adhesion to E-selectin or ICAM-1 may prevent radiation-mediated inflammation in oral mucosa.

Aged↗
PubMed2003

The beta1 and beta3 integrins promote T cell receptor-mediated cytotoxic T lymphocyte activation.

Recognition by CD8+ cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that beta1 and beta3 integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC.peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling.

Animals↗
PubMed1997

Ascorbic acid alters collagen integrins in bone culture.

The effects of ascorbic acid on collagen synthesis, mineralization, and integrins were investigated in a mineralizing organ culture system derived from 20-day fetal rat parietal bones. A significant dose-dependent decrease in calcification at 96 h was demonstrated with decreasing concentrations of ascorbic acid (100-0 microg/ml). No effect on DNA content, [3H]thymidine incorporation, or dry weight was found in control (100 microg/ml ascorbic acid) bones compared with bones treated with decreased ascorbic acid concentrations (10, 1, and 0 microg/ml). Collagen synthesis, measured by [3H]proline incorporation, and alpha1(I) procollagen messenger RNA levels were also unaffected. However, ascorbic acid produced a dose-dependent decrease in the hydroxyproline content, with a maximal 76.8% decrease in bones without ascorbic acid compared with the control bones with 100 microg/ml ascorbic acid. Light microscopy of the ascorbic acid-deficient bones revealed a disruption of the osteoblast layer with misshapen osteoblasts and a decrease in the osteoid seam. The loss of osteoblast organization was also confirmed by analyzing the integrins for collagen by Northern and Western blot and immunofluorescence microscopy. A dose-dependent decrease in alpha2 and beta1 integrin messenger RNA levels and in alpha1, alpha2, and beta1 protein were found in 96-h bone cultures deficient in ascorbic acid. These integrin subunits mediate the binding of osteoblasts to collagen. Immunofluorescence microscopy also demonstrated a dose-dependent decrease in alpha2 and beta1 staining of the osteoblast layer. However, the protein levels of alpha3 and alpha5 subunits were not affected. No beta5 was detected, whereas only bones cultured without ascorbic acid demonstrated a small decrease in alpha(v) and beta3 protein levels. The alpha3, alpha5, alpha(v), and beta3 subunits are involved in cell binding to extracellular matrix proteins other than collagen. Thus, the integrins for collagen are down-regulated, probably in response to the underhydroxylated collagen fibrils, which causes a disruption of osteoblast organization leading to a decrease in mineralization of bone. Integrin assays for specific extracellular proteins may be useful tools in detecting matrix defects in various metabolic bone diseases.

Animals↗
PubMed2001

A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins.

Leukocyte adhesion deficiency type I (LAD-1) is a disorder associated with severe and recurrent bacterial infections, impaired extravascular targeting and accumulation of myeloid leukocytes, altered wound healing, and significant morbidity that is caused by absent or greatly diminished surface expression of integrins of the beta2 class. We report clinical features and analysis of functions of cells from a patient with a myelodysplastic syndrome and infectious complications similar to those in the severe form of LAD-1, but whose circulating neutrophils displayed normal levels of beta2 integrins. Analysis of adhesion of these cells to immobilized ligands and to endothelial cells and assays of cell-cell aggregation and chemotaxis demonstrated a profound defect in adhesion mediated by beta2 integrins indicative of a variant form of LAD-1. A novel cell line established from Epstein-Barr virus-transformed lymphoblasts from the subject demonstrated deficient beta2 integrin-dependent adhesive function similar to that of the primary leukocytes. In addition, these cells had markedly impaired beta1 integrin-dependent adhesion. Sequence analysis and electrophoretic mobility of beta1 and beta2 proteins from the cell line demonstrated that the defects were not a result of structural abnormalities in the integrin subunit chains themselves and suggest that the adhesive phenotype of these cells is due to one or more abnormalities of inside-out signaling mechanisms that regulate the activity of integrins of these classes. These features define a unique LAD-1 variant syndrome that may reveal important insights that are generally relevant to inside-out signaling of integrins, a molecular process that is as yet incompletely understood.

CD18 Antigens↗
PubMed2006

Cytotrophoblasts infected with a pathogenic human cytomegalovirus strain dysregulate cell-matrix and cell-cell adhesion molecules: a quantitative analysis.

Studies of intrauterine human cytomegalovirus (CMV) infection have shown suppressed replication in the decidua and placenta of strongly seropositive women. Biopsy specimens often contain CMV virion glycoprotein B and DNA in syncytiotrophoblasts and villus core macrophages without productive infection. Focal replication occurs in placentas of women with low to moderate neutralizing antibody titres. Infected cytotrophoblasts downregulate key adhesion and immune molecules required for invasiveness and maternal immune tolerance and reduce matrix metalloproteinase-9 protein and activity, impairing degradation of the extracellular matrix. Here, we used flow cytometry and quantitative RT-PCR analyses to quantify differentiation molecules expressed in freshly isolated cytotrophoblasts purified from placentas at term and differentiating cells infected in vitro with VR1814, a pathogenic clinical strain. Cell surface proteins including E-cadherin, VE-cadherin, HLA-G, and CMV receptors--epidermal growth factor receptor and integrins beta1 and alphavbeta3--were expressed on purified cells, as were integrins alpha9 and beta6, which were not previously studied. Infected cytotrophoblasts dysregulate the levels of particular cell-matrix and cell-cell adhesion proteins and their transcripts. CMV replication in late gestation placentas with considerable reserves could deplete cytotrophoblast progenitors, thereby impairing syncytiotrophoblast development and increasing the risk of virus transmission to fetal blood vessels.

Cell Adhesion↗