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PubMed2001

An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase.

Membrane type-1 matrix metalloproteinase (MT1-MMP) and alpha(v)beta(3) integrin are both essential to cell invasion. Maturation of integrin pro-alpha(v)chain (pro-alpha(v)) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light alpha chains. Our report presents evidence of an alternative pathway of pro-alpha(v) processing involving MT1-MMP. In breast carcinoma MCF7 cells deficient in MT1-MMP, pro-alpha(v) is processed by a conventional furin-like PC, and the mature alpha(v) integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp(891). In contrast, in cells co-expressing alpha(v)beta(3) and MT1-MMP, MT1-MMP functions as an integrin convertase. MT1-MMP specifically cleaves pro-alpha(v), generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu(892). PC-cleavable alpha(3) and alpha(5) but not the PC-resistant alpha(2) integrin subunit are also susceptible to MT1-MMP cleavage. These novel mechanisms involved in the processing of integrin alpha subunits underscore the significance and complexity of interactions between MT1-MMP and adhesion receptors and suggest that regulation of integrin functionality may be an important role of MT1-MMP in migrating tumor cells.

Amino Acid Sequence↗
PubMed1993

Characterization of a cDNA encoding the beta-chain of baboon receptor glycoprotein GPIb.

A cDNA probe, encoding part of the baboon integrin polypeptide, GPIIb, was used to screen a cDNA library derived from baboon platelet polyadenylated mRNA. One cross-hybridizing clone was found to be 94% similar to a human cDNA encoding the beta-chain of the receptor for von Willebrand factor, a major component of the platelet-subendothelium attachment mechanism.

Amino Acid Sequence↗
PubMed2002

Biochemical engineering of the acyl side chain of sialic acids stimulates integrin-dependent adhesion of HL60 cells to fibronectin.

Sialylation of glycoproteins and glycolipids plays an important role during development, regeneration and pathogenesis of several diseases. The physiological precursor of all sialic acids is N-acetyl- D-mannosamine. The N-acyl side chain of sialic acid can be modified by exposure of cells to synthetic N-acyl-modified D-mannosamines. In a new experimental approach cells were cultivated in the presence of N-propanoyl- D-mannosamine. This unnatural precursor of sialic acid is taken up by cells and efficiently metabolized to the respective N-acyl-modified neuraminic acid in vitro and in vivo. Here we report on the biological consequences of the incorporation of the unnatural N-propanoylneuraminic acid into glycoconjugates of HL60 cells. Biochemical engineering of the acyl side chain of neuraminic acids activates beta(1)-integrins (VLA4 or VLA5), resulting in an increased adhesion of HL60 cells to fibronectin.

Blotting, Western↗
PubMed1995

Differential expression of laminin chains and their integrin receptors in human gastric mucosa.

The proliferating cells of the gastric mucosa are found among the pit and mucous neck cells. These cells migrate upward to renew the surface epithelium and downward to restitute the glandular cells. As the epithelial basement membranes (BMs) function as substrate for cell adhesion and migration as well as signals for their differentiation, we studied, by indirect immunofluorescence microscopy, the distribution of different laminin chains and their integrin receptors in adult human stomach. The immunoreactivity for laminin alpha 2 chain localized to the BMs of glands and the lower parts of the gastric pits whereas the laminin alpha 3 chain (laminin-5/kalinin) immunoreactivity was strictly confined to BMs underneath the surface epithelium and the upper parts of the pits. Proliferating mucosal epithelial cells, identified by Ki-67 antibodies, were confined to the areas containing both alpha 2 and alpha 3 laminin chains. The alpha 1, beta 1, and gamma 1 laminin chains were found in all BMs of the mucosa whereas the beta 2 chain was prominent in mucosal blood vessels and also detectable in some glands. Among the laminin integrin receptors, the alpha 3 and beta 4 subunits were seen to be expressed in cells along the BMs with the alpha 3 laminin chain. The alpha 6 integrin, on the other hand, was seen in all gastric epithelia. The present results demonstrate that in the adult human stomach laminin alpha 2 and alpha 3 chains show zonal distribution in BM underlying gastric mucosal epithelium whereas other laminin chains show a more general distribution.

Adult↗
PubMed1992

Adhesion of T and B lymphocytes to extracellular matrix and endothelial cells can be regulated through the beta subunit of VLA.

Investigating the regulation of very late antigen (VLA)-mediated functions, we found that TS2/16, a mAb directed against the beta chain of the VLA group of integrins, can induce binding of resting peripheral blood lymphocytes, cloned T lymphocytes, and Epstein Barr virus-transformed B cells to extracellular matrix components, fibronectin, laminin, and collagen, but not to fibrinogen. The antibody stimulates VLA-4-, VLA-5-, and VLA-6-mediated binding. Furthermore, it induces VLA-4-mediated binding to vascular cell adhesion molecule-1 expressed by rTNF-alpha-stimulated endothelial cells, but it does not stimulate homotypic aggregation of cells as described for a number of anti-VLA-4 alpha antibodies (Bednarczyk, J.L., and B. W. McIntyre. 1990. J. Immunol. 144: 777-784; Campanero, M. R., R. Pulido, M. A. Ursa, M. Rodríguez-Moya, M. O. de Landázuri, and F. Sánchez-Madrid. 1990. J. Cell Biol. 110:2157-2165). Therefore, the stimulating activity of this anti-beta 1 antibody clearly contrasts with that of the anti-VLA-4 alpha antibodies, which induce homotypic cell aggregation, but not binding of cells to extracellular matrix components or endothelial cells, indicating that TS2/16 may generate different signals. The observation that also F(ab')2 or Fab fragments of this anti-beta 1 antibody stimulate binding to extracellular matrix components and endothelial cells excludes the possibility that binding requires receptor crosslinking, or is Fc receptor mediated. Induction of this adhesion is cation and energy dependent and requires an intact cytoskeleton. Although changes in the conformation of VLA integrins induced by this antibody may regulate their functional activity, the dependence on metabolic energy indicates that intracellular processes may also play a role.

Antibodies, Monoclonal↗
PubMed2001

Localization of matrix metalloproteinases on endometrial cancer cell invasion in vitro.

OBJECTIVES: In this study, we have established an in vitro three-dimensional (3D) coculture, where normal endometrial stromal cells and endometrial cancer cells were cocultured under defined hormonal conditions, to investigate the potential paracrine effects on synthesis and secretion of matrix metalloproteinases (MMPs) and, thus, cancer invasion. METHODS: Endometrial stromal cells were obtained by biopsy, cultured in the presence of 100 nM estrogen for 3 days, and then mixed with extracellular matrix (ECM) composed of collagen I and matrigel in a 4:1 ratio. After 3 more days in culture, a 3D coculture was established with HEC-1A cells, an endometrial adenocarcinoma cell line, grown on top of the mixture under various ovarian steroids (no steroid, 100 nM beta-estradiol (E2), or 1.0 microM progesterone (P4)) for 10 days. The expression and localization of MMP-2, MMP-9, and integrin beta 3 subunit were visualized by immunocytochemistry and analyzed by reverse transcription polymerase chain reaction (RT-PCR). The extent of cancer invasion was quantified by Boyden's chamber assay. RESULTS: Integrin beta 3 subunit was localized along the cell surface of HEC-1A cell under all three hormonal conditions. MMP-2 was located in the cytoplasm of stromal cells and on the surface of HEC-1A cells. Synthesis and secretion of stromal MMP-2 were increased in the presence of ovarian steroids. In contrast, expression of stromal MMP-9 was suppressed in the presence of ovarian steroids. No MMPs were synthesized in HEC-1A cells. Invasion assay revealed that HEC-1A cells achieved high tumoral invasiveness in the presence of beta-estradiol. CONCLUSIONS: These findings suggest that stromal cell-derived MMP-2 is translocated to the surface of HEC-1A cells. Integrin beta 3 subunit might contribute, in part, to providing a binding site for MMP-2. Thus, HEC-1A cells invade by recruiting MMP-2 secreted by stromal cells, which is greatly enhanced in the presence of beta-estradiol. The 3D coculture provides an excellent experimental system in which single parameters can be isolated from a complex in vivo system in the process of endometrial cancer invasion.

Adenocarcinoma↗
PubMed2002

Decreased stroma adhesion capacity of CD34+ progenitor cells from mobilized peripheral blood is not lineage- or stage-specific and is associated with low beta 1 and beta 2 integrin expression.

Molecular mechanisms leading to mobilization of hematopoietic cells from bone marrow (BM) to peripheral blood (PB) involve modulation of adhesion molecule expression on these cells that probably result in changes in adhesion capacity to the microenvironment. However, it is not clear whether these changes involve different stages or lineages of progenitor cells. In this study, we compared the capacity of mature and immature clonogenic progenitor cells from granulocyte colony-stimulating factor (G-CSF)-mobilized PB and normal BM CD34+ cells to adhere to complete marrow stroma. This functional capacity was assessed concurrently with molecular expression on CD34+ cells of integrins VLA-4 (alpha 4/beta 1), VLA-5 (alpha 5/beta 1), and LFA-1 (alpha L/beta 2) by interindividual (between mobilized PB and normal BM) and intraindividual (between mobilized PB and steady-state BM and PB in the same patient) analysis. The proportion of adherent clonogenic progenitor cells was significantly lower in PB than in BM, not only for total progenitor cells but also for mature and immature progenitor cells, and the difference was found for granulocytic and particularly for erythroid lineages. The lower adhesion capacity of PB CD34+ cells to stroma was associated with decreased expression (signal/noise MFI ratio) of integrin alpha 4, beta 1, alpha L, and beta 2 chains whereas that of alpha 5 chain did not differ from BM cells with the lowest expression level. Similar differences in integrin expression levels were also found between mobilized PB and steady-state BM CD34+ cells in the same patient except for the alpha L chain. Moreover, we demonstrated for the first time a strong positive correlation between mobilizing capacity and expression levels on mobilized CD34+ cells for the LFA-1 alpha L chain but not for VLA-4 or VLA-5. In conclusion, the decreased adhesion capacity of mobilized PB progenitor cells to stroma involves different maturation stages and different lineages. This is associated with down-regulation of integrins VLA-4 and LFA-1, but mobilizing capacity appears positively correlated with LFA-1 levels.

Antigens, CD34↗
PubMed1991

Distinct determinants on collagen support alpha 2 beta 1 integrin-mediated platelet adhesion and platelet activation.

Recent studies have revealed that the sequence of amino acids asp-gly-glu-ala represents an essential determinant of the site within the alpha 1(I)-CB3 fragment of collagen recognized by the alpha 2 beta 1 integrin cell surface collagen receptor (Staatz et al., 1991). Studies employing chemical modifications of collagen amino acid side chains confirm both the essential nature of the acidic side chains of aspartic acid and glutamic acid residues and the nonessentiality of lysine epsilon-amino groups in supporting adhesion mediated by the alpha 2 beta 1 integrin. The approach also indicates the presence of a distinct determinant on collagen separate from the alpha 2 beta 1 recognition site that contains essential lysine side chains and that is necessary for subsequent interactions with the platelet surface that give rise to collagen-induced platelet activation and secretion. The two-step, two-site model for cellular signaling involving both an integrin and a signal-transducing coreceptor suggested by these data may be common to other integrin-mediated processes.

Acetylation↗
PubMed1993

Neutrophils and neutrophil-endothelial cell adhesion in adult respiratory distress syndrome.

The neutrophil has been implicated as a pivotal player in the pathogenesis of adult respiratory distress syndrome (ARDS) and multiple organ failure. An important first step in the process of neutrophil-mediated organ injury involves the binding of neutrophils to endothelial cells. This process is largely regulated by complementary adhesion molecules, some of which are present constitutively on the cell surface and others that can be up-regulated in response to chemotactic and proinflammatory stimuli. Several different adhesion molecules have been described. The leukocyte integrins consist of a common beta 2 chain (CD18) covalently linked to one of three different alpha chains (CD11a, CD11b, CD11c). CD11a/CD18 is expressed on all leukocytes, whereas CD11b/CD18 and CD11c/CD18 are restricted to cells of myeloid origin. CD11b/CD18 is involved in transendothelial migration and adherence-dependent formation of reactive oxygen species. Recently, a relationship between CD11b/CD18 expression, as an indication of neutrophil activation, and the development of ARDS has been suggested. The potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. Protective effects with anti-CD18 antibodies have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries. Blockage of CD18, however, would affect all leukocytes, as would antibodies to CD11a/CD18. Targeting CD11b/CD18 would affect cells of the myeloid lineage only, which could prove to be beneficial. Anti-CD11b treatment has been used effectively to reduce tissue injury initiated by ischemia-reperfusion, complement activation, and endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Regulation of integrin alpha 5 beta 1 affinity during myogenic differentiation.

The antigen recognized by U1 alpha, a monoclonal antibody to the alpha chain of a chicken integrin fibronectin receptor, was identified as alpha 5. It identifies the same polypeptide as antisera raised to a sequence from the alpha 5 cytoplasmic domain. The U1 alpha antibody has the unusual functional property for alpha chain antibodies of enhancing the binding of alpha 5 beta 1 for its ligand fibronectin. U1 alpha was used to examine the function of alpha 5 beta 1 during myogenic differentiation. As myogenic cells differentiated from replicating myoblasts to bipolar myocytes there was a decrease in their adhesion to the substrate caused by inactivation of alpha 5 beta 1, which could be reversed by treatment of the cells with U1 alpha. The U1 alpha induced increased adhesion to fibronectin but did not inhibit the differentiation process as measured by formation of myotubes. However, U1 alpha did interfere with both cell migration and morphogenesis of myotubes. The resulting myotubes were smaller, more branched, and showed less regular alignment of nuclei. The results suggest that the ability of the cell to regulate alpha 5 beta 1 affinity is critical to myogenic morphogenesis.

Animals↗
PubMed2005

Identification of expressed genes in carp (Cyprinus carpio) head kidney cells after in vitro treatment with immunostimulants.

We analysed a total of 530 expressed genes from the head kidney cells of common carp (Cyprinus carpio) treated by immunostimulants. Sequences of the cDNA clones were compared with sequences in the GenBank database. Immune-related genes identified after in vitro stimulation of carp head kidney cells were: BPI/LBP, C-type lectins, fucolectins, CC-chemokine, CXC-chemokine, CD18, cyclophilin, FcgammaR, G-CSFR, HSP 70, Ig heavy and light chains, NITR, integrin beta2-alpha, Mx, interleukin-1beta, beta thymosin, lysozyme G & C, MHC class II associated invariant chain 1 and 2, granulin, CAAT binding protein and tumour necrosis factor-alpha induced protein. The expression of these immune-related genes may be important for estimating the efficacy of immunostimulants.

Adjuvants, Immunologic↗
PubMed1992

Functional role of alpha 2/beta 1 and alpha 4/beta 1 integrins in leukocyte intercellular adhesion induced through the common beta 1 subunit.

Whereas all of the integrins in the VLA protein subfamily are involved in cell-extracellular matrix interactions, only VLA-4 (through the alpha 4 subunit) has been implicated in the triggering of intercellular adhesion. Here we describe that the VLA protein beta 1 subunit (CD29) is also involved in the induction of homotypic cell aggregation. We have obtained three novel anti-beta 1 monoclonal antibodies (mAb) with the ability to induce cell aggregation on different leukocyte cell types. These mAb recognize an antigenic site on the common beta 1 chain of VLA proteins which is topographically and/or functionally distinct from other epitopes previously defined by several prototype anti-beta 1 mAb. Induction of cell aggregation by anti-beta 1 mAb is epitope specific, isotype and Fc independent, and displays kinetics similar to alpha 4-mediated aggregation. This cell aggregation requires an intact cellular metabolism, the presence of divalent cations in the extracellular medium, and the integrity of the cytoskeleton. We also have found that the Na+/H+ antiporter may be essential for this process. For Ramos cells, which bear only the VLA alpha 4/beta 1 heterodimer, intercellular adhesion induced through the VLA-beta 1 chain could be selectively inhibited by other anti-beta 1 mAb as well as by anti-alpha 4 mAb. Interestingly, anti-beta 1 mAb which induced strong aggregation of VLA-alpha 2- or VLA-alpha 4-transfected K562 cells, had minimal effect on the alpha 2- alpha 4- alpha 5+ K562 cell line. Furthermore, the beta 1-mediated induction of cell aggregation on alpha 2-K562- and alpha 4-K562-transfected cells was blocked by preincubation with either anti-alpha 2 or anti-alpha 4 mAb, respectively, as well as by other anti-beta 1 mAb. Interestingly, parental K562 cells were able to interact with both alpha 2- and alpha 4-transfected K562 cells, thus suggesting that counter-receptors for both integrins (VLA-2 and VLA-4) might exist on these cells. Together these results provide strong evidence supporting the involvement of alpha 2/beta 1 and alpha 4/beta 1 heterodimers in intercellular interactions and underline the pivotal role of the common beta 1 chain of VLA proteins in the integrin-mediated induction of cell aggregation.

Animals↗
PubMed2003

Redox regulation of surface protein thiols: identification of integrin alpha-4 as a molecular target by using redox proteomics.

Thiols affect a variety of cell functions, an effect known as redox regulation. We show here that treatment (1-2 h) of cells with 0.1-5 mM N-acetyl-L-cysteine (NAC) increases surface protein thiol expression in human peripheral blood mononuclear cells. This effect is not associated with changes in cellular glutathione (GSH) and is also observed with a non-GSH precursor thiol N-acetyl-D-cysteine or with GSH itself, which is not cell-permeable, suggesting a direct reducing action. NAC did not augment protein SH in the cytosol, indicating that they are already maximally reduced under normal, nonstressed, conditions. By using labeling with a non permeable, biotinylated SH reagent followed by two-dimensional gel electrophoresis and analysis by MS, we identified some of the proteins associated with the membrane that are reduced by NAC. These proteins include the following: integrin alpha-4, myosin heavy chain (nonmuscle type A), myosin light-chain alkali (nonmuscle isoform), and beta-actin. NAC pretreatment augmented integrin alpha-4-dependent fibronectin adhesion and aggregation of Jurkat cells without changing its expression by fluorescence-activated cell sorter, suggesting that reduction of surface disulfides can affect proteins function. We postulate that some of the activities of NAC or other thiol antioxidants may not only be due to free radical scavenging or increase of intracellular GSH and subsequent effects on transcription factors, but could modify the redox state of functional membrane proteins with exofacial SH critical for their activity.

Acetylcysteine↗
PubMed1996

Attachment, invasion, chemotaxis, and proteinase expression of B16-BL6 melanoma cells exhibiting a low metastatic phenotype after exposure to dietary restriction of tyrosine and phenylalanine.

We previously reported that low levels of tyrosine (Tyr) and phenylalanine (Phe) alter the metastatic phenotype of B16-BL6 (BL6) murine melanoma and select for tumor cell populations with decreased lung colonizing ability. To more specifically characterize the effects of Tyr and Phe restriction on the malignant phenotype of BL6, we investigated in vitro attachment, invasion, proteinase expression, and chemotaxis of high and low metastatic BL6 variants. High metastatic variant cells were isolated from subcutaneous tumors of mice fed a nutritionally complete diet (ND cells) and low metastatic variant cells were isolated from mice fed a diet restricted in Tyr and Phe (LTP cells). Results indicate that attachment to reconstituted basement membrane (Matrigel) was significantly reduced in LTP cells as compared to ND cells. Attachment to collagen IV, laminin, and fibronectin were similar between the two variants. Invasion through Matrigel and growth factor-reduced Matrigel were significantly decreased in LTP cells as compared to ND cells. Zymography revealed the presence of M(r) 92,000 and M(r) 72,000 progelatinases, tissue plasminogen activator, and urokinase plasminogen activator in the conditioned medium of both variants; however, there were no differences in activity of these secreted proteinases between the two variants. Growth of the variants on growth factor-reduced Matrigel similarly induced expression of the M(r) 92,000 progelatinase. The variants exhibited similar chemotactic responses toward laminin. However, the chemotactic response toward fibronectin by LTP cells was significantly increased. MFR5, a monoclonal antibody which selectively blocks function of the alpha 5 chain of the alpha 5 beta 1 integrin, VLA-5, decreased the chemotactic response toward fibronectin of ND cells by 37%; the chemotactic response by LTP cells was reduced by 49%. This effect was specific for fibronectin-mediated chemotaxis since the chemotaxis toward laminin and invasion through Matrigel were not altered by the presence of MFR5. The surface expression of VLA-5 was significantly increased in LTP cells as compared to ND cells by flow cytometric analysis. These observations suggest that limitation of Tyr and Phe either directly modifies BL6 or selects for subpopulations with altered in vitro invasion, chemotaxis, and integrin expression.

Animals↗
PubMed2001

Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array.

BACKGROUND: A number of changes in gene expression have been described in abdominal aortic aneurysms (AAAs), but the spectrum of molecular alterations in this disease is unknown. The purpose of this study was to characterize the expression of approximately 1000 gene products in human AAA tissue and to compare the profile of genes expressed in AAAs with that observed in normal aorta. MATERIALS AND METHODS: Total RNA was isolated from abdominal aortic wall tissues (4 AAAs and 4 normal aortas), and array-specific [(32)P]-labeled complementary DNA (cDNA) probes were created with reverse transcription. The cDNA probes were hybridized with nylon membranes containing an array of 1176 cDNA clones (AtlasArray Human 1.2 I; Clontech, Palo Alto, Calif), and autoradiographs were scanned to identify the patterns of gene expression characteristic of each tissue type. Densitometric analysis was used to standardize the expression of individual genes to a panel of housekeeping controls, and differential gene expression was defined by a signal ratio of at least 2:1. RESULTS: One hundred forty-five (12.3%) of the 1176 genes were consistently expressed in aortic tissue. Thymosin beta-4 was the most abundant of 101 transcripts detected in both AAAs and normal aorta, whereas 44 genes exhibited differential patterns of expression (39 predominant in AAAs and 5 in normal aorta). Densitometric analysis confirmed differences in expression for 20 of these gene products between AAAs and normal aorta, with the greatest increases seen for myeloid cell nuclear differentiation antigen (31-fold), cathepsin H (30-fold), platelet-derived growth factor-A (23-fold), apolipoprotein E (13-fold), gelatinase B/matrix metalloproteinase-9 (12-fold), and interleukin-8 (11-fold). The only gene products substantially decreased in AAAs were myosin light chain kinase (39-fold) and beta-1 integrin (twofold). AAA tissues thereby exhibited a distinct pattern of gene expression reflecting chronic inflammation, extracellular matrix degradation, atherosclerosis, and smooth muscle cell depletion. CONCLUSIONS: cDNA expression arrays provide a powerful new approach to help identify the molecular mechanisms responsible for aneurysmal degeneration. Further studies will be needed to elucidate the functional and pathophysiologic significance of the individual genes that exhibit altered levels of expression in AAA tissue.

Aged↗
PubMed2002

Bovine CD18 is necessary and sufficient to mediate Mannheimia (Pasteurella) haemolytica leukotoxin-induced cytolysis.

Leukotoxin (Lkt) secreted by Mannheimia (Pasteurella) haemolytica is an RTX toxin which is specific for ruminant leukocytes. Lkt binds to beta(2) integrins on the surface of bovine leukocytes. beta(2) integrins have a common beta subunit, CD18, that associates with three distinct alpha chains, CD11a, CD11b, and CD11c, to give rise to three different beta(2) integrins, CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), and CD11c/CD18 (CR4), respectively. Our earlier studies revealed that Lkt binds to all three beta(2) integrins, suggesting that the common beta subunit, CD18, may be the receptor for Lkt. In order to unequivocally elucidate the role of bovine CD18 as a receptor for Lkt, a murine cell line nonsusceptible to Lkt (P815) was transfected with cDNA for bovine CD18. One of the transfectants, 2B2, stably expressed bovine CD18 on the cell surface. The 2B2 transfectant was effectively lysed by Lkt in a concentration-dependent manner, whereas the P815 parent cells were not. Immunoprecipitation of cell surface proteins of 2B2 with monoclonal antibodies specific for bovine CD18 or murine CD11a suggested that bovine CD18 was expressed on the cell surface of 2B2 as a heterodimer with murine CD11a. Expression of bovine CD18 and the Lkt-induced cytotoxicity of 2B2 cells were compared with those of bovine polymorphonuclear neutrophils and lymphocytes. There was a strong correlation between cell surface expression of bovine CD18 and percent cytotoxicity induced by Lkt. These results indicate that bovine CD18 is necessary and sufficient to mediate Lkt-induced cytolysis of target cells.

Animals↗
PubMed1998

Adhesion and signaling mediated by the cytoplasmic tails of leucocyte integrins.

Integrins not only mediate cell adhesion but also contribute to a variety of other cellular processes including proliferation, cytokine production, cytotoxicity and apoptosis. They act as bi-directional signal transducers, mediating signaling from inside-to-outside the cell and from outside-to-inside the cell. Evidence is emerging that signaling through leukocyte integrins (beta 2 and beta 7) is distinct from signaling by the more widely distributed beta 1 integrins. Here we discuss the role of the cytoplasmic domains of leukocyte integrins and that of cytosolic proteins that bind integrins in mediating signal transduction. Distinct sites in the alpha as well as the common beta chain contribute to this process. We also show that beta 2 integrin distribution on the cell surface is of particular relevance for leukocytes to rapidly alter their adhesive state and display their highly dynamic adhesive behavior. From these and recently published findings the picture is arising that particular cell functions may be supported by integrin-specific signaling pathways.

Amino Acid Sequence↗
PubMed1992

Role of LFA-1 and VLA-4 in the adhesion of cloned normal and LFA-1 (CD11/CD18)-deficient T cells to cultured endothelial cells. Indication for a new adhesion pathway.

Patients with the leukocyte adhesion deficiency (LAD) syndrome have a genetic defect in the common beta 2-chain (CD18) of the leukocyte integrins. This defect can result in the absence of cell surface expression of all three members of the leukocyte integrins. We investigated the capacity of T cell clones obtained from the blood of an LAD patient and of normal T cell clones to adhere to human umbilical vein endothelial cells (EC). Adhesion of the number of LAD T cells to unstimulated EC was approximately half of that of leukocyte function-associated antigen (LFA)-1+ T cells. Stimulation of EC with human rTNF-alpha resulted in an average 2- and 2.5-fold increase in adhesion of LFA-1+ and LFA-1- cells, respectively. This effect was maximal after 24 h and lasted for 48 to 72 h. The involvement of surface structures known to participate in cell adhesion (integrins, CD44) was tested by blocking studies with mAb directed against these structures. Adhesion of LFA-1+ T cells to unstimulated EC was inhibited (average inhibition of 58%) with mAb to CD11a or CD18. Considerably less inhibition of adhesion occurred with mAb to CD11a or CD18 (average inhibition, 20%) when LFA-1+ T cells were incubated with rTNF-alpha-stimulated EC. The adhesion of LFA-1- T cells to EC stimulated with rTNF-alpha, but not to unstimulated EC, was inhibited (average inhibition, 56%) by incubation with a mAb directed to very late antigen (VLA)-4 (CDw49d). In contrast to LAD T cell clones and the LFA-1+ T cell line Jurkat, mAb to VLA-4 did not inhibit adhesion of normal LFA-1+ T cell clones to EC, whether or not the EC had been stimulated with rTNF-alpha. We conclude that the adhesion molecule pair LFA-1/intercellular adhesion molecule (ICAM)-1 plays a major role in the adhesion of LFA-1+ T cell clones derived from normal individuals to unstimulated EC. Adhesion of LFA-1-T cells to TNF-alpha-stimulated EC is mediated by VLA-4/vascular cell adhesion molecule (VCAM)-1 interactions. Since we were unable to reduce significantly the adhesion of cultured normal LFA-1+ T cells to 24 h with TNF-alpha-stimulated endothelium with antibodies that block LFA-1/ICAM-1 or VLA-4/VCAM-1 interactions, and lectin adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 appeared not to be implicated, other as yet undefined cell surface structures are likely to participate in T cell/EC interactions.

Cell Adhesion↗