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PubMed2003

Engineering integrin-specific surfaces with a triple-helical collagen-mimetic peptide.

Integrin-mediated cell adhesion to extracellular matrix proteins anchors cells and triggers signals that direct cell function. The integrin alpha(2)beta(1) recognizes the glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) motif in residues 502-507 of the alpha(1)(I) chain of type I collagen. Integrin recognition is entirely dependent on the triple-helical conformation of the ligand similar to that of native collagen. This study focuses on engineering alpha(2)beta(1)-specific bioadhesive surfaces by immobilizing a triple-helical collagen-mimetic peptide incorporating the GFOGER binding sequence onto model nonadhesive substrates. Circular dichroism spectroscopy verified that this peptide adopts a stable triple-helical conformation in solution. Passively adsorbed GFOGER-peptide exhibited dose-dependent HT1080 cell adhesion and spreading comparable to that observed on type I collagen. Subsequent antibody blocking conditions verified the involvement of integrin alpha(2)beta(1) in these adhesion events. Focal adhesion formation was observed by immunofluorescent staining for alpha(2)beta(1) and vinculin on MC3T3-E1 cells. Model functionalized surfaces then were engineered using three complementary peptide-tethering schemes. These peptide-functionalized substrates supported alpha(2)beta(1)-mediated cell adhesion and focal adhesion assembly. Our results suggest that this peptide is active in an immobilized conformation and may be applied as a surface modification agent to promote alpha(2)beta(1)-specific cell adhesion. Engineering surfaces that specifically target certain integrin-ligand interactions and signaling cascades provides a biomolecular strategy for optimizing cellular responses in biomaterials and tissue engineering applications.

3T3 Cells↗
PubMedDate not supplied

The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression.

BACKGROUND: Osteoclast activation plays an essential role in the development of bone metastasis (BM). Integrin alpha(v)beta3 mediates the attachment of osteoclasts to bone matrix, and it is overexpressed in bone-residing breast cancer cells. We studied BM from breast cancer in relation to its Integrin alpha(v)beta3 expression. MATERIALS AND METHODS: Integrin alpha(v)beta3 expression in 4 human breast cancer cell lines (MDA-MB-231, MDA-MB-435, MKL-4 and T-47D) was determined by immunohistochemistry, flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Integrin alpha(v)beta3 was expressed in MDA-MB-231 and MDA-MB-435, but not in MKL-4 or T-47D, using both immunohistochemistry and flow cytometry. By RT-PCR, positive bands for both alpha(v) and beta3 subunits were identified in MDA-MB-231 and 435, while only the alpha(v) subunit mRNA was present in MKL-4 and T-47D. BM was common in vivo following inoculation with MDA-MB-231 or 435, but not with MKL-4. CONCLUSION: Integrin alpha(v)beta3 expression appears to play a key role in the development of BM from breast cancer.

Animals↗
PubMed1997

[Adhesion molecules in squamous cell carcinoma of the larynx: possible indication of prognosis].

Thirty patients with laryngeal tumors were divided into two groups on the basis of whether clinical and pathological features indicated good or bad prognosis. Samples of each tumor group were selected and examined by immunohistochemistry using mAbs, raised against integrin chains (beta 1, beta 4, alpha 2, alpha 3, alpha 6) and their ligands laminin 1 and 5, collagen type IV, two fibronectin isoforms (ED-A and ED-B) and two isoforms of tenascin known to be associated with neoplasm. Controls were provided by samples of tumor-free laryngeal mucosa removed during the surgical procedure. The normal topographical integrin pattern and the continuity of the basement membrane components was altered in both groups but the extent of these changes was significantly greater in those tumors with poor prognosis. Therefore, the groups could easily and reliably be distinguished by simply observing their immunohistochemical features. It is suggested that performing immunohistochemical analysis on biopsies may aid in early diagnosis as well as in adopting the proper therapeutic strategy to follow for these tumors. The above molecules may become one of the diagnostic tools available for head and neck surgical pathologists.

Adult↗
PubMed1992

A peptide corresponding to GPIIb alpha 300-312, a presumptive fibrinogen gamma-chain binding site on the platelet integrin GPIIb/IIIa, inhibits the adhesion of platelets to at least four adhesive ligands.

The platelet fibrinogen (Fg) receptor (GPIIb/IIIa) is an integrin which plays a critical role in hemostasis by recognizing at least the four adhesive ligands: Fg, fibronectin (Fn), vitronectin (Vn), and von Willebrand factor (vWf). We reported that residues 309-312 of GPIIb alpha appear to comprise at least part of a Fg binding site on the Fg receptor (Gartner, T. K., and Taylor, D. B. (1990) Thromb. Res. 60, 291-309). Here we report that the peptide GPIIb alpha 300-312 (G13) inhibits platelet aggregation and binds Fg and Vn. Significantly, this peptide inhibits the adhesion of stimulated platelets to Fg, Fn, Vn, and vWf, but not the adhesion of resting platelets to Fn. Thus, GPIIb 300-312 may constitute a specific but common recognition site on GPIIb/IIIa for both LGGAKQAGDV- and RGD-containing ligands.

Amino Acid Sequence↗
PubMed1996

A novel monoclonal antibody mNI-58A against the alpha-chain of leukocyte function-associated antigen-1 (LFA-1) blocks the homotypic cell aggregation and actively regulates morphological changes in the phorbol myristate acetate (PMA)-activated human monocyte-like cell line, U937.

A monoclonal antibody (mAb), designated mNI-58A, was produced by immunizing mice with the lipopolysaccharide (LPS)-stimulated monocyte-like cell line, U937. The antigen defined by mNI-58A was widely expressed on various lymphoid cells and all cell lines examined except the erythroid cell line, K562. When the reactive patterns between mNI-58A and the mAbs to various human differentiation antigens (CD11a, CD11b, CD11c, CD14, CD16, CD18, CD23, CD28, CD29, CD31, CD43, CD44, CD45RA, CD50, CD54, CD58, CD80, CD102, CD106, HLA-class I and-class II antigen) were compared, that of mNI-58A was found to be similar to those of the leukocyte function-associated antigen-1 (LFA-1) mAbs. Using a competitive immunofluorescence binding assay it was found that the preincubation with one of the CD11a mAbs, 2F12 completely blocked the subsequent binding of mNI-58A. mNI-58A prevented the homotypic cell aggregation of the phorbol myristate acetate (PMA)-activated U937 cells (referred to as PMA-U937) and PMA-activated Epstein-Barr virus (EBV)-transformed B cell lines, B-85 and Mann. mNI-58A markedly induced the spread formation of the PMA-U937 cells following this blocking of the homotypic cell aggregation, whereas 2F12 did not under the same condition. The spread formation induced by mNI-58A was completely blocked by cytochalasin B (CyB), cytochalasin D (CyD), cycloheximide (CHX) or protein kinase C inhibitors, sphingosine and H-7. The U937 cells markedly adhered to the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs) and also to the extracellular matrix protein, fibronectin, but mNI-58A did not enhance or block these adhesion process. mNI-58A precipitated two glycoproteins with molecular weight 180 kDa and 95 kDa as determined by SDS-PAGE analysis, which were identical to the LFA-alpha (CD11a) and beta (CD18) chains of leukocyte integrin precipitated by the CD11a mAbs, respectively. Sequential immunoprecipitation studies using the CD11a mAb (2F12) also indicate that mNI-58A recognizes an epitope on the alpha-chain of the LFA-1 molecule. The ability of mNI-58A to block the PMA-U937 cells and to induce the spread formation of these cells suggests that mNI-58A is a novel mAb reacting with an epitope on the alpha-chain of LFA-1 different from those recognized with the existing CD11a mAbs.

Antibodies, Blocking↗
PubMed1995

Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrin-derived signals.

We have shown previously that the expression of collagenase is upregulated in rabbit synovial fibroblasts cultured on a substrate of antibody to the alpha 5 chain of the alpha 5 beta 1 integrin fibronectin receptor or on the 120-kD cell-binding chymotryptic fragment of plasma fibronectin, but remains at basal levels in cells plated on intact plasma fibronectin. We now have identified some of the components of a signaling pathway that couples the fibronectin receptor to the induction of collagenase transcription. We studied the control of collagenase gene expression in cells adhering to the 120-kD fragment of fibronectin, to antifibronectin receptor antibody, or to plasma fibronectin by transiently introducing promoter-reporter constructs into rabbit synovial fibroblasts before plating cells on these matrices. The constructs contained segments of the human collagenase promoter regulating transcription of chloramphenicol acyl transferase. Expression of constructs containing the -1200/-42-bp segment or the -139/-42-bp segment of the collagenase promoter inserted upstream from the reporter gene was induced to similar extents in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in fibroblasts plated on fibronectin. The expression of the construct containing the -66/-42-bp segment of the promoter was not regulated and was similar to that of the parent pBLCAT2 plasmid, suggesting that the -139/-67 region of the collagenase promoter, which contains PEA3- and AP1-binding sites, regulates the transcription of collagenase caused by integrin-derived signals. Expression of a reporter construct containing only the PEA3 and AP1 sites in the collagenase promoter (-90/-67) also increased in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. Mutations in either the AP1 or PEA3 site of this minimal promoter abrogated its activity in cells plated on these inductive ligands. Expression of c-fos mRNA increased within 1 h of plating cells on the 120-kD fibronectin fragment or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. c-Fos protein accumulated in the nuclei of fibroblasts within 10 min of plating on the 120-kD fibronectin fragment. The increase in c-Fos was required for the increase in collagenase in cells plated on the 120-kD fibronectin fragment: incubation of cells with antisense, but not sense, c-fos oligonucleotides diminished both basal and induced expression of the -139/-42 collagenase promoter-reporter construct and decreased expression of the endogenous collagenase gene.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Laminin-binding integrin alpha 7 beta 1: functional characterization and expression in normal and malignant melanocytes.

A novel integrin, alpha 7 beta 1, that specifically binds with high affinity to laminin has been identified on melanoma cells. This complex was purified from both human and murine melanoma cells by laminin-affinity chromatography, and the alpha 7 subunit was recovered after gel electrophoresis. N-terminal amino acid sequence analysis of the alpha 7 subunit from both human and mouse cells verifies that this integrin is distinct from other alpha chains in the beta 1 family, although strikingly similar to the alpha 6 subunit. By using specific proteolytically derived fragments of laminin, it was determined that the alpha 7 beta 1 complex binds selectively to the E8 region, which represents part of the long arm of laminin. In contrast, the receptor failed to bind to the P1 fragment, which contains the intersection of the short arms of laminin. Although the alpha 7 beta 1 complex was commonly expressed in melanoma cells, this integrin was not detected in normal melanocytes, suggesting that alpha 7 expression may be associated with malignant transformation. These results establish the existence of a novel integrin that binds to the E8 domain of laminin and appears to mediate cell adhesion to this ligand.

Amino Acid Sequence↗
PubMed2026

Multi-omics-based study on the biological characteristics of kidney renal deficiency and blood stasis in ankylosing spondylitis.

OBJECIVE: To explore the objective biological evidence for the classification and diagnosis of Traditional Chinese Medicine (TCM) syndromes in ankylosing spondylitis (AS) using multiomics analysis. METHODS: Patients with AS were categorized into kidney deficiency and blood stasis syndrome (SX group) and damp-heat stasis syndrome (SR group). Transcriptomic sequencing and quantitative plasma proteomics were performed on patients with AS and healthy volunteers. Multiomics integration was used to characterize the biological basis of AS with renal deficiency and blood stasis syndrome. Specific proteins were validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Transcriptomic sequencing identified 31 significantly upregulated genes in patients with AS compared to healthy controls. These genes were primarily involved in tumor necrosis factor, interleukin-17, and nuclear factor kappa-B signaling pathways, as well as osteoblast differentiation and various viral infection pathways. Differentially expressed genes, including intercellular adhesion molecule 1 (ICAM1), 6-phosphofructo-2-kinase, cyclin-dependent kinase inhibitor 1A, interleukin 1 receptor antagonist, integrin alpha IIb, and myosin light chain 9 were more upregulated in the SX group than in the SR group. Quantitative proteomics identified 723 differential proteins associated with the disease and 788 differential proteins between the SX and SR groups. Notable proteins such as myeloperoxidase, cluster of differentiation 14, macrophage simulating 1 (MST1), and Ras homolog enriched in brain may serve as characteristic proteins of the SX group. By integrating transcriptomic and proteomic data, 45 associated differential molecules involved in platelet activation, pathogenic intestinal flora infection, glycolysis/gluconeogenesis, and T-cell receptor signaling pathways were identified in patients with AS compared to healthy controls. Additionally, ICAM1, MST1, C-X-C motif chemokine ligand 8 (CXCL8), suppressor of cytokine signaling 3 (SOCS3), and insulin-like growth factor binding protein 1 (IGFBP1) were detected in TCM syndromes by RT-qPCR and ELISA, showing upregulation in AS renal deficiency and blood stasis syndromes, which is consistent with the proteomic and transcriptomic results. CONCLUSIONS: ICAM1, MST1, CXCL8, SOCS3, and IGFBP1 were identified as biomarkers of renal deficiency and blood stasis syndrome in AS. This study provides a biological basis for the differential diagnosis of TCM syndromes in AS, offering new insights into Chinese medicine evidence and more precise Chinese medicine treatments for AS.

Humans↗
PubMed1996

Integrin synthesis and utilization in cultured human osteoblasts.

This study describes the adhesion of human osteoblasts, cultured in vitro, to proteins of the extracellular matrix, the biosynthesis of integrins, their topography and organization in focal contacts. The adhesion of osteoblasts to laminin, type I collagen, vitronectin and fibronectin was 77-100%, in 2 h and at 55 nM substrata concentration, and it was accompanied by spreading of the cells. Adhesion to fibronectin (FN), laminin (LN) and type I collagen (COL) was inhibited by antibodies to the beta 1 integrin and antibodies to the alpha 5 chain affected adhesion only to fibronectin. Using a panel of polyclonal antibodies against alpha 2, alpha 3, alpha 5, alpha v, beta 1 and beta 3 integrins we detected synthesis of alpha 3 beta 1, alpha 5 beta 1, alpha v beta 3, and an alpha v beta 1-like dimer by immunoprecipitation of metabolically labelled cell lysates. Studies of immunolocalization demonstrated the presence of the same integrins identified in lysates, plus alpha 4, alpha 1 and beta 5 subunits. In cells adhering in the presence of serum we showed organization of beta 3 and alpha v integrins in focal contacts. In cells adhering to fibronectin alpha 5 and beta 1 integrins were localized in focal contacts. In cells spread on laminin or type I collagen none of the integrins investigated was localized in focal contacts.

Adult↗
PubMed1991

An abundant chick gizzard integrin is the avian alpha 1 beta 1 integrin heterodimer and functions as a divalent cation-dependent collagen IV receptor.

The alpha-subunit of an abundant chick gizzard integrin was isolated (T. Kelly, L. Molony, and K. Burridge, 1987, J. Biol. Chem. 262, 17,189-17,199) and fragmented by proteolytic digestion. The N-terminal sequences of the intact polypeptide and of several internal peptides were determined and were found to be highly homologous to the mammalian integrin alpha 1-subunit. Monoclonal antibodies to the chick integrin beta 1-chain react on immunoblots with the gizzard integrin beta-subunit (U. Hofer, J. Syfrig, and R. Chiquet-Ehrismann, 1990, J. Biol. Chem. 265, 14,561-14,565). The chain composition of the abundant chick gizzard integrin is therefore alpha 1 beta 1. Polyclonal antibodies to the avian integrin alpha 1-subunit block attachment of embryonic gizzard cells to human and chick collagen IV completely and inhibit attachment to mouse Engelbreth-Holm-Swarm (EHS) tumor laminin partially. In ELISA-style receptor assays, the isolated alpha 1 beta 1 integrin bound to human and chick collagen IV and to mouse EHS tumor and chick heart laminin. While the binding to collagen IV was abolished by removal of divalent cations, the binding to laminin was not sensitive to EDTA under the conditions used. Collagen I bound the isolated avian alpha 1 beta 1 integrin only weakly. As collagen IV was the only extracellular matrix protein for which a consistent, divalent cation-dependent, binding to the avian alpha 1 beta 1 integrin could be demonstrated in both cellular and molecular assays we suggest that it is a preferred ligand for this integrin.

Amino Acid Sequence↗
PubMed1998

Glomerular extracellular matrix components and integrins.

It has become apparent that extracellular matrix components and their cellular receptors, the integrins, are important regulators of glomerular development and function. In this rapidly evolving field we studied the production of extracellular matrix components and integrins by rat glomerular visceral epithelial and mesangial cells, using molecular probes and antibodies that have recently become available. Special attention was paid to laminin isoforms and to splice variants of the integrin subunits alpha 3 and alpha 6. Results were compared to the in vivo expression in human fetal, newborn and adult kidneys. The mesangial cells were found to produce laminin-1, nidogen and two as yet unidentified laminin isoforms with putative alpha chains of about 395 (alpha x) and of 375 kDa (alpha y), tentatively described before as bovine kidney laminin. Furthermore, they expressed the integrins alpha 1 beta 1, alpha 2 beta 1, alpha 3A beta 1, alpha 5 beta 1, alpha v beta 3, alpha v beta 5, and small amounts of alpha 6A beta 1 and alpha 6B beta 1. The glomerular visceral epithelial cells produced the two new laminin isoforms mentioned above, laminin-5, but no laminin-1 or nidogen. The integrins alpha 2 beta 1, alpha 3A beta 1, alpha 6A beta 4, alpha 6B beta 4 and the integrin subunit alpha v were found to be expressed. We show that during nephrogenesis, the laminin alpha 1 chain disappears and is replaced by another alpha chain, possibly one of the two as yet unidentified alpha chains mentioned above. The laminin beta 1 chain is replaced by the beta 2 chain somewhat later in glomerular development. In general, the integrins found to be expressed in glomeruli of adult kidney were consistent with those found in cultured glomerular visceral epithelial and mesangial cells. No splice variant switch of the integrin alpha 3 or alpha 6 subunits could be demonstrated during nephrogenesis. Our results suggest an important role for the mesangial cell in providing nidogen as a crucial component of the supramolecular structure of the glomerular basement membrane. Furthermore our results indicate that laminin alpha x beta 2 gamma 1 and alpha y beta 2 gamma 1 isoforms are important in the glomerulus of adult kidney and that the integrin alpha 3A beta 1 is the main integrin receptor for laminin isoforms on glomerular visceral epithelial and mesangial cells, both in vitro and in vivo.

Adult↗
PubMed1992

Involvement of beta 2-integrins in the migration of human natural killer cells.

Human large granular lymphocytes with the NK cell phenotype (CD16+ or CD56+CD3-) were greatly enriched among the cells which migrated spontaneously through untreated or albumin-coated, 3-microns pore size polycarbonate filters for 1 to 8 h. Three days of rIL-2 treatment (300 IU/ml) and 3 to 5 wk of rIL-2 treatment (100 IU/ml) generated a 2.7 +/- 0.9-fold and 5.6 +/- 0.8-fold increase in cell migration, respectively. The adhesion and subsequent migration of freshly isolated NK cells was mainly mediated by CD11b/CD18, because migration could be inhibited by 80 +/- 8% anti-CD11b (Mac-1) antibodies but not with antibodies against CD11a (LFA-1) or CD11c (p150,95), the other alpha-chains of the beta 2-integrins. After rIL-2 activation, however, CD11a/CD18 was the major receptor utilized in migration, inasmuch as anti-CD11a antibody caused a 69 +/- 8% reduction in the number of migrated cells. Anti-CD11b antibody decreased migration by 43 +/- 12%, and together these antibodies inhibited migration by 82 +/- 7%. Anti-CD11a alone did not have any effect on adhesion, but CD11a/CD18 cooperated in the adhesion because anti-CD11b decreased adhesion by 40 +/- 11% and together these antibodies inhibited adhesion by 74 +/- 6%. The ability of large granular lymphocytes to rapidly utilize beta 2-integrins and unidentified ubiquitous ligands for binding and migration may be significant for their capacity to function in the first line of immune defense under highly variable conditions.

Antibodies, Monoclonal↗
PubMed1992

Role of fibrinogen alpha and gamma chain sites in platelet aggregation.

Fibrinogen (Fbg) mediates platelet aggregation by its interaction with the platelet glycoprotein IIb-IIIa (integrin alpha IIb beta 3). Peptides containing the amino acid sequence RGD derived from the alpha chain (residues alpha 95-97 and residues alpha 572-574) and the sequence HHLGGAKQAGDV derived from the carboxyl terminus of the gamma chain of Fbg (residues gamma 400-411) inhibit these interactions. To determine the role of these sequences in intact Fbg, recombinant human Fbg (rFbg), mutant rFbgs with an RGD-->RGE substitution at either position alpha 97 or alpha 574, and a rFbg gamma'-containing variant that has a carboxyl-terminal interruption in the HHLGGAKQAGDV sequence have been expressed in transfected BHK cells. Purified rFbg and the two RGE mutant Fbgs were similar to plasma Fbg in platelet aggregation assays. In contrast, the gamma' variant Fbg was markedly defective in platelet aggregation. These data support the proposals that the carboxyl-terminal region of the gamma chain of Fbg is essential for optimal platelet aggregation and that the alpha-chain RGD sequences are neither necessary nor sufficient for platelet aggregation.

Amino Acid Sequence↗
PubMed1991

Cellular invasion into matrix beads: localization of beta 1 integrins and fibronectin to the invadopodia.

We have examined the contribution of adhesion mechanisms to cell invasiveness by growing chicken embryo fibroblasts (CEF) or Rous sarcoma virus-transformed cells (RSVCEF) on fibronectin-coated crosslinked gelatin beads (FN-beads). RSVCEF attached more readily and spread more rapidly on FN-beads than CEF, suggesting an increase in the adhesion-related motility of the transformed cells. In addition, RSVCEF invaded the FN-beads, but CEF did not, by extending specialized cell surface protrusions called invadopodia at sites of cell invasion. FN removal by RSVCEF cultured on prelabeled fluorescent FN-beads (FL-FN) was evident at sites of invadopodia, and internalized FL-FN occurred in vacuoles near the ventral membrane of cells at sites of FN removal. The precise distribution of FN and integrins in cells invading FN-beads was determined by immunofluorescence and immunoelectron microscopy of frozen thin-sections. In both CEF and RSVCEF, beta 1 integrins and FN occupied separate intracellular compartments during the early stage of spreading on FN-beads. Later, beta 1 integrins were largely localized at the ventral cell surface of both CEF and RSVCEF. Polyclonal anti-integrin antibody recognizing beta 1 and several alpha chains, however, labeled both ventral and dorsal cell surfaces. During invasion by RSVCEF, beta 1 integrins were concentrated at extended invadopodia and also colocalized with internalized FL-FN material in phagocytic vesicles. Furthermore, secreted FN was deposited by RSVCEF at the base of invadopodia colocalizing with beta 1 integrin. Both FL-FN matrix removal and formation of the invadopodia were found to be resistant to treatment with GRGDS at concentrations that inhibit the interaction between cells and FN-beads. Thus, the localization of beta 1 integrins to the plasma membrane contacting immobilized FN results in an extremely tight cellular adherence to the matrix bead, that stabilizes invadopodia and also mediates endocytic clearance of degraded FN-matrix material.

Animals↗
PubMed2003

Non-peptide alpha(v)beta(3) antagonists: identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint.

Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity antagonists demonstrated marked differences in log P values, which translated into differing dog pharmacokinetic properties. One member of this set was demonstrated to be effective in reducing bone resorption in rats.

Adrenergic alpha-Antagonists↗
PubMed2000

Suppression of integrin alpha(v) expression by endothelin-1 in vascular smooth muscle cells.

Both integrins and endothelins (ETs) are known to play important roles in vascular remodeling via proliferation, apoptosis, and migration of vascular smooth muscle cells (VSMCs), whose dysfunctions have been implicated in the pathogenesis of end-organ damage associated with hypertension and arteriosclerosis. However, whether there is any interaction between endothelin-1 (ET-1) and integrins remains unknown. Therefore, the aim of the present study was to elucidate whether ET-1 regulates the expression of integrin alpha(v) in rat VSMCs. ET-1 dose- and time-dependently suppressed the integrin alpha(v) messenger RNA (mRNA) transcripts, as quantified by a real-time quantitative polymerase chain reaction (PCR) method, and decreased the transcriptional activity of integrin alpha(v) gene, as demonstrated by integrin alpha(v)-luciferase assay. The inhibitory effect of ET-1 on integrin alpha(v) gene expression was abrogated by an ETA receptor antagonist (BQ123) but not by an ET(B) receptor antagonist (BQ788). ET-1 also suppressed the cell surface expression of integrin alpha(v)beta5 and the adhesion to vitronectin, but not to fibronectin. These results demonstrate that the adhesion of vitronectin to rat VSMCs is inhibited by ET-1 via the ET(A) receptors by suppressing integrin alpha(v) gene transcription, suggesting that ET-1 is involved in regulation of vascular integrin alpha(v) gene expression.

Animals↗
PubMed1995

CD23 regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18.

CD23 is expressed on a variety of haemopoietic cells and displays pleiotropic activities in vitro. We report that in addition to CD21 and IgE, CD23 interacts specifically with the CD11b and CD11c, the alpha chains of the beta 2 integrin adhesion molecule complexes CD11b-CD18 and CD11c-CD18, on monocytes. Full-length recombinant CD23 incorporated into fluorescent liposomes was shown to bind to COS cells transfected with cDNA encoding either CD11b-CD18 or CD11c-CD18 but not with CD11a-CD18. The interaction was specifically inhibited by anti-CD11b or anti-CD11c, respectively, and by anti-CD23 MAbs. The functional significance of this ligand pairing was demonstrated by triggering CD11b and CD11c on monocytes with either recombinant CD23 or anti-CD11b and anti-CD11c MAbs to cause a marked increase in nitrite-oxidative products and pro-inflammatory cytokines (IL-1 beta, IL-6, and TNF alpha). These CD23-mediated activities were decreased by Fab fragments of MAbs to CD11b, CD11c, and CD23. These results demonstrate that CD11b and CD11c are receptors for CD23 and that this novel ligand pairing regulates important activities of monocytes.

CD11 Antigens↗
PubMed1996

Integrins beta 5, beta 3 and alpha v are apically distributed in endometrial epithelium.

Several adhesion molecules have been shown to occur at the surface of endometrial cells. One of these is the integrin alpha v subunit which associates with various beta chains including beta 5. We demonstrate the presence of integrin beta 5 polypeptide in human endometrial epithelial cells throughout the menstrual cycle using immunocytochemistry with monospecific antibodies, and at the mRNA level by thermal amplification from endometrial cDNA. Integrin beta 5 is also found in a population of bone marrow-derived cells. A notable feature of the distribution of the beta 5 subunit in the glandular and luminal epithelium is its apical localization, which may suggest an involvement in implantation. However, no evidence was found for regulated expression of epithelial beta 5. In mouse, the beta 5 subunit is found at both the apical and basal surface of epithelial cells and expression is essentially oestrous cycle-independent. Comparisons are made in both species with the distribution of the alpha v and beta 3 subunits which also localize to the apical epithelium.

Animals↗