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PubMed1990

Alpha 2-macroglobulin and fibrinogen modulate inflammatory edema in man.

Animal experiments suggest that the response of acute-phase proteins (APPs) modulates the inflammatory reaction following tissue injury. To study this in man we investigated the relation between a number of APPs, including fibrinogen and alpha 2-macroglobulin, and the inflammatory edema induced by a primary immunization against cholera, typhoid, and yellow fever. Vaccination induces a significant APP response; however, only alpha 2-macroglobulin and fibrinogen were of importance to the amount of edema, measured 24 h after vaccination. High plasma levels of alpha 2-macroglobulin strongly inhibit the amount of edema, whereas a high level of fibrinogen proved to be a stimulating factor. This holds both for the basal prevaccination levels and the postvaccination levels. The normal variation of the plasma concentration of these proteins in healthy subjects seems to be a determining factor to the amount of edema in this kind of injury.

Acute-Phase Proteins↗

PubMed1992

Trypanosoma cruzi: enhanced alpha-macroglobulin levels correlate with the resistance of BALB/cj mice to acute infection.

Trypanosoma cruzi proteinases are very likely involved in host-cell invasion. Physiological plasma-proteinase inhibitors from the macroglobulin (MG) family, among them alpha-2-macroglobulin (A2M), are found in tissues and in the plasma of mammals. By complexing to all classes of proteinases, MGs inhibit their action on high-molecular-weight substrates. In vitro studies have shown that A2M impairs T. cruzi proteases and, consequently, the parasite's ability to invade host cells and enhances the phagocytic and microbicidal actions of resident macrophages against T. cruzi. To test the hypothesis of a putative "protective" effect for MG, we quantified it in BALB/cj mice during the course of an experimental T. cruzi infection, comparing a posteriori the levels in mice that died with those in animals that survived, which were considered as being susceptible and resistant to the infection, respectively. The results showed that surviving mice showed an increase in plasma concentrations of MG during the first few weeks after the infection, whereas the levels in mice that died during the acute phase did not differ significantly from those in non-infected mice. These findings and the previous in vitro data indicate a role for physiological proteinase inhibitors, particularly alpha-macroglobulins, in resistance to T. cruzi infection, whereby a balance between parasite proteases and host protease inhibitors may be crucial. MG may thus participate in the complex network of reactions involved in the early acute phase of the disease and contribute by conferring to the host an ability to survive the infection.

Acute Disease↗

PubMed1985

Human alpha 2-macroglobulin gene is located on chromosome 12.

A cDNA clone encoding amino acids 809-1451 of the protease inhibitor alpha 2-macroglobulin has been isolated from an adult human liver cDNA library. This cDNA was used to examine DNA samples prepared from a panel of human-mouse somatic cell hybrids with different numbers and combinations of human chromosomes for the presence of the human alpha 2-macroglobulin gene. The cosegregation of this gene and chromosome 12 in the cell hybrid panel indicated that the alpha 2-macroglobulin structural gene (designated A2M) is on human chromosome 12.

Amino Acid Sequence↗

PubMed1982

Inflammation, counter irritation and rat serum acute phase alpha 2-macroglobulin levels.

Following the injection of turpentine and carrageenan into rats, laboratory models for counter irritation were assessed by measuring changes in paw thicknesses and serum acute phase alpha 2-macroglobulin concentrations. Both indices of inflammation were also examined in groups of rats dosed with 6-mercaptopurine, the best inhibitor found so far of elevated levels of alpha 2-macroglobulin in rat serum. Results showed that there is no relationship between the degree of irritant-induced inhibition of inflammation and the serum concentration of the acute phase protein. Hence, at least in the models for counter irritation used in this study, alpha 2-macroglobulin cannot be viewed as an endogenous anti-inflammatory protein.

Animals↗

PubMed1982

Additional inhibitors of rat serum acute phase alpha 2-macroglobulin levels. Effect of 6-mercaptopurine and some lipoxygenase and cyclo-oxygenase inhibitors.

With the use of a previously described electroimmunoassay, 4 more compounds were found to depress acute phase alpha 2-macroglobulin levels in rat serum following the injection of turpentine. The compounds, meclofenamic acid, dextropropoxyphene, 5,8,11,14-eicosatetraynoic acid and 6-mercaptopurine are thus grouped with a variety of anti-inflammatory agents, cyclo-oxygenase inhibitors, hypolipidaemics and colchicine, all of which share the property of reducing the concentration of alpha 2-macroglobulin in rat serum. Compounds with immunosuppressant properties, namely amethopterin, azathioprine, cyclophosphamide and 5-fluorouracil, the steroids, betamethasone and dexamethasone, the lipoxygenase inhibitor, nordihydroguaiaretic acid, and MK477, a compound said to stimulate prostaglandin synthesis, did not reduce serum levels of the acute phase protein. 6-Mercaptopurine, a compound known to show anti-inflammatory properties in some systems, proved to be the strongest inhibitor found so far. The rat acute phase protein electroimmunoassay may thus be an effective screen for detecting a new class of anti-inflammatory agents. Knowledge of the mechanisms of action of drugs that depress rat serum alpha 2-macroglobulin concentrations may promote understanding of the control of acute phase protein production by the liver.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed2001

Disparity between the macroglobulin-producing components of 2 cases of follicular lymphoma with Waldenström's macroglobulinemia.

We report 2 patients with follicular lymphoma (FL) which was accompanied by Waldenström's macroglobulinemia (WM). One patient was a 65-year-old woman and the other a 60-year-old man. Both patients showed a high level of circulating macroglobulin (4.6 g/dL and 3.6 g/dL, respectively) and bone marrow involvement of small lymphoid cells. Moreover, in each case, the macroglobulin-producing component and the follicular component were determined to be of the same clone based on their identical light-chain restriction pattern and other factors. However, there was a difference in the histopathological characteristics of the macroglobulin-producing components of the 2 patients, especially the cytoplasmic immunoglobulin (Ig)M+ cell distribution in the biopsied lymph nodes. Test results for the female patient showed intrafollicular proliferation of those cells. The male patient's test results showed that IgM+ cells were located in the narrow extrafollicular areas of the lymph nodes. Our observations suggest that at least 2 different subtypes of FL may also be causative of a WM presentation.

Aged↗

PubMed1989

Interaction of lysosomal cysteine proteinases with alpha 2-macroglobulin: conclusive evidence for the endopeptidase activities of cathepsins B and H.

The lysosomal cysteine proteinases, cathepsins B, H, and L, were all shown to bind to alpha 2-macroglobulin. The bound enzymes remained active against low-molecular-weight synthetic substrates and bound the active-site-directed inhibitor, benzyloxycarbonyl-125I-Tyr-Ala-diazomethane. Binding of the radiolabeled inhibitor to high-molecular-weight protein on sodium dodecyl sulfate polyacrylamide gels indicated that a proportion of the enzymes was covalently bound to alpha 2-macroglobulin. Cleavage fragments of alpha 2-macroglobulin of Mr 92,000 and 86,000 were seen for cathepsins B, H, and L, indicating cleavage in the bait region. Binding and cleavage were observed for both single-chain and two-chain forms of cathepsin B from human, ox, and pig livers, showing that all active forms of cathepsins B, H, and L are endopeptidases.

Animals↗

PubMed1980

Studies on the complex between human alpha 2-macroglobulin and Crotalus adamanteus proteinase II. Release of active proteinase from the complex.

Proteinase II from Crotalus adamanteus venom formed a complex with human alpha 2-macroglobulin in which approx. 1.7 mol of enzyme were bound per mol inhibitor. The complex did not enzymatically inactivate human alpha 1 proteinase inhibitor. However, active proteinase II was released from the complex in the presence of a high molecular weight proteinase fraction from C. adamanteus venom. The alpha 2-macroglobulin-proteinase II complex was also unstable during incubation in serum, and the enzyme released from the complex caused inactivation of serum proteinase inhibitors. The results indicate conditions under which venom proteinases can be dissociated from their complexes with alpha 2-macroglobulin and thus remain functional in the presence of molar excesses of inhibitor.

Animals↗

PubMed1976

Purification of alpha 2-macroglobulin with trypsin-like activity from pleural fluids.

An alpha 2-macroglobulin with trypsin-like activity has been purified from pleural fluids of patients suffering from chronic pancreatitis. The isolation procedure includes ammonium sulphate precipitation, gel-filtration on Sephadex G-200 and DEAE-cellulose chromatography. It gives 46-fold purification of alpha 2-macroglobulin with a 13% recovery. Based on titration experiments with pancreatic inhibitor, the protein from three different patients contained 0.28, 0.46 and 0.80 mol of trypsin-like protease per mol of alpha 2-macroglobulin.

Chromatography, Gel↗

PubMed1984

Non-productive activation of the proteinase binding sites of alpha 2-macroglobulin on reaction of the inhibitor with matrix-linked trypsin.

The reaction of alpha 2-macroglobulin with matrix-linked trypsin is accompanied by apparently identical "bait" region cleavage, thioester cleavage and conformational change as the reaction with the soluble enzyme. However, no binding of proteinase occurs, but instead the inhibitor loses its ability to inactivate soluble trypsin. These findings indicate that the proteinase binding sites of alpha 2-macroglobulin are activated in the normal manner but decay before being able to bind the immobilized enzyme. Such non-productive activation of binding sites may occur also in the reactions of alpha 2-macroglobulin with soluble proteinases, thus explaining apparent enzyme inhibitor stoichiometries of less than 2:1 observed in these reactions.

Electrophoresis, Polyacrylamide Gel↗

PubMed1985

Binding of alpha 2-macroglobulin to hepatocytes: mechanism of in vivo clearance.

The binding of 125I-labeled human alpha 2-macroglobulin-methylamine to adult rat hepatocytes in primary culture was studied at 4 degrees C. Cells which had been in culture for 4 hours exhibited steady state ligand binding after 1 hour, a receptor number of 22,400 receptors per cell, and a dissociation constant of 0.6 nM. Adult rat hepatocytes exhibited a significant decrease in receptor number with increased time in primary culture with less than 10% of the initial number of receptors remaining after 2 days (p less than 0.01). In autopsy studies of mice injected intravenously with 125I-labeled alpha 2-macroglobulin-methylamine, greater than 90% of the cleared ligand was found in the liver. Autoradiography of the liver demonstrated that 80% of the ligand was cleared by hepatocytes. It is concluded that the hepatocytes are the primary pathway for clearance from the circulation of receptor recognized alpha 2-macroglobulin.

Animals↗

PubMed1989

Human alpha 2-macroglobulin as an inhibitor of insoluble trypsin.

alpha 2-Macroglobulin binds to insoluble trypsin bound on agarose beads inducing a reduction of proteolytic activity of the enzyme towards large substrates such as azocasein. When trypsin was bound on other matrices like sheep red blood cells or latex beads, the inhibition of proteolytic activity by alpha 2-macroglobulin was complete. These results show that alpha 2-macroglobulin inhibits similarly both soluble and insoluble proteinases.

Enzymes, Immobilized↗

PubMed1976

Demonstration and semiquantitative determination of complexes between various proteases and human alpha2-macroglobulin.

Complex formation in vitro between human alpha2-macroglobulin and the human proteases cationic trypsin, chymotrypsin, plasmin and granulocyte elastase and collagenase was clearly visualized by the use of thin-layer electrofocusing in polyacrylamide gel followed by electrophoresis in agarose gel containing antibodies against human alpha2-macroglobulin. The technique permits semi-quantitative determination of the amount of complex and can demonstrate the formation of complexes between alpha2-macroglobulin and protease in vivo in ascitic fluid in peritonitis.

Binding Sites↗

PubMed1981

Cleavage of peptide hormones by alpha 2-macroglobulin-trypsin complex and its relation to the pathogenesis and chemotherapy of acute pancreatitis.

Access to the active site of alpha 2-macroglobulin bound proteinases by macromolecular substrates and inhibitors is likely to be influenced by steric favourability and flexibility, as well as by molecular size. Hydrolysis of pure porcine cholecystokinin-pancreozymin 39, a flexible single chain peptide, by alpha 2-macroglobulin-trypsin complex resulted in a rapid up to 6-fold increase in cholecystokinin bioactivity; alpha 2-macroglobulin-trypsin rapidly abolished the bioactivity of endogenous parathormone in human plasma. Inhibition of both reactions was completed by low concentrations of antipain and leupeptin; Trasylol (aprotinin), a single chain peptide with three disulphide bonds, was an ineffective inhibitor even in massive molar excess. These findings may provide an explanation for the disordered calcium homeostasis in severe acute pancreatitis and for the failure of Trasylol to reduce mortality; they suggest that sterically favourable low molecular weight inhibitors may provide effective specific chemotherapy for the disease.

Acute Disease↗

PubMed1986

Distribution of serum zinc between albumin and alpha 2-macroglobulin in patients with different zinc metabolic disorders.

The distribution of total serum zinc between serum albumin and alpha 2-macroglobulin was evaluated by ultracentrifugation in patients with cirrhosis of the liver, insulin-dependent diabetes mellitus, or chronic renal failure. We found that the alpha 2-macroglobulin bound zinc fraction amounts to approximately 6 and 5% of the total serum zinc in patients with cirrhosis of the liver and diabetes mellitus, which corresponds to the distribution in controls. In patients with chronic renal failure, however, the alpha 2-macroglobulin-bound zinc fraction only constitutes approximately 2%, which is significantly less than in controls. Our findings indicate that most of the total serum zinc is bound to serum albumin.

Aged↗

PubMed1985

Rat plasma alpha 1-inhibitor3: a member of the alpha-macroglobulin family.

The overall mechanism of interaction with proteinases of alpha 1-inhibitor3, a plasma proteinase inhibitor so far specific to the rat, has been shown to be closely similar to that described for alpha-macroglobulins. This mechanism includes: (i) the cleavage of at least one susceptible peptidic bond which leads to structural changes in the molecule. (ii) The cleavage of a putative thiol ester bond in another site of the molecule which permits the covalent linkage of the enzyme. Moreover, fragmentation of alpha 1-inhibitor3 upon heating as observed for alpha-macroglobulin quarter subunits has been demonstrated. The question is raised of the presence of such a molecule in rat plasma in addition to two alpha-macroglobulin species, all of these proteinase inhibitors being antigenically unrelated.

Acute-Phase Proteins↗

PubMed1986

The structure around the thioester bond in bovine alpha 2-macroglobulin. Possible implications for the conformational stability of the inhibitor on thioester cleavage.

The residues contributing to the thioester bonds in bovine alpha 2-macroglobulin were differentially labelled by modification of the Glu moiety with [14C]methylamine and of the Cys moiety with iodo[3H]acetate. The labelled region was identified and analyzed in a tryptic peptide. Two amino acid replacements between human and bovine alpha 2-macroglobulin were found at positions +3 (Val/Ala) and +4 (Leu/Arg) from the Glu moiety of the thioester. Thus, marked differences exist between the human and bovine proteins in side chain size and charge close to the thioester bonds. These differences may explain the greater conformational stability of bovine alpha 2-macroglobulin, compared with that of the human inhibitor, after cleavage of the thioester bonds.

Amino Acid Sequence↗

PubMed1986

Preferential binding of collagenase to alpha 2-macroglobulin in the presence of the tissue inhibitor of metalloproteinases.

The binding of collagenase to both alpha 2-macroglobulin and the tissue inhibitor of metalloproteinases was studied using purified materials. Collagenase bound preferentially to alpha 2-macroglobulin although no transfer of collagenase to alpha 2-macroglobulin occurred if the enzyme was first mixed with the tissue inhibitor of metalloproteinases. The sequences of amino acids in both inhibitors likely to be responsible for the binding of collagenase are discussed and compared to the cleavage site in the collagen molecule.

Animals↗