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PubMed1996

Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule.

The avidity of integrin adhesion receptors for extracellular ligands is subject to dynamic regulation by intracellular programs that have yet to be elucidated. We describe here a protein, cytohesin-1, which specifically interacts with the intracellular portion of the integrin beta 2 chain (CD18). The molecule shows homology to the yeast SEC7 gene product and bears a pleckstrin homology (PH) domain. Overexpression of either the full-length cytohesin-1 or the SEC7 domain induces beta 2 integrin-dependent binding of Jurkat cells to ICAM-1, whereas expression of the isolated cytohesin-1 PH domain inhibits T cell receptor-stimulated adhesion. Similar inhibition is not exhibited by PH domains taken from other proteins, showing that the interaction is specific and that individual PH domains are capable of discriminating between alternative targets.

Amino Acid Sequence↗
PubMed1996

Generation of mutant cells with constitutively active beta 2-integrin LFA-1.

To elucidate the molecular mechanisms behind regulation of integrin adhesiveness, we have developed a system for the generation of mutant cell lines where the adhesive functions of specific molecules were modulated. The human lymphatic leukemia cell line HPB-ALL was chemically mutagenized and rare cells expressing constitutively active beta 2-integrin LFA-1 (alpha L beta 2, CD11a/CD18) were selected from the pool of mutagenized cells, by repeated cycles of binding to immobilized ICAM-1. The selected population showed 20-fold more binding to ICAM-1 compared to the starting population. A sub-clone of the selected population, termed HAP4, was further analyzed. In contrast to the original cell line, HAP4 had constitutively active LFA-1 and adherence to ICAM-1 was insensitive to inhibition by okadaic acid and cytochalasin B or to inhibition of ATP synthesis. The activation of LFA-1 appeared specific since the cells did not show a general increase in adhesiveness. No major aberration in cell surface carbohydrate expression was found and the expression of cell surface molecules including CD43, CD4, CD8, and MHC class I and II was normal. However, apparent cell surface expression of integrin beta 1 chain was lost and alpha 4 chain was greatly diminished. Our study demonstrates the feasibility of generating cells with mutated adhesive functions and the characterized cells will serve as tools to further dissect the mechanisms underlying integrin regulation.

CD18 Antigens↗
PubMed1990

Mesoderm induction and the control of gastrulation in Xenopus laevis: the roles of fibronectin and integrins.

Exposure of isolated Xenopus animal pole ectoderm to the XTC mesoderm-inducing factor (XTC-MIF) causes the tissue to undergo gastrulation-like movements. In this paper, we take advantage of this observation to investigate the control of various aspects of gastrulation in Xenopus. Blastomeres derived from induced animal pole regions are able, like marginal zone cells, but unlike control animal pole blastomeres, to spread and migrate on a fibronectin-coated surface. Dispersed animal pole cells are also able to respond to XTC-MIF in this way; this is one of the few mesoderm-specific responses to induction that has been observed in single cells. The ability of induced animal pole cells to spread on fibronectin is abolished by the peptide GRGDSP. However, the elongation of intact explants is unaffected by this peptide. This may indicate that fibronectin-mediated cell migration is not required for convergent extension. We have investigated the molecular basis of XTC-MIF-induced gastrulation-like movements by measuring rates of synthesis of fibronectin and of the integrin beta 1 chain in induced and control explants. No significant differences were observed, and this suggests that gastrulation is not initiated simply by control of synthesis of these molecules. In future work, we intend to investigate synthesis of other integrin subunits and to examine possible post-translational modifications to fibronectin and the integrins.

Animals↗
PubMed2005

Evidence for the presence of a low-mass beta1 integrin on the cell surface.

Although the cell line K562 reportedly expresses a single species of beta1 integrin, alpha5beta1, surface staining with monoclonal antibodies JB1A, 12G10 and B3B11 to the beta1 chain clearly demonstrated differences in the expression levels of the epitopes detected by these antibodies. The present studies were initiated to determine the basis for this molecular heterogeneity in the integrins. Cross-linking of surface integrins with B3B11 caused their selective aggregation. This distribution was similar to that observed for the alpha5 chain. In contrast, cross-linking the beta1 chains with 12G10 did not cause codistribution of alpha5, suggesting that these two species were not associated on the cell surface. Immunoprecipitates of the surface integrins of K562 cells indicated the presence of 120 and 140 kDa forms of the beta1 chain which were detected by 12G10 and B3B11, respectively. Immunological, biochemical and mass spectrometric analysis of K562 surface integrins also failed to demonstrate the presence of any alpha chain in association with the 120 kDa species of beta1 of K562 cells. Treatment of the two forms of beta1 with PGNase reduced their masses to approximately 90 kDa, suggesting that N-glycosylation was responsible for the mass differences. Collectively, these results provide evidence for a novel species of beta1 on the cell surface, which does not appear to be associated with any alpha chain. The data also suggest that differences in glycosylation may be involved in defining the association between the integrin alpha and beta chains and the functional properties of these integrins.

Antibodies, Monoclonal↗
PubMed1989

Human melanoma cells express a novel integrin receptor for laminin.

This study sought to determine whether human melanoma cells express integrin-related receptors that mediate their adhesion to laminin. We found that antibodies against the integrin beta 1 chain blocked cell attachment to laminin-coated surfaces. Furthermore, immunofluorescence staining demonstrated beta 1 complexes in vinculin-positive focal adhesion plaques on the basal surface of cells attached to laminin substrates. Chromatography of detergent extracts of 125I-surface-labeled cells on laminin-Sepharose columns recovered two major laminin-binding proteins (100 and 130 kDa, reduced) that bound with high affinity to the columns and were eluted with EDTA. Both proteins were specifically immunoprecipitated from column fractions with monoclonal and polyclonal antibodies to the integrin beta 1 subunit, indicating that they form a noncovalent heterodimer complex. The alpha-like subunit is composed of a 30-kDa light chain that is joined by a disulfide bond to the 100-kDa heavy chain. This complex was not recovered from columns of fibronectin- or collagen type I- or IV-Sepharose. Laminin-binding by the alpha beta 1 complex was independent of Arg-Gly-Asp or Tyr-Ile-Gly-Ser-Arg-like sequences, but required the presence of divalent cations. The 100-kDa alpha-like subunit was electrophoretically and immunochemically distinct from the other known alpha subunits, alpha 1-alpha 6. The results indicate that human melanoma cells express a novel laminin-specific integrin beta 1 complex which may mediate the cells' interactions with this ligand.

Antibodies, Monoclonal↗
PubMed2001

[Effects of transforming growth factor beta 1 on the expression of integrin beta 3 and the activity of focal adhesion kinase on human vascular endothelial cell].

OBJECTIVE: To observe the effects of transforming growth factors beta 1 (TGF beta 1) on the expression of integrin beta 3 and the activity of focal adhesion kinase (FAK). METHODS: This study was performed on cultured human endothelial cells (EC) by using cell-ELISA and immunoprecipitation-tyrosine kinase assay respectively. RESULTS: Under the stimulus of TGF beta 1, there a dose-dependent increase in the expression of integrin beta 3 chain in the surface of EC. And after the cultured EC were treated with 5 ng/ml or 10 ng/ml TGF beta 1 for 6 or 24 hours, the FAK activity in EC increased significantly as compared with the control group (P < 0.05). CONCLUSION: The expression of integrin beta 3 and the activity of FAK on EC were regulated by TGF beta 1, and this regulation may be important in cell adherence, angiogenesis, and in the pathophysiology of atherosclerosis.

Cells, Cultured↗
PubMed1990

Constitutive and induced phosphorylation of the alpha- and beta-chains of the CD11/CD18 leukocyte integrin family. Relationship to adhesion-dependent functions.

We sought to determine whether the activation event which renders the CD11/CD18 leukocyte integrin/Leu-CAM glycoproteins capable of promoting cell to cell adhesion was associated with the induced posttranslational modification of phosphorylation. In neutrophils, two species of alpha-chains, a predominant CD11b 165-kDa subunit and a minor 150-kDa CD11c subunit were found to be constitutively phosphorylated. However, the 95-kDa CD18 common beta-chain was not phosphorylated in resting cells but became strongly phosphorylated in cells incubated with PMA. The beta-chain was phosphorylated in a dose-related manner within 1 min of the addition of PMA, reached maximal intensity between 4 to 10 min, and remained fully phosphorylated at 30 min. The similarities of the kinetics of homotypic aggregation induced by PMA to the time course of phosphorylation suggest that phosporylation may be relevant to at least this type of Leu-CAM-dependent adhesion. In contrast, in the presence of FMLP which induces aggregation with different kinetics than PMA, no phosphorylation of the common beta-chain was observed over a time interval of from 30 s to 10 min further emphasizing the apparent differences in the two modes of activation to an adhesive state. The phosphorylated species on neutrophils were readily detected by immunoprecipitation with each CD18 mAb and most but not all CD11b mAb which otherwise precipitated 125I-labeled CD11b species suggesting that the CD11b alpha-chain labelled with 32P may differ slightly from the 125I-labeled species in terms of its recognition by certain CD11b mAb. In mononuclear cells, similar constitutive phosphorylation of the CD11a and CD11c alpha-chains was observed that remained unchanged in the presence of either FMLP or PMA. As was demonstrated in neutrophils, phosphorylation of the CD18 beta-chains of mononuclear cells was not constitutive but was induced in the presence of PMA and not FMLP. Taken together these data suggest the existence of specific recognition sites on beta-chains for a regulatory kinase-phosphatase system.

Amino Acid Sequence↗
PubMed1992

Nephrotoxic antiserum identifies a beta 1-integrin on rat glomerular epithelial cells.

A postulated mechanism of immune glomerular injury is a direct interaction between antibody and glomerular epithelial cell (GEC) surface antigens. To explore this hypothesis, we examined the interaction of the noncomplement-fixing gamma 2-subclass of sheep anti-rat nephrotoxic serum (NTS), which causes immediate complement- and neutrophil-independent proteinuria in vivo, with rat GECs in culture. Reactivity of NTS with GEC surface antigens was determined by positive immunofluorescence of GEC plasma membranes and by the ability of NTS-coated tissue culture wells to provide an adhesive substrate for GECs. NTS immunoprecipitated two proteins (135 and 118 kDa) from surface-labeled GECs. Proteins of similar molecular mass were precipitated by a polyclonal rabbit antibody that identifies the beta 1-integrin chain of the mouse fibronectin receptor (anti-FnR). In addition, NTS identified similarly sized bands on Western blot analysis of cell membranes from isolated rat glomeruli. Similar reactivity was eluted from the glomeruli of proteinuric rats injected with NTS. NTS significantly inhibited GEC adhesion to laminin, types I and IV collagen, and fibronectin and prevented GEC spreading on types I and IV collagen. Anti-FnR similarly inhibited GEC adhesion. Cell viability was not affected. These results show that NTS recognizes a pair of GEC surface proteins that have the characteristics of an alpha- and beta 1-integrin and, at low concentrations, disrupt cell-matrix interactions.

Animals↗
PubMed1997

Integrin signaling transduces shear stress--dependent vasodilation of coronary arterioles.

A direct relationship exists between shear stress and endothelium-dependent NO-mediated vasodilation of blood vessels. The transduction of shear stress to the biochemical signals resulting in the production of NO is, however, unknown. We tested the hypothesis that integrin binding to Arg-Gly-Asp(RGD) peptide sequences in extracellular matrix proteins is a critical step in initiation of the signaling sequence whereby shear stress activates endothelial tyrosine kinase(s) and induces vasodilation of isolated arterioles. Isolated coronary arterioles were exposed to increasing shear stress under control conditions and in the presence of a synthetic peptide, GRGDNP, to competitively inhibit integrin binding to extracellular matrix proteins containing RGD peptide sequences. Intraluminal GRGDNP (0.1, 0.5, and 1.0 mmol/L) inhibited shear stress-induced vasodilation in a concentration-dependent manner. Application of GRGDNP had no effect on endothelium-dependent relaxation to substance P (10(-12) to 10(-8) mol/L). An inactive structural analogue, GRGESP, did not alter shear stress-induced vasodilation. To further elucidate the integrin involved in shear stress-induced vasodilation, we administered a blocking antibody to the integrin beta 3 chain (F11) and observed significant attenuation of the vasodilation. Shear stress was also associated with an increase in tyrosine kinase activity, as assessed by anti-phosphotyrosine binding. Application of GRGDNP significantly decreased anti-phosphotyrosine binding during shear stress, suggesting a link between tyrosine kinase activation and integrin signaling during this vasodilatory response. Taken together, these results indicate that integrin-matrix interactions, possibly at focal adhesions, are of cardinal importance in the signaling pathway of shear stress-induced vasodilation.

Animals↗
PubMed1996

Monoclonal antibody 2F4/11 recognizes the alpha chain of a porcine beta 2 integrin involved in adhesion and complement mediated phagocytosis.

The characterization of a new mAb, named 2F4/11, specific for porcine myelomonocytic cells is described. This mAb immunoprecipitates a non-covalently linked heterodimer of 155,000/95,000, which is expressed by granulocytes, monocytes and tissue macrophages but not by lymphocytes, erythrocytes or platelets. Immunoblot analysis localizes the 2F4/11 epitope on the largest subunit of the heterodimer. Mab 2F4/11 is able to block phagocytosis of complement-opsonized zymosan particles by PMN granulocytes and alveolar macrophages, as well as adherence to plastic surfaces of PMA-activated PMN. Together, these results suggest that mAb 2F4/11 recognizes the CD11b or alpha chain of the porcine complement type 3 receptor (CR3).

Animals↗
PubMed1999

cDNA cloning and chromosomal localization of human alpha(11) integrin. A collagen-binding, I domain-containing, beta(1)-associated integrin alpha-chain present in muscle tissues.

We previously identified a novel integrin alpha-chain in human fetal muscle cells (Gullberg, D., Velling, T., Sjöberg, G., and Sejersen, T. (1995) Dev. Dyn. 204, 57-65). We have now isolated the full-length cDNA for this integrin subunit, alpha(11). The open reading frame of the cDNA encodes a precursor of 1188 amino acids. The predicted mature protein of 1166 amino acids contains seven conserved FG-GAP repeats, an I domain with a metal ion-dependent adhesion site motif, a short transmembrane region, and a unique cytoplasmic domain of 24 amino acids containing the sequence GFFRS. alpha(11), like other I domain integrins, lacks a dibasic cleavage site for generation of a heavy chain and a light chain, and it contains three potential divalent cation binding sites in repeats 5-7. The presence of 22 inserted amino acids in the extracellular stalk portion (amino acids 804-826) distinguishes the alpha(11) integrin sequence from other integrin alpha-chains. Amino acid sequence comparisons reveal the highest identity of 42% with the alpha(10) integrin chain. Immunoprecipitation with antibodies to alpha(11) integrin captures a 145-kDa protein distinctly larger than the 140-kDa alpha(2) integrin chain when analyzed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions. Fluorescence in situ hybridization maps the integrin alpha(11) gene to chromosome 15q23, in the vicinity of an identified locus for Bardet-Biedl syndrome. Based on Northern blotting, integrin alpha(11) mRNA levels are high in the adult human uterus and in the heart and intermediate in skeletal muscle and some other tissues tested. During in vitro myogenic differentiation, alpha(11) mRNA and protein are up-regulated. Studies of ligand binding properties show that alpha(11)beta(1) binds collagen type I-Sepharose, and cultured muscle cells localize alpha(11)beta(1) into focal contacts on collagen type I. Future studies will reveal the importance of alpha(11)beta(1) for muscle development and integrity in adult muscle and other tissues.

Adult↗
PubMed1991

Involvement of leukocyte (beta 2) integrins (CD18/CD11) in human monocyte tumoricidal activity.

Appropriately activated mononuclear phagocytes mediate contact-dependent tumoricidal activity. Adhesion structures involved in contact-dependent tumor cytotoxicity have not been defined. The present study was aimed at identifying the adhesion structures involved in the tumoricidal activity of activated (IFN-gamma + LPS) human monocytes. Tumor cells of different histological origin were used as targets in a 48-hr cytolysis assay. Anti-CD18 (integrin beta 2 chain) monoclonal antibodies (MAbs) substantially (50-80%) inhibited human monocyte cytotoxicity. When the role of different a-chains was studied, anti-alpha L (CD11a, LFA1), anti-alpha M (CD11b, Mac-1) and anti-alpha X (CD11c, p150,95) caused marginal inhibition, but the effect of the 3 combined was comparable to that of anti-CD18. Anti-CD18 MAb did not affect the release of various cytotoxic molecules (e.g. TNF) by activated human monocytes. Activated monocytes showed augmented binding to target cells and anti-CD18 MAb inhibited the binding of resting and activated monocytes to tumor target cells. While IFN-gamma alone augmented expression of leukocyte integrins and LPS had no effect, the 2 activation signals, combined for optimal stimulation of tumoricidal activity, resulted in no appreciable increase in these leukocyte adhesion molecules, as assessed by flow cytometry. Our results suggest that the augmented CD18-dependent binding of activated monocytes on tumor cells depends mainly upon changes in the adhesive properties of these molecules rather than upon increased numbers on the cell surface. Anti-ICAM-1 MAb significantly reduced monocyte cytotoxicity on tumor cells, which is consistent with a role of the CD11/CD18 adhesion pathway. These results implicate "activated" leukocyte (beta 2) integrins (CD11/CD18) as important adhesion molecules in the contact-dependent tumoricidal activity of human monocytes.

Antibodies, Monoclonal↗
PubMed1994

Porcine platelet antigens recognized by human xenoreactive natural antibodies.

Hyperacute xenograft rejection of porcine organs by primates is initiated by the binding of recipient natural antibodies to endothelium in the donor organ. We showed previously that human natural antibodies recognize 3 porcine endothelial cell glycoproteins with molecular masses of 115 kDa, 125 kDa, and 135 kDa; we called the glycoproteins gp115/135. We also showed that porcine platelets contain glycoprotein antigens that are the same or very similar to gp115/135 from endothelial cells. The studies reported here were aimed at identifying these porcine platelet antigens and evaluating their potential relevance for the pathogenesis of xenograft injury. The importance of gp115/135 as targets of human natural antibodies was supported by the demonstration that (a) antibodies against porcine platelet gp115/135 are absorbed from the blood of nonhuman primates during the perfusion of a porcine kidney; (b) purified gp115/135 glycoproteins at concentrations < 500 pM, block the binding of human natural antibodies to cultured porcine endothelial cells; (c) the binding of human antibodies to porcine platelet extracts is significantly decreased by removal of gp115 or gp135 from the extracts; (d) antibody binding to gp115/135 initiates the activation of complement. Amino-terminal sequencing of gp115/135 revealed that gp115 has significant homology to human integrin beta 3 chains, gp125 to human alpha IIb chains, and gp135 to human alpha 2 chains. Ligand binding properties of the porcine glycoproteins were consistent with the identity of the antigens revealed by amino acid sequencing and molecular weight. Human natural antibodies also recognized a 250 kDa porcine platelet glycoprotein which was found to be homologous to human von Willebrand factor (vWF). Antibodies against vWF in the blood of nonhuman primates are absorbed during ex vivo perfusion of a porcine organ. The identification of gp115/135 as integrins, the functions of which in endothelium might include cell signaling and maintenance of barrier function, provides potential insight into the pathogenesis of the rejection reaction in which these processes are manifestly aberrant. The identification of vWF as a potential target antigen raises several questions, including whether vWF provides one basis for antibody binding to xenogeneic endothelium or whether upon secretion from an endothelial cell vWF might actually block antibody binding.

Amino Acid Sequence↗
PubMed2003

Enhanced adhesion to laminin by apoptotic eosinophils.

Apoptotic cells are regarded as inert bodies that turn off intracellular processes and functional capabilities. The objective was to study adhesion by eosinophils in relation to the apoptotic process. Eosinophils were cultured for up to 72 h. The living cells were separated from the apoptotic cells, and their adhesion to transfected cell lines expressing vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and laminin was measured. To relate the functional studies with cell structure, the surface receptor expression of beta1- and beta2-integrins was investigated by flow cytometry. Apoptotic eosinophils evidenced an increased expression of the alpha-chain of the laminin receptor and CD49f and an increased ability to adhere to a laminin-coated surface. Adhesion to the endothelial cell adhesion receptors E-selectin, VCAM-1 and ICAM-1 was absent in apoptotic eosinophils and was paralleled by a low expression of CD11b, CD29, CD49d and CD66b. The specifically increased adhesion to laminin and expression of the laminin receptor alpha-chain is a unique feature of apoptotic eosinophils. When an eosinophil goes into apoptosis, it still possesses the ability to interact with its environment. Our results point to new ideas as to how the apoptotic eosinophil behaves in apoptosis.

Apoptosis↗
PubMed1993

Basement membrane formation and re-distribution of the beta 1 integrins in a human intestinal co-culture system.

We have developed a co-culture system suited for the study of epithelial-mesenchymal interactions in the human fetal small intestine. As the epithelial component of this model, we used the human intestinal cell line Caco-2 that is unique in its property to differentiate in vitro into a mature fetal enterocyte-like cell type. A sheet of human intestinal mesenchymal cells, which we derived from an 18-week-old fetus, was used as mesenchymal element. Expression and distribution of cell-specific markers (cytokeratin 18 and dipeptidyl peptidase IV), major basement membrane components, and beta 1 integrins were analyzed. In 14-day co-cultures, Caco-2 cells formed a cytokeratin 18-positive epithelial-like sheet covering the vimentin-positive HIM cell layers. As assessed by brush border dipeptidyl peptidase IV expression, co-cultured Caco-2 cells achieved cytodifferentiation as when cultured on plastic. A complete deposition of all known major human fetal intestinal basement membrane components occurred at the Caco-2/HIM interface. Type IV collagen and tenascin were produced from the mesenchymal compartment, whereas laminin and fibronectin were contributed by both cell types. Interestingly, synthesis and deposition of basement membrane heparan sulfate proteoglycan were exclusively observed in co-cultures, suggesting modulation of epithelial expression of this molecule by HIM cells. Finally, we observed that epithelial integrin-beta 1 chains redistributed at the basal domain of co-cultured Caco-2 cells. Taken together, these observations indicate that the Caco-2/HIM co-culture model is a valuable system to study in vitro human basement membrane formation in the context of intestinal epithelial-mesenchymal interactions.

Basement Membrane↗
PubMed1991

Changes in the gene expression of collagens, fibronectin, integrin and proteoglycans during matrix-induced bone morphogenesis.

Subcutaneous implantation of demineralized bone matrix in rat results in the local cartilage and bone development. This in vivo model of bone formation was used to examine the expression patterns of cartilage and bone specific extracellular matrix genes. The steady state levels of mRNA in implants for cartilage specific type II collagen, type IX collagen, proteoglycan link protein and cartilage proteoglycan core protein (aggrecan) were increased during chondrogenesis and cartilage hypertrophy. Fibronectin mRNA levels were high during mesenchymal cell migration, attachment and chondrogenesis. Integrin (beta 1 chain) mRNA was expressed throughout the endochondral bone development. Type I collagen mRNA levels in implants increased as early as day 3, reached its peak during osteogenesis. These gene markers will be useful in the study of the mechanism of action of bone morphogenetic proteins present in the demineralized bone matrix.

Animals↗
PubMed1992

Tumor necrosis factor mediates experimental pulmonary edema by ICAM-1 and CD18-dependent mechanisms.

(TNF alpha)-induced sequestration of neutrophils (PMN) in lungs and of the resultant PMN-dependent pulmonary edema. Guinea pig lungs perfused with Ringers-albumin were challenged with TNF alpha (1,000 U/ml) for 90 min, followed by addition of fresh perfusate containing 2 x 10(7) human PMN. TNF alpha challenge caused sequestration of PMN in the pulmonary vascular bed as indicated by a threefold increase in lung tissue myeloperoxidase activity (MPO). The activation of the sequestered PMN with phorbol 12-myristate 13-acetate (PMA; 5 x 10(-9) M) produced threefold increases in pulmonary artery (Ppa) and pulmonary capillary hydrostatic (Pcap) pressures, and twofold increases in lung wet-to-dry weight (W/D) ratio and capillary filtration coefficient (Kf,c) over baseline. TNF alpha prestimulation was required for these responses since activation of PMN with PMA in control lungs produced smaller increases in Ppa and Pcap (P less than 0.01) and did not change the W/D and Kf,c. TNF alpha prestimulation also induced the expression of intercellular adhesion molecule (ICAM-1) on pulmonary vascular endothelial cells. Monoclonal antibodies (mAbs) to the neutrophil CD18 integrin (beta-chain of CD11/CD18 complex) (mAb IB4) and to its endothelial cell ligand ICAM-1 (mAb RR1/1) were used to examine the role of PMN adhesion in the TNF alpha-induced responses. Pretreatment of PMN with mAb IB4 prevented PMN uptake and increases in Ppa, Pcap, Kf,c, and W/D ratio. Addition of mAb RR1/1 to the perfusate reduced PMN uptake by 58%, and prevented the increases in Ppa, Pcap, Kf,c, and W/D ratio, as with mAb IB4. The findings indicate that TNF alpha prestimulation of lungs mediates PMN uptake and that this requires the expression of ICAM-1 and its interaction with CD18 integrin on PMN. The activation of PMN sequestered by ICAM-1-dependent mechanism contributes to the development of pulmonary vascular injury and edema.

Animals↗
PubMed1993

Integrins and L-selectin in lymphocyte-endothelium interactions and homing into gut-associated tissue.

The selective entry of subpopulations and distinct differentiation stages of lymphocytes into different tissues is thought to be mediated by interaction of endothelial ligands with adhesion molecules on lymphocytes. L-selectin has been considered as a peripheral lymph node-specific homing receptor and alpha 4-integrins have been supposed to mediate entry into mucosa-associated lymphoid tissue. In vivo homing studies show that the specificity is not so clear-cut. The MEL-14 antibody indeed blocks almost completely lymphocyte homing into peripheral lymph nodes. However, entry into Peyer's patches and even the intestine itself is also affected. Thus, L-selectin plays a broader part as previously thought. Some antibodies against the alpha 4 and beta 1-integrin chain inhibit selectively lymphocyte homing to Peyer's patches by 50-70%. alpha 4-integrins therefore seem to be important for homing into mucosa-associated tissue, although a considerable fraction of cells does not require this molecule (or this epitope) for recognition of Peyer's patch endothelium. In vitro and in vivo data indicate that neither VCAM-1 nor fibronectin play a role for homing into Peyer's patches; most likely a further ligand recognized by distinct epitopes of alpha 4 is used for recognition of Peyer's patch HEV. A combination of the mAbs MEL-14 and PS/2.3 blocks nearly completely the localization in Peyer's patches. Beside alpha 4-integrins, the beta 2-integrin LFA-1 has been shown to be involved in lymphocyte recirculation. Also combinations of antibodies against LFA-1 and L-selectin as well as of anti LFA-1 with anti alpha 4 show synergistic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗