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PubMed2006

Laminin alpha1 chain mediated reduction of laminin alpha2 chain deficient muscular dystrophy involves integrin alpha7beta1 and dystroglycan.

Transgenically introduced laminin (LN) alpha1 chain prevents muscular dystrophy in LNalpha2 chain deficient mice. We now report increased integrin alpha7Bbeta1D synthesis in dystrophic LNalpha2 chain deficient muscle. Yet, immunofluorescence demonstrated a reduced expression of integrin alpha7B subunit at the sarcolemma. Transgenic expression of LNalpha1 chain reconstituted integrin alpha7B at the sarcolemma. Expression of alpha- and beta-dystroglycan is enhanced in LNalpha2 chain deficient muscle and normalized by transgenic expression of LNalpha1 chain. We suggest that LNalpha1 chain in part ameliorates the development of LNalpha2 chain deficient muscular dystrophy by retaining the binding sites for integrin alpha7Bbeta1D and alpha-dystroglycan, respectively.

Animals↗
PubMed1990

A human monoclonal autoantibody specific for human platelet glycoprotein IIb (integrin alpha IIb) heavy chain.

Splenocytes from a patient with chronic, immune-mediated thrombocytopenic purpura (ITP) were transformed with Epstein-Barr virus. A stable lymphoblastoid cell line (LCL) derived from this transformation (2A3) produces IgM antibody reactive with platelet glycoprotein IIb. 2A3 was fused to the 6-thioguanine-resistant ouabain-resistant, murine-human heteromyeloma cell line, F6. The resultant heterohybridomas were selected by growth in medium containing hypoxanthine/aminopterin/thymidine and ouabain. One hybridoma line, 2E7, produces high levels of IgM antibody (2 to 4 micrograms IgM/ml/24 hr/10(5) cells) reactive with glycoprotein IIb. 2E7 has been repeatedly subcloned by limiting dilution and has been maintained in continuous culture for 26 months. 2E7 binds to human platelets but not endothelial cells, as determined by flow cytometry, and does not react with platelets of patients with Glanzmann's thrombasthenia that lack IIb-IIIa. The epitope recognized by 2E7 is likely to be a contiguous peptide sequence since the antibody binds to the IIb heavy chain in immunoblot assays of denatured, reduced platelet protein. Treatment of intact platelets or purified IIb-IIIa with papain or chymotrypsin, but not SV8 protease, destroys the epitope. Thus, the 2E7 epitope may be at or very close to a site on IIb that is cleaved by these proteases. The expression of the 2E7 epitope is significantly affected by the presence of divalent cations. Treatment of intact platelets with EDTA at 37 degrees C results in a three-to four-fold increase in the number of 2E7 molecules bound per platelet and an eight-fold increase in the affinity of the antibody. The binding of 2E7 to normal platelets does not inhibit any of the functions attributed to IIb-IIIa, such as fibrinogen-dependent platelet aggregation or clot retraction. 2E7 represents the first human monoclonal antibody reported to recognize an epitope on platelet glycoprotein IIb. The epitope is unique to IIb and not shared by other integrin alpha subunits.

Adolescent↗
PubMed1997

Localization of laminin, fibronectin, E-cadherin, and integrins in endometrium and endometriosis.

OBJECTIVE: To compare the localization of adhesion proteins (laminin and fibronectin) and their receptors of the integrin family in endometriosis and endometrium. DESIGN: An immunohistochemical study. SETTING: University Hospital, Department of Gynecology and Department of Cell Biology. PATIENT(S): Eighteen endometriosis patients undergoing laparoscopy for pain or infertility and nine control patients undergoing laparoscopy for sterilization or hysterectomy. MAIN OUTCOME MEASURE(S): The expression of adhesion glycoproteins (laminin and fibronectin), their receptors alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1, and E-cadherin was determined by immunohistochemistry on frozen sections. RESULT(S): The distribution of both adhesive glycoproteins, laminin and fibronectin, and their receptors was identical in endometriosis and endometrium. Fibronectin receptors (alpha 4 beta 1, alpha 5 beta 1) displayed distinct expression patterns in endometrium and endometriosis. No endometrial glands showed positive staining for the alpha 5 chain, whereas this integrin subunit was detected in almost all endometriotic lesions. The integrin alpha 4 chain was present in all endometriotic glands but was absent from endometrial glands in the proliferative phase of the cycle. CONCLUSION(S): No difference in cell adhesion molecule localization nor receptors was observed between endometriotic and endometrial samples, except for fibronectin receptors. Their expression persisted around endometriotic glands but not in endometrium. These results suggest that fibronectin receptors could play a role in the persistence of endometriotic lesions, despite menstruation in corresponding eutopic endometrium.

Adult↗
PubMed1994

Comparative evaluation of integrin alpha- and beta-chain expression in colorectal carcinoma cell lines and in their tumours of origin.

The integrin family consists of broadly expressed cell surface adhesion receptors, each member of which is composed of a non-covalently linked alpha/beta heterodimer. Integrin receptors are involved in the interaction with matrix proteins and may contribute to invasion and metastasis of carcinomas. To examine the biological role integrins play in colorectal carcinoma we compared the expression of integrin alpha- and beta-subunits in situ and in vitro. Eight newly established cell lines derived from immunohistochemically characterized colorectal carcinomas together with two sublines obtained after nude mouse passage and the commonly used colon carcinoma lines HT-29, SW480, SW620, and COLO 205 were investigated by immunocytochemistry and flow cytometry. The carcinomas in situ expressed alpha 1-, alpha 2-, alpha 3-, alpha 6-, alpha v- and beta 1-subunits in variable amounts while being devoid of alpha 4, alpha 5, and beta 3. The individual integrin profile of the tumour in tissue was essentially maintained in vitro. However, a neo expression of the alpha 5 chain was found, together with an induction or increase in alpha 1, alpha 2, alpha 3, alpha v and beta 1 levels. No decrease in integrin subunit expression was observed. Standard-serum and serum-free medium revealed no striking differences in alpha- and beta-chain expression in the cell lines HT-29 and COLO 205. In serum-free medium, SW480 showed a slight increase of alpha 1 and alpha 5 and a decrease of alpha 3 and alpha v while SW620 expressed more alpha 1. We conclude that the great variability of adhesion receptor expression of the integrin family in colorectal carcinomas in situ is essentially maintained in vitro, although culture conditions which are only marginally influenced by serum factors unpredictably lead to some increase in expression or even induction of several integrin subunits.

Antibodies, Monoclonal↗
PubMed1994

Minimum alpha chain cytoplasmic tail sequence needed to support integrin-mediated adhesion.

Previously, we found that deletion of the integrin alpha 4 and alpha 2 subunit cytoplasmic domains, just after the conserved GFFKR motif, causes a loss of adhesive activity mediated by VLA-4 or VLA-2, respectively (Kassner, P.D., and Hemler, M. E. (1993) J. Exp. Med. 178, 649-60; Kawaguchi, S., and Hemler, M. E. (1993) J. Biol. Chem. 268, 16279-12685). Here, we show for alpha 4 and alpha 2 chains (expressed in MIP101 and Chinese hamster ovary cells) that adding only 3-4 amino acids after the GFFKR motif restores substantial adhesive activity and that 5-7 amino acids confers maximal adhesive activity (to VCAM-1, CS1 peptide, or collagen, respectively). Point mutations within the most critical 5 alpha 4 residues had no effect on alpha 4 adhesive activity, nor did exchange of the alpha 4 tail with that of alpha 2. Thus, only a short and relatively nonspecific stretch of alpha chain cytoplasmic domain amino acids may be required to achieve maximal integrin adhesive activity. Also, comprehensive divalent cation titration assays revealed (i) that deletion of alpha chain cytoplasmic domains caused a marked decrease in the efficiency of divalent cation utilization during cell adhesion assays and (ii) that cytoplasmic domain deletion effects could be either suppressed or accentuated depending on the type and amount of divalent cation and the cellular environment utilized. Notably, integrin alpha chain tail deletions did not appear to alter the intrinsic ability to interact with ligand because deletion effects were minimal in the presence of metabolic energy inhibitors and were absent during cell-free ligand binding assays.

Amino Acid Sequence↗
PubMed1999

Specific binding of integrin alpha v beta 3 to the fibrinogen gamma and alpha E chain C-terminal domains.

Integrin alpha v beta 3, a widely distributed fibrinogen receptor, recognizes the RGD572-574 motif in the alpha chain of human fibrinogen. However, this motif is not conserved in other species, nor is it required for alpha v beta 3-mediated fibrin clot retraction, suggesting that fibrinogen may have other alpha v beta 3 binding sites. Fibrinogen has conserved C-terminal domains in its alpha (E variant), beta, and gamma chains (designated alpha EC, beta C, and gamma C, respectively), but their function in cell adhesion is not known, except that alpha IIb beta 3, a platelet fibrinogen receptor, binds to the gamma C HHLGGAKQAGDV400-411 sequence. Here we used mammalian cells expressing recombinant alpha v beta 3 to show that recombinant alpha EC and gamma C domains expressed in bacteria specifically bind to alpha v beta 3. Interaction between alpha v beta 3 and gamma C or alpha EC is blocked by LM609, a function-blocking anti-alpha v beta 3 mAb, and by RGD peptides. alpha v beta 3 does not require the HHLGGAKQAGDV400-411 sequence of gamma C for binding, and alpha EC does not have such a sequence, indicating that the alpha v beta 3 binding sites are distinct from those of alpha IIb beta 3. A small fragment of gamma C (residues 148-226) supports alpha v beta 3 adhesion, suggesting that an alpha v beta 3 binding site is located within the gamma chain 148-226 region. We have reported that the CYDMKTTC sequence of beta 3 is responsible for the ligand specificity of alpha v beta 3. gamma C and alpha EC do not bind to wild-type alpha v beta 1, but do bind to the alpha v beta 1 mutant (alpha v beta 1-3-1), in which the CYDMKTTC sequence of beta 3 is substituted for the corresponding beta 1 sequence CTSEQNC. This suggests that gamma C and alpha EC contain determinants for fibrinogen's specificity to alpha v beta 3. These results suggest that fibrinogen has potentially significant novel alpha v beta 3 binding sites in gamma C and alpha EC.

Animals↗
PubMed1992

The human intraepithelial lymphocyte marker HML-1 is an integrin consisting of a beta 7 subunit associated with a distinctive alpha chain.

The membrane antigen defined by the monoclonal antibody (mAb) HML-1 is abundantly expressed on, and largely restricted to, the T cells which populate the intestinal epithelium. We show that the mature form of the antigen is a heterodimer comprising a 150-kDa alpha chain and a 120-kDa beta chain. Direct sequencing of tryptic peptides cleaved from the purified beta chain identified this polypeptide with the integrin beta 7 isotype. cDNA clones coding for the beta 7 chain have recently been isolated from T cell cDNA libraries, but the beta 7 chain had not been identified at the protein level. No information is available concerning the primary structure of the HML-1 alpha chain. We show that this subunit is synthesized as a precursor form that undergoes, like several other integrin alpha subunits, a post-translational cleavage of a peptide bond. Among the 11 human integrin alpha chains previously identified, 10 have biochemical features and/or a distribution different from those of HML-1 alpha. One, VLA alpha 4 (CD49d), has a molecular mass of 150 kDa and is expressed on HML-1+ cells but is not recognized by HML-1 mAb. We conclude that HML-1 is a novel member of the integrin family made of the beta 7 chain and of an as-yet-undescribed human alpha chain characterized by the post-translational cleavage of a 10-kDa peptide. HML-1 is, thus, probably the human counterpart of the mouse antigen M290.

Antibodies, Monoclonal↗
PubMed1996

Recirculation and homing of lymphocyte subsets: dual homing specificity of beta 7-integrin(high)-lymphocytes in nonobese diabetic mice.

The beta 7-integrin subunit can pair with two alpha-chains, alpha 4 and alpha E, and is expressed mainly on lymphocytes. As an alpha 4-heterodimer it binds to the mucosal addressin MAdCAM-1, thus acting as a mucosal homing receptor. As an alpha E-heterodimer it binds to E-cadherin and is mainly found on intestinal intraepithelial lymphocytes. Consequently, beta 7 is mostly expressed on lymphocytes of the mucosal immune system. To study the compartmentalization of these cells further we compared the distribution of such lymphocytes in two strains of mice (BALB/c and NOD) and found that the distribution of beta 7-positive lymphocytes among various lymphoid tissues in these strains was very different. In NOD mice a conspicuous population of beta 7-integrin(high) lymphocytes expressing either alpha 4, alpha E, or both, was found in nonmucosal lymphoid tissues such as peripheral lymph nodes (PLNs). They mostly expressed the PLN homing receptor L-selectin, and included both naive and memory cells on the basis of their expression of CD44/pgp-1 and CD45RB, as did the few beta 7(high) lymphocytes in BALB/c PLNs. Their homing to Peyer's patches (PPs) and PLNs was equally effective and the cells homing to PPs and PLNs were equal in their level of L-selectin and alpha 4/beta 7 expression. However, functional studies indicated that their homing to PPs mostly depended on alpha 4/beta 7-integrin, whereas they mainly used L-selectin to home to PLNs. beta 7(high) lymphocytes were found also in circulating blood of unmanipulated NOD mice, and their L-selectin expression was higher than in BALB/c mice. These results show that lymphocytes of the mucosal immune system may also express the peripheral node homing receptor L-selectin during their recirculation and that in NOD mice they frequently retain a dual homing specificity, which leads to their accumulation in nonmucosal tissues.

Animals↗
PubMed1999

Integrin expression on neutrophils and mononuclear cells in blood and induced sputum in stable asthma.

BACKGROUND: We speculated that the expression of integrins in the airway lumen of asthmatic subjects might be altered compared with normal subjects during cell recruitment from circulation. METHODS: To test this hypothesis, we investigated the expression of integrin alpha-chains (CD11a, CD11b, and CD11c) in hypertonic saline-induced sputum and peripheral blood leukocytes in mild to moderate stable asthmatic and control subjects. Immunoreactivity for integrin alpha-chains was assessed by immunocytology on cytospin preparations of sputum and blood. RESULTS: In comparison of the percentages of CD11a+, CD11b+ and CD11c+ mononuclear cells in sputum with their blood counterparts, no significant differences were observed in control subjects, whereas CD11a and CD11b in asthmatic subjects were less expressed on sputum cells. In both control and asthmatic subjects, sputum neutrophils tended to decrease their expression of integrin alpha-chains compared with circulating neutrophils. CONCLUSIONS: We showed that the sputum of asthmatics, unlike normal subjects, is characterized by decreased expression of integrins on mononuclear cells compared with their blood counterparts. The results suggest that downregulation of integrins occurs in asthmatic airways after cell recruitment from circulation.

Adult↗
PubMed1999

Cloning, sequence analysis, and chromosomal localization of the novel human integrin alpha11 subunit (ITGA11).

The integrins are a large family of cell adhesion molecules consisting of noncovalently associated alphabeta heterodimers. We have cloned and sequenced the cDNA of a novel human integrin alpha-subunit, designated alpha11. The alpha11 cDNA encodes a mature protein with a large 1120-residue extracellular domain that contains an I-domain of 207 residues and is linked by a transmembrane domain to a short cytoplasmic domain of 24 amino acids. The deduced alpha11 protein shows the typical structural features of integrin alpha-subunits and is similar to a distinct group of alpha-subunits from collagen-binding integrins. However, it differs from most integrin alpha-chains by an incompletely preserved cytoplasmic GFFKR motif. The human ITGA11 gene was localized to bands q22.3-q23 on chromosome 15, and its transcripts were found in a variety of tissues, but predominantly in bone, cartilage, cardiac muscle, and skeletal muscle. Expression of a 5.5-kb alpha11 mRNA was detectable in small intestine.

Amino Acid Sequence↗
PubMed1989

Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha.

Lymphocyte homing is controlled by organ-specific interactions of lymphocytes and high endothelial venules (HEV). Adhesion of lymphocytes to Peyer's patch HEV, but not to peripheral node HEV, is inhibited by an antibody recognizing the murine lymphocyte antigen LPAM-1. Lymphoma cell variants were selected on the FACS for differences in LPAM-1 expression: the binding capacity of these variants to Peyer's patch HEV directly correlates with the level of LPAM-1 expression. The anti-LPAM-1 antibody recognizes the alpha subunit of an Mr 160,000/130,000 cell surface alpha beta heterodimer. The association of LPAM-1 alpha and beta chains requires the presence of Ca2+ ions. Proteins of Mr 84,000 and Mr 62,000 present in LPAM-1 immunoprecipitates appear to be products of the proteolytic processing of alpha chains. The structure of LPAM-1 is virtually identical to that of the human integrin receptor VLA-4. The cross-reactivity of a monospecific rabbit antiserum demonstrated the similarity between the human VLA-4 alpha chain and the alpha subunit of LPAM-1.

Animals↗
PubMed1995

Interaction of the cell-binding domain of fibronectin with VLA-5 integrin induces monokine production in cultured human monocytes.

The effect of fibronectin on IL-1 alpha, IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by both ELISA and bioassay. Fibronectin markedly stimulated the secretion of IL-1 alpha, IL-1 beta, TNF-alpha and IL-6 from cultured monocytes in a dose-dependent manner, with the maximal effect apparent within 24 h. Northern blot analysis revealed a marked increase in the abundance of mRNA specific for each monokine on exposure of monocytes to fibronectin. Monoclonal antibodies to the alpha chain of very late antigen (VLA)-5, the beta 1 integrin, the alpha chain of Mac-1, and the beta 2 integrin, as well as the synthetic peptide of GRGDSP (which corresponds to the cell-binding domain of fibronectin), inhibited (> 50%) fibronectin-induced monokine production. Monoclonal antibodies to the alpha chain of VLA-4, and the alpha chain of LFA-1, as well as the synthetic peptide CS-1 (which corresponds to the alternatively spliced connecting segment of fibronectin) and the control peptide GRADSP, had no inhibitory effect on monokine production. A MoAb, R60, that recognizes an epitope of the fibronectin molecule that includes the RGD sequence, inhibited monokine production, whereas the MoAb Y16, which recognizes another epitope of fibronectin not including RGD, did not. These results indicate that fibronectin-induced production of IL-1 alpha, IL-1 beta, TNF-alpha and IL-6 from cultured monocytes is mediated predominantly by interaction of the cell-binding domain of fibronectin with VLA-5, although Mac-1 also may contribute to this effect of fibronectin. Our results indicate that the interaction of fibronectin with integrins may contribute to the cytokine network in inflammatory response.

Binding Sites↗
PubMed2006

Morphological analysis of integrin-mediated adhesion of immature human mast cells to extracellular matrix proteins.

Specific heterodimers of alpha and beta integrins are implicated in mediating adhesion and functional activation of mast cells to extracellular matrix (ECM) proteins, determining thus homing, secretion and tissue distribution of these cells. In the present study, we have examined integrin expression and associated morphological features of mast cells adhering to ECM, also depending on cell activation and under the influence of protein kinase C (PKC) inhibitors. Unstimulated and PMA-activated human leukaemic mast cells (HMC-1 line) were allowed to adhere to fibronectin or vitronectin-coated surfaces. Cells were specifically stained for actin, beta(1, )alpha(1)-alpha(6), alpha(v) and alpha(v)beta(5 )integrins and were evaluated by fluorescence microscopy and confocal laser scan microscopy. Spontaneously adhering cells rapidly assumed an oblong shape, with pronounced formation of filopodia, whereas PMA-stimulated cells were round in shape. Clustering of integrins on filopodia and on comma-like shapes at the cell circumference in rounded cells was noted only for alpha(4), alpha(5) and beta(1 )chains in fibronectin-adhering cells, and for alpha(v) and alpha(v)beta(5) chains in vitronectin-adhering cells. On double staining, clustered integrins co-localized with each other and with actin at the cell membrane and along intracellular tension lines of actin filaments. PKC inhibitors affected the shape of cells, but adhesion was maintained. These data provide a morphological correlate to previously reported functional studies, demonstrating clustering of selected integrins during ECM adhesion at the cell membrane. This was associated with alignment of integrins along actin filaments within the cytoplasm, PKC signalling and changes in shape and activation of mast cells.

Cell Adhesion↗
PubMed1993

Ligand-dependent and -independent integrin focal contact localization: the role of the alpha chain cytoplasmic domain.

Many integrin receptors localize to focal contact sites upon binding their ligand. However, unoccupied integrin receptors do not localize to focal contact sites. Because the integrin beta 1 cytoplasmic domain appears to have a focal contact localization signal, there must be a mechanism by which this domain is kept inactive in the unoccupied state and becomes exposed or activated in the occupied receptor. We considered that this mechanism involves the alpha subunit cytoplasmic domain. To test this hypothesis, we have established two NIH 3T3 cell lines that express either the human alpha 1 wild-type subunit (HA1 cells) or the cytoplasmic domain deleted alpha 1 subunit (CYT cells). Both cell lines express similar levels of the human alpha 1 subunit, and there is no significant effect of the deletion on the dimerization and surface expression of the receptor. Furthermore, the deletion had no effect on the binding or adhesion via alpha 1 beta 1 to its ligand collagen IV. However, when these two cell lines are plated on fibronectin (FN), which is a ligand for alpha 5 beta 1 but not for alpha 1 beta 1, there is a striking difference in the cellular localization of alpha 1 beta 1. The HA1 cells show only alpha 5 in focal contacts, without alpha 1, demonstrating that all of the integrin localization is ligand dependent. In contrast, when the CYT cells are plated on FN, the mutant alpha 1 appears in focal contacts along with the alpha 5/beta 1. Thus, there is both ligand-dependent (alpha 5/beta 1) and ligand-independent (alpha 1/beta 1) focal contact localization in these cells. The truncated alpha 1 also localized to focal contacts in a ligand-independent manner on vitronectin. We conclude that the mutant alpha 1 no longer requires ligand occupancy for focal contact localization. These data strongly suggest that the alpha cytoplasmic domain plays a role in the normal ligand-dependent integrin focal contact localization.

3T3 Cells↗
PubMed1989

Structure of the gene for cartilage matrix protein, a modular protein of the extracellular matrix. Exon/intron organization, unusual splice sites, and relation to alpha chains of beta 2 integrins, von Willebrand factor, complement factors B and C2, and epidermal growth factor.

The entire gene for chicken cartilage matrix protein (CMP) has been isolated and characterized by restriction mapping, electron microscopy, nuclease S1 mapping, and sequence analysis. The gene, which is present in a single copy in the chicken genome, is 18 kilobase pairs long and comprises eight exons and seven introns. It has two transcription initiation sites, 8 base pairs from each other. A sequence very homologous to the consensus nuclear factor III binding-site sequence, a CAT- and a TATA-like sequence are found in the promoter region and ATTAAA is used as a polyadenylation signal. The nucleotide sequence defines a primary translation product of 493 amino acids which consists of a 23-amino acid signal peptide and two large repeated domains connected by an epidermal growth factor module. Amino acid sequences homologous to those of the repeated domains are present in the type A repeats of von Willebrand factor, complement factors B and C2, and in the alpha chains of the integrins Mac-1, p150,95, and LFA-1. The exon-intron structure indicates that the CMP gene may have arisen by exon duplication and exon shuffling during evolution. The GT-AG splice rule cannot be applied for the excision of the last intron of the CMP pre-mRNA. The donor splice site of intron G is basically different from the consensus sequence indicating that a novel type of splicing mechanism might exist in cartilage.

Amino Acid Sequence↗
PubMed1994

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express alpha 1, alpha 3 and alpha 5 chains of beta 1 integrins.

The expression of the beta 1 integrins was examined immunohistochemically in synoviocytes from normal synovitis membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were alpha 6 beta 1-positive but lacked alpha 1 through alpha 5. In mild inflammation type A synoviocytes neo-expressed alpha 1, alpha 3, and alpha 5 chains. In severe inflammation both type A and B synoviocytes expressed alpha 3, alpha 4, alpha 5, and alpha 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the beta 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The alpha 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). This effect was enhanced by combining IL-1 beta and TNF-alpha. Expression of the alpha 3 chain was up-regulated by IL-1 beta and, more intensely, by IFN-gamma. Transforming growth factor beta (TGF-beta) inhibited the up-regulating effect of IL-1 beta and antagonized the effect of IFN-gamma on alpha 3 chain expression. Expression of the alpha 5 chain was up-regulated significantly by co-stimulation through IL-1 beta together with TGF-beta or TNF-alpha. Thus, the beta 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1 beta, TNF-alpha, IFN-gamma, and TGF-beta are likely to be among the effectors regulating beta 1 integrin expression in synoviocytes in vivo.

Cells, Cultured↗
PubMed1995

A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3.

The leukocyte-restricted beta 2 (CD18) integrins mediate cell adhesion in a variety of events essential for normal immune function. Despite extensive research in this field, only three members of this integrin subfamily have been described: CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), and CD11c/CD18 (p150,95). We have identified a cDNA encoding a fourth alpha chain, alpha d, that associates with CD18. The alpha d subunit is more closely related to CD11b and CD11c than to CD11a. This integrin is expressed at moderate levels on myelomonocytic cell lines and subsets of peripheral blood leukocytes, and more strongly on tissue-compartmentalized cells such as foam cells, specialized macrophages found in aortic fatty streaks that may develop into atherosclerotic lesions. The alpha d/CD18 molecule exhibits preferential recognition of ICAM-3 over ICAM-1.

Amino Acid Sequence↗
PubMed2000

Expression of alpha and beta integrins during terminal differentiation of cardiomyocytes.

BACKGROUND: In the myocardium, myocyte cell division is irreversibly blocked shortly after birth. The signal that initiates cell cycle withdrawal is unknown. The purpose of this study was to relate changes in expression of beta1 integrin and its associated alpha subunits to cardiomyocyte cell cycle progression during the fetal-to-neonatal developmental transition in rat. METHODS AND RESULTS: The developmental expression pattern and function of beta 1 integrin and several of its associated alpha subunits were examined using reverse transcription (RT) polymerase chain reaction (PCR) and beta 1 blocking antibodies. During the fetal to neonatal transition, a dramatic shift occurred in the levels of beta1 and alpha isoforms. At the 17-day fetal stage only beta 1A was present, which remained relatively constant until immediately after birth then decreased by 30% at the adult stage. By contrast, beta 1D appeared at fetal day 18, increased at neonatal day 2, and afterwards remained constant. This resulted in a ratio of beta 1A to beta 1D of about 1:1 in the adult heart. The integrin beta 1-associated subunits, alpha 3, alpha 6, and alpha 7, were expressed at extremely low levels in 17-day fetal cardiomyocytes. After birth alpha 3 and alpha 6 transiently increased at the 2-day neonatal stage, while alpha 7 isoforms B, C, and X2 progressively increased to the adult stage. Unlike skeletal muscle cells, fluorescence-activated cell sorting analysis (FACS) showed no down regulation of the alpha 5 beta 1 fibronectin receptor during cell cycle withdrawal. Treatment of cultured cardiomyocytes with beta1 blocking antibody inhibited the cell cycle in fetal but not in neonatal cells. CONCLUSION: These results suggest that progression through the cardiomyocyte cell cycle may be dependent upon cell attachment via integrin beta1 and correlate with changes that occur in beta1 spliced variants and their respective alpha isoforms.

Animals↗