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PubMed1995

Modification of alpha 2-macroglobulin into a macrophage-activating factor through the action of liposome-stimulated B-cell membranous glycosidases.

The serum glycoprotein alpha 2-macroglobulin can be converted into a potent macrophage-activating factor that promotes the Fc gamma receptor-mediated phagocytosis of macrophages, through modification of the sugar moiety with liposome-treated B-cell glycosidase(s). This paper discusses the activation mechanism of B-cell membranous glycosidase by liposomes using mouse splenic B cells. B-cell membranous beta-galactosidase and beta-N-acetylglucosaminidase were significantly activated by liposome treatment, and this process can be regulated by trypsin-sensitive protein. To clarify the contribution of trypsin-sensitive protein to enzyme activities, the B-cell surface antigen receptor was studied. With the addition of a Fab' fragment of anti-mouse IgM but not IgD antibody, the activation of both glycosidases induced by liposomes was significantly inhibited and was essentially the same as that of saline-treated glycosidase activities. Consequently, interactions of liposomes with cell-surface IgM may cause B-cell membranous glycosidase activation. A significant decrease in membrane fluidity, particularly near the membrane surface rather than deep within the membrane, was observed in liposome-treated B cells using electron spin resonance. Liposomes would thus appear to interact with B cells via cell-surface IgM, with a consequent decrease in membrane fluidity, as well as the activation of B-cell membranous glycosidases, causing alpha 2-macroglobulin to be converted into a macrophage activating factor.

Animals↗

PubMed1994

[The effect of plasmin-modified proteinase inhibitors on macroglobulin production by human blood mononuclear cells in culture].

A study was made of the influence of plasmin (PL) complexes with alpha 2-macroglobulin (MG) and alpha 2-antiplasmin on secretion of MG, pregnancy-associated alpha 2-glycoprotein (PAG), and pregnancy-associated plasma protein A (PAPP-A) by mononuclear cells (MC), obtained from human peripheral blood. It has been shown that incubation of the MG-PL complexes with MC resulted in the increase in concentrations of all these macroglobulins (MG, PAG, and PAPP-A) in supernatants of cultured MC. We revealed the same effects of AP-PL with regard to the secretion of PZP and PAPP-A. However, this complex was found to suppress MG production by cultured MC. The effects found were dose dependent and some of them differed greatly in men and women, resp.

Cells, Cultured↗

PubMed1993

Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes.

The low density lipoprotein receptor-related protein (LRP) is a cell surface receptor that binds and internalizes several macromolecules including apolipoprotein E-enriched remnant lipoproteins and protease/antiprotease complexes such as activated alpha 2-macroglobulin. Its function has been studied primarily in cultured fibroblasts and in liver. In the current studies, we provide evidence that LRP is present on the surface of primary adipocytes isolated from rat epididymal fat pads. The activity of the receptor increases 2-3-fold within minutes after the adipocytes are exposed to physiological concentrations of insulin as indicated by an increase in the uptake of 125I-labeled activated alpha 2-macroglobulin. There is a corresponding increase in the uptake of [3H]cholesteryl esters from radiolabeled apoE-enriched beta-very low density lipoprotein. The latter uptake was inhibited by an antibody against LRP and by a fusion protein containing the 39-kDa protein, also called receptor-associated protein, a known inhibitor of LRP function. In vivo, rats that had been fed ad libitum accumulated approximately 24-fold more chylomicron cholesteryl esters in their epididymal fat pads than did fasted control animals. We suggest that insulin stimulation of LRP, in a synergistic action with lipoprotein lipase, increases the endocytic uptake of cholesteryl esters and triglycerides from remnant lipoproteins in postprandial adipocytes.

Adipose Tissue↗

PubMed1978

[Progressive antithrombin activity in rabbit plasma. Role of alpha macroglobulins].

Immunological methods associated with a kinetic study of blood coagulation allowed us to show the influence of the 2 rabbit alpha macroglobulins on the plasma progressive antithrombin activity. This study allowed the authors to discuss the participation of the alpha macroglobulins during the fibrinoformation and to think that these proteins have an immediate antithrombin activity.

Animals↗

PubMed1975

Identification and properties of J chain isolated from catfish macroglobulin.

After the cleavage of disulfide bonds of macroglobulin isolated from channel catfish (Ictalurus punctatus), an electrophoretically fast-moving polypeptide, which resembled human J chain, was released. On a Sephadex G-200 column equilibrated in 5 M guanidine, the elution position of the J chain overlapped with the descending part of the L chain peak. Further purification was achieved by DEAE ion-exchange chromatography. The isolated polypeptide, which had a molecular weight of 14,800 +/- 500, as determined ultracentrifugally by sedimentation equilibrium in 5 M guanidine, contained 7% carbohydrate with one residue of fucose, two of mannose, one of galactose, two of glucosamine, and one of sialic acid per chain. A comparison of catfish and human J chain amino acid analyses showed the former to have a higher content of serine, glycine, and phenylalanine and a lower content of aspartic acid, isoleucine, and arginine. Tryptic peptide maps of catfish and human J chains revealed very few common peptides. Rabbit and guinea pig antisera to human J chain did not cross-react with catfish J chain. Untreated, resuced and alkylated, S-sulfonated, or cyanogen bromide cleaved macroglobulin from the gar (Lepisosteus osseus) contained no polypeptide analogous to either catfish or human J chain by the criteria employed in this study.

Acetates↗

PubMed1978

Immunofluorescent evaluation of platelet alpha-1-antitrypsin and alpha-2-macroglobulin.

Rabbit raised anti-alpha-1-antitrypsin or anti alpha-2-macroglobulin antisera at dilution of less than 1:80 yielded non-specific staining on human platelets by indirect immunofluorescent technique. A similar pattern was in fact obtained by using normal rabbit sera at the same dilution and was due to the presence of smooth muscle autoantibodies. This indicates that human platelets do not contain significant quantities of these antigens. In agreement with the above, only microamounts of alpha-1-antitrypsin and alpha-2-macroglobulin were found to be present in human platelets by means of the electroimmunoassay.

Blood Platelets↗

PubMedDate not supplied

[Study of structural features of macroglobulins complexed with plasmin].

Activities of plasmin and trypsin contained in complexes with alpha 2-macroglobulin, related to pregnancy alpha 2-glycoprotein and with protein A were studied in presence of various inhibitors with a molecular mass of 0.2-70.0 kDa. Specific characteristics of interaction between plasmin and these macroglobulins inhibitors as well as with alpha 1-inhibitor of proteinases, antithrombin III and alpha 2-antiplasmin were studied using electrophoresis and immunoblotting.

Blotting, Western↗

PubMed1979

Specific precipitation of mouse and rat alpha 2-macroglobulin by immune sera directed against murine leukemia viruses.

Leukemia viruses preparations obtained from plasma of leukemic mice or rats were used to immunize rabbits. By immunoelectrophoresis, these non-absorbed antisera reacted specifically with one single mouse serum alpha 2 globulin which was further identified as alpha 2-macroglobulin by several criteria, including gel chromatography and nitracentrifugation. When mouse plasma derived virions were used as antigen, they gave rise to antibodies cross-reacting completely with the corresponding mouse and guinea pig protein and partially with rat and calf globulin. Immunization of rabbits with rat plasma derived virions induced antibodies directed preferentially against the rat alpha 2-macroglobulin.

Animals↗

PubMed1997

Topical azelastine has a 12-hour duration of action as assessed by histamine challenge-induced exudation of alpha 2-macroglobulin into human nasal airways.

BACKGROUND: Oral anti-histamine drugs are widely used in the treatment of seasonal allergic rhinitis. Recently, anti-histamines have become available also for topical treatment. OBJECTIVE: The present study, involving healthy subjects, examined the effect of topical azelastine on luminal entry of alpha 2-macroglobulin and symptoms evoked by repeat histamine challenges during 24 h. The effect was compared to a clinical dose of the oral anti-histamine cetirizine and to placebo treatments. METHODS: Placebo and azelastine (0.254 mg per nasal cavity) were delivered as two consecutive actuations per nasal cavity using a nasal spray device. Oral placebo and cetirizine (10 mg) were given as single doses in a placebo-controlled (double-dummy), double-blind, and cross-over design. Histamine-challenges were given 1 h before treatment, and 1, 6, 9, 12, and 24 h after each treatment. The nasal mucosal surface was lavaged after each challenge. The lavage-fluid levels of alpha 2-macroglobulin were determined to assess mucosal exudation of bulk plasma, and nasal symptoms were scored. RESULTS: Histamine (40-400 micrograms/mL) produced dose-dependent exudation and symptoms. Compared between each treatment and placebo, azelastine and cetirizine reduced the 40 and/or 400 micrograms/mL histamine-induced mucosal exudation of plasma from 1-12 h after treatment. In addition, cetirizine reduced the 40 micrograms/mL histamine-induced mucosal exudation of plasma 24 h after treatment. Differences between the two treatments were not evident regarding nasal symptoms. CONCLUSION: Histamine challenge-induced mucosal exudation of plasma appears to be a useful method for studies of the duration of action of antihistamines. We conclude that topical azelastine is suited for b.i.d. therapy and that neither the exudative process nor watery secretion may impede the efficacy or the duration of action of this nasal drug.

Administration, Intranasal↗

PubMed1998

A modified human alpha 2-macroglobulin derivative that binds tumor necrosis factor-alpha and interleukin-1 beta with high affinity in vitro and reverses lipopolysaccharide toxicity in vivo in mice.

The plasma protein alpha 2-macroglobulin (alpha 2M) has been reported to bind the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta), which play a central role in the pathogenesis of chronic inflammatory disorders, including Crohn's disease and rheumatoid arthritis. In this study, we chemically modified alpha 2M to stabilize a conformation of the protein (termed MAC, Macroglobulin Activated for Cytokine binding) with greatly increased TNF-alpha- and IL-1 beta-binding activity. The equilibrium dissociation constant (KD) for the binding of TNF-alpha to MAC was 80 +/- 20 nM, reflecting a 100-fold increase in affinity compared with native alpha 2M. To test the ability of MAC to neutralize proinflammatory cytokines in vivo, we treated mice with lipopolysaccharide (LPS) by intravenous injection. When MAC (2.5 mg) was administered by intraperitoneal injection 1 hour before the LPS, 12 of 12 mice survived and were without signs of toxicity at 5 days. None of the mice survived in the untreated control group (0/26) or in the group treated with 2.5 mg of unmodified alpha 2M (0/4). MAC also prevented the large increase in expression of inducible nitric oxide synthase in the liver, kidneys, and heart of LPS-treated mice. A novel property of MAC, compared with previously studied anticytokine agents, was its ability to reverse LPS toxicity in 12 of 24 mice when administered after the plasma level of TNF-alpha was elevated. These studies demonstrate that a naturally occurring protein, alpha 2M, can be modified so that it acquires the properties of clinically active monoclonal antibodies. Thus, MAC may have therapeutic potential in the control of chronic inflammatory disorders.

Animals↗

PubMed1996

Binding of rat alpha 1-inhibitor-3-methylamine to the alpha 2-macroglobulin signaling receptor induces second messengers.

Binding of receptor-recognized forms of tetrameric human alpha 2-macroglobulin (alpha 2M*) to a macrophage signaling receptor induces cAMP synthesis, increases in inositol 1,4,5-triphosphate (IP3) synthesis, and a concomitant rise in cytosolic free calcium ([Ca2+]i). The alpha 2M* signaling receptor is coupled to a pertussis-toxin insensitive G protein. Binding of alpha 2M* also occurs to the low density lipoprotein receptor-related protein/alpha 2M receptor (LRP/alpha 2MR), but this binding does not induce signal transduction. Rat alpha 1-inhibitor-3 (alpha 1I3) is a monomeric member of the alpha-macroglobulin/complement superfamily. Like alpha 2M, it can react with proteinases or methylamine which induces a conformational change causing activated alpha 1I3 to bind to LRP/alpha 2MR. We now report that alpha 1I3-methylamine binds to the macrophage alpha 2M* signaling receptor inducing a rapid rise in the synthesis of IP3 with a subsequent 1.5- to 3-fold rise in [Ca2+]i. alpha 1I3-methylamine binding to macrophages also caused a statistically significant elevation in cAMP. Native alpha 1I3, like alpha 2M, was unable to induce signal transduction. alpha 1I3 forms a complex with alpha 1-microglobulin, which has a distinct conformation from alpha 1I3 and is recognized by LRP/alpha 2MR. This complex also induces an increase in [Ca2+]i comparable to the effect of alpha 1I3-methylamine on macrophages. It is concluded that activation of alpha 1I3 by methylamine or binding of alpha 1-microglobulin causes similar conformational changes in the inhibitor, exposing the receptor recognition site for the alpha 2M* signaling receptor, as well as for LRP/alpha 2MR.

Acute-Phase Proteins↗

PubMed1998

Expression of alpha2-macroglobulin receptor-associated protein in normal human epidermal melanocytes and human melanoma cell lines.

Alpha2-Macroglobulin receptor/low-density lipoprotein receptor-related protein is a multifunctional cell surface receptor known to bind and internalize a large number of ligands. alpha2-Macroglobulin receptor-associated protein acts as an intracellular "chaperone" for this receptor, and it has been shown to inhibit binding of all its known ligands. In this paper, we characterize the expression of the receptor-associated protein in both normal human epidermal melanocytes and in six different human melanoma cell lines, by the use of flow cytometry and Western blotting analysis. We show that all the melanoma cell lines and the normal melanocytes express the receptor-associated protein at similar levels, with most located intracellularly. No receptor-associated protein was detected at the cell surface in the melanocytes or in three of the cell lines. However, in two of the melanoma cell lines, large amounts of receptor-associated protein were found on the cell surface, these having the largest amounts of it reported to date; in a further melanoma cell line, there was a small amount at the cell surface. We have also shown that the melanocytes and all the melanoma cell lines express the receptor itself at a wide range of levels, the highest levels of both the cell surface receptor and the cell surface receptor-associated protein being found in one particular melanoma cell line. By growing the cell lines under controlled conditions, we have demonstrated that, although the total cellular content of the receptor is markedly increased at high cell culture density, this treatment has no effect on the level of expression of the receptor-associated protein.

Cell Line↗

PubMed1992

Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues.

The hepatic alpha 2-macroglobulin receptor (alpha 2MR)/low density lipoprotein receptor-related protein (LRP) binds and endocytoses alpha 2-macroglobulin-proteinase complexes in plasma. In addition, it binds lipoproteins, a novel 40 kDa protein, and complexes between plasminogen activators and plasminogen activator inhibitor type-1. This study shows, for the first time, the tissue distribution of alpha 2MR/LRP as determined by immunohistochemistry with specific monoclonal antibodies. The analysis revealed alpha 2MR/LRP-expression in a restricted spectrum of cell types, including neurons and astrocytes in the central nervous system, epithelial cells of the gastrointestinal tract, smooth muscle cells, fibroblasts, Leydig cells in testis, granulosa cells in ovary, and dendritic interstitial cells of kidney. Monocyte-derived cells displayed marked alpha 2MR/LRP expression in the phagocytes of liver, lung and lymphoid tissues, but no or low expression in antigen-presenting cells including Langerhans' cells of the skin. The high abundance of alpha 2MR/LRP in certain cell types of most organs suggests two main routes for alpha 2MR/LRP-mediated ligand clearance: (1) systemic removal in liver of circulating ligands, and (2) non-hepatic interstitial removal in different organs, including the brain.

Antibodies, Monoclonal↗

PubMed1969

Mise en evidence de la formation d'un complexe ternaire entre trypsine, alpha(2)-macroglobuline et inhibiteur basique de pancreas.

The complex formed between trypsin and alpha(2)-macroglobulin retains the whole hydrolytic activity for benzoylarginine-p-nitroanilide (DL BAPNA). We have observed that the inhibition of this activity is dependent on the inhibitor used. While soya bean inhibitor (MW = 20 000) is ineffective, the basic pancreatic inhibitor (MW = 6 500) progressively inhibits the complex. In this latter case, we have observed the formation of a very weakly active ternary compound by two methods: kinetic and fluorescence polarization.Such differences suggest either that the contact site of trypsin for binding is not the same for each inhibitor or that the steric hindrance by macroglobulin prevents large inhibitors from reaching the active site. The pancreatic inhibitor can reach this site but its affinity is lower for the complex than for free trypsin.

Journal Article↗

PubMed1993

Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.

Lipoprotein (a) (Lp(a)) is a complex of low density lipoprotein (LDL) with apolipoprotein (apo) (a). To examine the size distribution of Lp(a), plasma was separated by fast flow gel filtration and Lp(a):B complexes were determined in the eluate by enzyme immunoassays, in which detection was performed with monoclonal antibodies specific for apoB. Lp(a):B particles displayed apparent molecular masses (M(r)) of 2 x 10(6) to at least 10 x 10(6). Lp(a) size isoforms differed by the expression of apoB epitopes and their interaction with cultured human skin fibroblasts. LDL was more effective in inhibiting binding, uptake, and degradation of low M(r) Lp(a) than of high M(r) Lp(a). In contrast, Glu-plasminogen, alpha 2-macroglobulin and tissue-type plasminogen activator were more effective in competing for the cellular degradation of high M(r) Lp(a) than of low M(r) Lp(a). Ligand blotting revealed that Lp(a) bound to the low density lipoprotein receptor, the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and to two other endosomal membrane proteins. We propose that the LDL receptor preferentially internalizes low M(r) Lp(a), whereas LRP may have a role in the clearance of high M(r) Lp(a).

Cells, Cultured↗

PubMed1997

Modulation of the alpha 2 macroglobulin receptor/low density lipoprotein receptor related protein by interferon-gamma in human astroglial cells.

Alpha 2 macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2 Mr/LRP) is a multi-functional cell surface receptor that has been implicated in important processes, such as atherogenesis, cellular migration, immune response and degenerative diseases. Its expression increases in human brain during Alzheimer's disease, tissue injury and neoplastic transformation. In the present paper we studied the regulation of alpha 2 Mr expression by interferon-gamma (IFN gamma) in human astrocytoma cell lines and in fetal astrocytes. Western blots demonstrated an increase of the alpha 2 Mr expression after 24 h of IFN gamma treatment. This effect paralleled the up-regulation of alpha 2 Mr mRNA, as detected by PCR. By prolonging incubation with IFN gamma, we observed a decrement of alpha 2 Mr in IFN gamma treated cells, both by western blot and cytometric analysis. Since in the same cells IFN gamma also up-regulates alpha 2 macroglobulin, this effect may be due to an augmented degradation of the receptor during its recycling.

Antibodies, Monoclonal↗

PubMed1995

Structure of heparin fragments with high affinity for lipoprotein lipase and inhibition of lipoprotein lipase binding to alpha 2-macroglobulin-receptor/low-density-lipoprotein-receptor-related protein by heparin fragments.

Heparin-derived deca- and octa-saccharides were subjected to affinity chromatography on lipoprotein lipase-Sepharose and the fractions eluted at high salt concentration were analysed by strong-anion-exchange chromatography. Two high-affinity decasaccharides were isolated and the structure determined by one- and two-dimensional 1H-n.m.r. spectroscopy. The affinities of 3H-labelled low-molecular-mass heparin and size-fractionated deca-, octa-, and hexa-saccharides for lipoprotein lipase immobilized on microtitre plates were determined from saturation curves. From competition experiments the affinities of unlabelled heparins and pure deca- and hexa-saccharide fragments were determined. The binding was size- and charge-dependent, but structural dependency was also indicated. Thus substitution of a 2-O-sulphated L-iduronic acid with D-glucuronic acid was less important than the sulphation pattern of the D-glucosamine residue for affinity for lipoprotein lipase. Heparin inhibits binding of lipoprotein lipase to alpha 2-macroglobulin-receptor/low-density-lipoprotein receptor-related protein. The effects of size, charge and structure for this inhibition were studied. The ability of the heparin fragments to inhibit binding correlated with their affinity for lipoprotein lipase. This indicates that the inhibition of the binding of lipoprotein lipase to alpha 2-macroglobulin-receptor/low-density-lipoprotein receptor-related protein by heparin is exclusively mediated by binding of heparin to lipoprotein lipase.

Amino Acid Sequence↗

PubMed1992

Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.

Tissue-type plasminogen activator and urokinase are serine proteases secreted by many cell types that participate in biological processes, such as tissue restructuring, cell migration, and tumor metastasis. Clinically, these proteases are used to dissolve coronary fibrin clots that are the proximal causes of acute myocardial infarction. In vivo, the activity of these enzymes is controlled by plasminogen-activator inhibitors, members of the serpin family of protease inhibitors. This study shows that tissue-type plasminogen activator-inhibitor complexes bind in solution to low density lipoprotein receptor-related protein (LRP), a large heterodimeric ubiquitous membrane receptor. In cultured cells, endocytosis and degradation of these complexes is reduced by polyclonal antibodies directed against LRP and inhibited by a M(r) 39,000 protein that binds to LRP and inhibits its interaction with previously known ligands, including apolipoprotein E and alpha 2-macroglobulin. We propose a role for LRP in the clearance of plasminogen activator-inhibitor complexes that is analogous to its function in the endocytosis of alpha 2-macroglobulin-protease complexes.

Animals↗