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PubMed2000

Structure of a rat α₁-macroglobulin receptor-binding domain dimer.

Alpha-macroglobulin inhibits a broad spectrum of proteinases by forming macromolecular cages inside which proteinases are cross-linked and trapped. Upon formation of a complex with proteinase, alpha-macroglobulin undergoes a large conformational change that results in the exposure of its receptor-binding domain (RBD). Engagement of this domain by alpha-macroglobulin receptor permits clearance of the alpha-macroglobulin: proteinase complex from circulation. The crystal structure of rat alpha1-macroglobulin RBD has been determined at 2.3 A resolution. The RBD is composed of a nine-stranded beta-sandwich and a single alpha-helix that has been implicated as part of the receptor binding site and that lies on the surface of the beta-sandwich. The crystallographic asymmetric unit contains a dimer of RBDs related by approximate twofold symmetry such that the putative receptor recognition sites of the two monomers are contiguous. By gel filtration and ultracentrifugation, it is shown that RBD dimers form in solution with a dissociation constant of approximately 50 microM. The structure of the RBD dimer might mimic a conformation of transformed alpha-macroglobulin in which the proposed receptor binding residues are exposed on one face of the dimer. A pair of phenylalanine residues replaces a cystine that is conserved in other members of the macroglobulin family. These residues participate in a network of aromatic side-chain interactions that appears to stabilize the dimer interface.

Amino Acid Sequence↗

PubMed1988

Human hepatocytes exhibit receptors for alpha 2-macroglobulin and pregnancy zone protein-proteinase complexes.

Hepatocytes were isolated by application of the two-step collagenase technique to pieces of human liver. 125I-labelled alpha 2-macroglobulin-trypsin complex bound to hepatocytes at 4 degrees C with a half time of approximately 4.5 h. At near equilibrium half of the receptors were saturated at an alpha 2-macroglobulin-trypsin complex concentration of about 60 pmol 1(-1) and the Scatchard plot was linear. Dissociation of the labelled complex was slow (T1/2 = 24 h) at low receptor occupancies. At high receptor occupancies dissociation was biphasic with a rate constant (K-1) for the initial rapid phase of about 2.4 x 10(-2) min-1. Labelled alpha 2-macroglobulin-trypsin complex bound at 4 degrees C was rapidly internalized at 37 degrees C (T1/2 = 1.9 min), and in 3.5 h approximately 10% of the label was released into the medium in a trichloroacetic acid-soluble form. At 37 degrees C, 125I alpha 2-macroglobulin-trypsin was taken up by hepatocytes and trichloroacetic acid soluble radioactivity appeared in the medium following a sigmoidal curve. Similar results were obtained with 125I-pregnancy zone protein-chymotrypsin complex. At 4 degrees C, hepatocytes bound nearly equal amounts of labelled alpha 2-macroglobulin-trypsin and pregnancy zone protein-chymotrypsin complex, and a large excess (100 nmol 1(-1) of one of the macroglobulins could almost completely abolish binding of trace amounts (5-20 pmol 1(-1] of the other. The present findings strongly suggest that the hepatocyte is of major importance for removal of alpha 2-macroglobulin- and pregnancy zone protein-proteinase complex in humans, in agreement with previous results in rats and mice.

Biological Transport, Active↗

PubMed1987

Repression of alpha 2-macroglobulin and stimulation of alpha 1-proteinase inhibitor synthesis in human mononuclear phagocytes by endotoxin.

Mononuclear phagocytes are a bone-marrow-derived subgroup of white blood cells which circulate as monocytes and, after differentiation into macrophages, become resident in many tissues. By synthesizing the important proteinase inhibitors alpha 2-macroglobulin and alpha 1-proteinase inhibitor mononuclear phagocytes contribute to the control of proteolysis both in blood and tissues. Applying a culture system which enables human blood monocytes to differentiate into macrophages in vitro, synthesis of alpha 2-macroglobulin and alpha 1-proteinase inhibitor was studied. The normal course of monocyte-macrophage maturation is accompanied by a strong increase of specific alpha 2-macroglobulin synthesis and a concomitant slight decrease of alpha 1-proteinase inhibitor. alpha 2-Macroglobulin can be designated as a marker protein of the monocyte/macrophage differentiation. Endotoxin (Salmonella typhi) in a concentration as low as 100 ng/ml strongly represses alpha 2-macroglobulin synthesis both in monocytes and macrophages. Furthermore, endotoxin completely abolishes the induction of alpha 2-macroglobulin synthesis during the course of normal monocyte in vitro cultivation, indicating that endotoxin is a strong inhibitor of the monocyte-macrophage maturation. In contrast to alpha 2-macroglobulin, alpha 1-proteinase inhibitor synthesis is strongly stimulated by endotoxin in monocytes as well as in macrophages.

Blood Proteins↗

PubMed1983

Structural arrangement of the proteinase binding sites in human alpha 2-macroglobulin.

Using singlet-singlet energy transfer measurements with labeled-chymotrypsin-alpha 2-macroglobulin complexes, we find that the two proteinase binding sites of alpha 2-macroglobulin are separated from each other by 44 A. The free thiol groups generated upon reaction of alpha 2-macroglobulin with trypsin or chymotrypsin react with thiopropyl Sepharose, indicating that they are located at the surface of the complexes. Singlet-singlet energy transfer experiments from labeled proteinases to labeled thiols of alpha 2-macroglobulin show that the thiol groups are in close contact with the proteinase molecules whether the latter are covalently or noncovalently bound to alpha 2-macroglobulin. In addition, they are remote from the association interface between the Mr = 360,000 halves of alpha 2-macroglobulin. Using the same approach we demonstrate that the active sites of chymotrypsin molecules are separated by a distance of at least 20 A from the thiols group of each alpha 2-macroglobulin subunit.

Binding Sites↗

PubMed1981

Serum and sputum alpha 2 macroglobulin in patients with chronic obstructive airways disease.

Serum alpha 2 macroglobulin concentrations were measured in patients with chronic obstructive airways disease and an age-matched group of control subjects. The mean serum level of alpha 2 macroglobulin was significantly lower in bronchitic subjects with acute chest infections than the mean value of the controls. No significant differences were observed between serum alpha 2 macroglobulin values in controls, subjects with "emphysema", and bronchitic patients who did not have chest infections. Sputum alpha 2 macroglobulin concentrations were compared in sputum samples from bronchitic patients with and without acute chest infections. The protein was detected (greater than 0.2 mg/l) in 94% of sputum samples from infected subjects but only 60% of non-infected sputum samples. Concentrations of alpha 2 macroglobulin in infected samples were significantly higher than the non-infected samples. Sputum/serum concentration ratios of alpha 2 macroglobulin were also significantly higher in infected samples but this difference was eliminated by "correcting" the values with the albumin sputum/serum ratios of the same samples. The results suggest that alpha 2 macroglobulin concentrations are higher in bronchial secretions during chest infection because of increased transudation from the blood rather than the presence of significant local secretion.

Aged↗

PubMed1980

Trypsin binding activity of alpha 2-macroglobulin in cystic fibrosis and other lung diseases.

Abnormalities of the interaction between alpha 2-macroglobulin and proteases have been suspected in cystic fibrosis. We measured the binding activity for trypsin of alpha 2-macroglobulin in 65 patients with cystic fibrosis, 41 obligate heterozygotes for cystic fibrosis, 18 children with asthma, 21 adult patients with chronic obstructive pulmonary disease, and 21 healthy control subjects. The assay was based on the observation that, once it is bound to alpha 2-macroglobulin, trypsin is no longer inhibited by soybean trypsin inhibitor. The bound trypsin retains activity against synthetic substrates such as N-alpha-benzoyl-arginine-p-nitroanilide. We found a moderately increased molar binding ratio of trypsin to alpha 2-macroglobulin in all patient groups and heterozygotes compared to healthy control subjects. The absolute concentration of alpha 1-macroglobulin was related to age rather than to the disease of the patient. Our data argue against a defect in protease-binding activity of alpha 2-macroglobulin in cystic fibrosis. The moderately increased binding activity observed could have been related to a structural difference in alpha 2-macroglobulin or to binding of ligands. This finding however, was not unique to patients with cystic fibrosis; the binding activity was increased in heterozygotes and in patients with other pulmonary diseases.

Adolescent↗

PubMed1985

In vitro preparation of nonenzymatically glucosylated human transferrin, alpha 2-macroglobulin, and fibrinogen with preservation of function.

Human transferrin, alpha 2-macroglobulin, and fibrinogen were incubated with [3H]-glucose. After a 7-day, 37 degrees C incubation at 20 mM glucose, transferrin incorporated 1.1 mol of glucose/mol protein; alpha 2-macroglobulin, 10 mol of glucose/mol; and fibrinogen, 3.8 of glucose/mol, or approximately 14 mumol of glucose/g for each protein. These results were the same for glucose labeled in the 1 or 6 position. No radiolabel was incorporated into the proteins during incubations with glucose labeled in the 2 position. The rate and extent of iron binding were identical for both glucosylated and nonglucosylated transferrin. Glucosylated transferrin bound to Wil-2 human lymphoblast cells with a Kd = 33 nM and receptor number of 3.4 X 10(5) receptors/cell; nonglucosylated transferrin with a Kd = 31 nM and receptor number of 3.9 X 10(5) receptors/cell. Glucosylated and nonglucosylated alpha 2-macroglobulin showed the same conformational change as determined on native PAGE after reaction with trypsin, plasmin, or methylamine and had the same activity in the Ganrot assay after reaction with trypsin or plasmin. The clearance of 125I-labeled, methylamine-treated alpha 2-macroglobulin from the mouse circulation was identical for both glucosylated and nonglucosylated alpha 2-macroglobulin, t1/2 = 3 min. alpha 2-Macroglobulin that was first glucosylated then reacted with methylamine bound to mouse peritoneal macrophages with a Kd of 2.5 nM and receptor activity of 370 fmol/mg cell protein. alpha 2-Macroglobulin that was first reacted with methylamine and then glucosylated bound with a Kd of 3 nM and receptor activity of 320 fmol/mg cell protein. Glucosylated fibrinogen had the same clotting time as control fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Binding of alpha2-macroglobulin and limulin: regulation of the plasma haemolytic system of the American horseshoe crab, Limulus.

The mediator of haemolysis in the plasma of the horseshoe crab, Limulus polyphemus, is limulin, a sialic acid-binding lectin. The haemolytic activity of limulin is inhibited by thiol ester-reacted forms of Limulus alpha(2)-macroglobulin, the third-most abundant protein of the plasma. Limulus alpha(2)-macroglobulin that has experienced cleavage of its internal thiol ester bond, consequent to reaction with proteases, or with the small primary amine, methylamine, reduces the haemolytic activity of limulin when present at molar excesses that approximate the relative concentrations of these two proteins in the plasma. Native, unreacted Limulus alpha(2)-macroglobulin has no effect on the haemolytic activity of limulin. Limulin binds thiol ester-reacted forms of Limulus alpha(2)-macroglobulin both in a solid-phase assay and in solution with an avidity 10-25 times higher than native, unreacted Limulus alpha(2)-macroglobulin. Protease-reacted alpha(2)-macroglobulin functions as a marker for the presence of foreign proteases in the blood of Limulus, and thus of pathogenic organisms that release proteases as facilitators of invasion and pathogenicity. Modulation of the haemolytic system represents a novel function for alpha(2)-macroglobulin.

Animals↗

PubMed1987

Sequence of rat liver alpha 2-macroglobulin and acute phase control of its messenger RNA.

Six alpha 2-macroglobulin cDNA clones were isolated from two liver cDNA libraries produced from rats undergoing acute inflammation. The coding sequence for rat alpha 2-macroglobulin including its 27-residue signal peptide and the 3' - and part of the 5' nontranslated regions were determined. The mature protein consisting of 1445 amino acids is coded for by a 4790 +/- 40 nucleotide messenger RNA. It contains a typical internal thiol ester region and 25 cysteine residues which are conserved between rat and human alpha 2-macroglobulin. Although the amino acid sequences of rat and human alpha 2-macroglobulin share 73% identity, two small divergent areas of 17 and 38 residues were found, corresponding to 29 and 11% identity, respectively. These areas are located in the bait region and, therefore, may confer specific proteinase recognition capabilities on rat alpha 2-macroglobulin. Following an inflammatory stimulation, rat alpha 2-macroglobulin mRNA levels increased 214-fold over control values and reached a maximum at 18 h. By 24 h the levels had decreased to less than 30% of the maximum value. Transcription rates from the alpha 2-macroglobulin gene as measured in nuclear run-on experiments showed a less than 3-fold increase in nuclei from acutely inflamed rats as compared to controls. These results suggest that the accummulation of alpha 2M mRNA is due to the combined effects of increased transcription rates and post-transcriptional processing.

Amino Acid Sequence↗

PubMed1989

alpha 2-macroglobulin traps a proteinase in the midregion of its arms. An immunoelectron microscopic study.

alpha 2-Macroglobulin, one of the major plasma proteinase inhibitors with Mr = 720,000, is known to inhibit proteinases of all four classes through the "trap mechanism" (Barrett, A. J., and Starkey, P. M. (1973) Biochem. J. 133, 709-724), but the proteinase binding site of alpha 2-macroglobulin has not been identified precisely. We localized bound proteinase molecules on the electron microscopic images of alpha 2-macroglobulin, using anti-proteinase IgG. Serratial Mr = 56,000 proteinase produced by Serratia marcescens was chosen as the antigenic probe in this study because its affinity to specific antibodies was retained in its bound state to alpha 2-macroglobulin. Dimers of alpha 2-macroglobulin/Mr = 56,000 proteinase complexes cross-linked with anti-Mr = 56,000 proteinase IgG were prepared and subjected to electron microscopic observations. The electron microscopic image of alpha 2-macroglobulin complexed with Mr = 56,000 proteinase had four straight arms with an overall shape looking like the character "H." From the way anti-Mr = 56,000 proteinase IgG linked two alpha 2-macroglobulins, it was concluded that the proteinase existed in the midregion of one of the arms. This result helps us to form a more concrete view of the trap mechanism in that one of the arms of alpha 2-macroglobulin wraps the trapped proteinase and holds it isolated from high molecular weight substrates in the surrounding medium.

Binding Sites↗

PubMed1989

4-O-acetyl-N-acetylneuraminic acid in the N-linked carbohydrate structures of equine and guinea pig alpha 2-macroglobulins, potent inhibitors of influenza virus infection.

To investigate the molecular basis of the differential ability of human, equine, and guinea pig alpha 2-macroglobulins to inhibit hemagglutination and infectivity of a human influenza virus, A/Memphis/102/72 (H3N2), the structures of oligosaccharides released from the three glycoproteins by hydrazinolysis were analyzed comparatively. Approximately seven to eight sugar chains were released from each subunit of two potent inhibitors (equine and guinea pig alpha 2-macroglobulins) and a weak inhibitor (human alpha 2-macroglobulin). More than 70% of the oligosaccharides contained sialic acids in all three cases. Structural analysis of these sialo-oligosaccharides revealed that all of the three glycoproteins contain biantennary oligosaccharides with one and two sialic acids as major sugar chains (70-80% of total sugar chains). Four percent of the biantennary oligosaccharides from equine sample, 10% of those from guinea pig, and 24% of those from human contain a fucosylated trimannosyl core. No triantennary oligosaccharide was detected in equine alpha 2-macroglobulin. However, human and guinea pig alpha 2-macroglobulins contain both fucosylated and nonfucosylated triantennary oligosaccharides. All sialic acid residues occur as the Sia alpha 2----6Gal group. The one unique feature of the carbohydrate groups of equine and guinea pig alpha 2-macroglobulins was the presence of 4-O-Ac-Neu5Ac as 30-50% of the total sialic acids, while human alpha 2-macroglobulin contained only Neu 5Ac. However, 4-O-Ac-Neu5Ac is not responsible for the potent inhibition of influenza virus infection and hemagglutination as will be described in the accompanying paper.

Animals↗

PubMed1989

Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3.

The inhibitory capacity of the alpha-macroglobulins resides in their ability to entrap proteinase molecules and thereby hinder the access of high molecular weight substrates to the proteinase active site. This ability is thought to require at least two alpha-macroglobulin subunits, yet the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3 (alpha 1I3) also inhibits proteinases. We have compared the inhibitory activity of alpha 1I3 with the tetrameric human homolog alpha 2-macroglobulin (alpha 2M), the best known alpha-macroglobulin, in order to determine whether these inhibitors share a common mechanism. alpha 1I3, like human alpha 2M, prevented a wide variety of proteinases from hydrolyzing a high molecular weight substrate but allowed hydrolysis of small substrates. In contrast to human alpha 2M, however, the binding and inhibition of proteinases was dependent on the ability of alpha 1I3 to form covalent cross-links to proteinase lysine residues. Low concentrations of proteinase caused a small amount of dimerization of alpha 1I3, but no difference in inhibition or receptor binding was detected between purified dimers or monomers. Kininogen domains of 22 and 64 kDa were allowed to react with alpha 1I3- or alpha 2M-bound papain to probe the accessibility of the active site of this proteinase. alpha 2M-bound papain was completely protected from reaction with these domains, whereas alpha 1I3-bound papain reacted with them but with affinities several times weaker than uncomplexed papain. Cathepsin G and papain antisera reacted very poorly with the enzymes when they were bound by alpha 1I3, but the protection provided by human alpha 2M was slightly better than the protection offered by the monomeric rat alpha 1I3. Our data indicate that the inhibitory unit of alpha 1I3 is a monomer and that this protein, like the multimeric alpha-macroglobulins, inhibits proteinases by steric hindrance. However, binding of proteinases by alpha 1I3 is dependent on covalent crosslinks, and bound proteinases are more accessible, and therefore less well inhibited, than when bound by the tetrameric homolog alpha 2M. Oligomerization of alpha-macroglobulin subunits during the evolution of this protein family has seemingly resulted in a more efficient inhibitor, and we speculate that alpha 1I3 is analogous to an evolutionary precursor of the tetrameric members of the family exemplified by human alpha 2M.

Acute-Phase Proteins↗

PubMed1984

Effects of diethyldithiocarbamate and nine other nucleophiles on the intersubunit protein cross-linking and inactivation of purified human alpha 2-macroglobulin by cis-diamminedichloroplatinum(II).

The cross-linking and inactivation of the plasma protein alpha 2-macroglobulin by cis-diamminedichloroplatinum(II) (cisplatin; Gonias, S. L., and Pizzo, S. V. J. Biol. Chem., 256: 12478-12484, 1981) was used to study platinum(II)-protein binding in the presence of compounds of therapeutic or biochemical significance. Diethyldithiocarbamate, potassium cyanide (KCN), sodium thiocyanate, L-methionine, N-acetyl-L-cysteine, 2-aminoethanethiol, L-cysteine, L-lysine, L-histidine, and L-arginine demonstrated variable capacity to inhibit reaction of cisplatin with protein and to reverse bidentate platinum(II)-protein binding in the in vitro model system. alpha 2-Macroglobulin lost 90% of its activity and was completely cross-linked, as determined with polyacrylamide gel electrophoresis, after reaction with cisplatin (0.6 to 1.0 mM). When diethyldithiocarbamate (4 to 15 mM) was incubated with alpha 2-macroglobulin and cisplatin, protein inactivation and cross-linking were totally prevented. In experiments with alpha 2-macroglobulin-platinum(II) complex, purified by gel filtration chromatography, 1.0 mM diethyldithiocarbamate completely reactivated the protein and eliminated nearly all of the intersubunit cross-links. Only KCN was comparably effective as an inhibitor of the reaction of cisplatin with alpha 2-macroglobulin; however, KCN was significantly less reactive with preformed platinum(II)-protein bonds than was diethyldithiocarbamate. N-Acetyl-L-cysteine, 2-aminoethanethiol, and L-cysteine were moderately reactive with free cisplatin. This group of compounds also demonstrated a low level of reactivity with the purified alpha 2-macroglobulin-platinum(II) complex. L-Methionine inhibited reaction of cisplatin with the protein, but was ineffective at reversing the reaction in the concentration range studied. The remaining compounds had little or no effect on the reaction of cisplatin with alpha 2-macroglobulin. The ability of diethyldithiocarbamate to displace nucleophilic protein groups from highly stable bonds with platinum(II) may be critical in its function as a rescue agent, limiting cisplatin toxicity towards nontumor cells.

Amino Acids↗

PubMed1998

Uptake of 125I-labelled alpha2-macroglobulin and albumin by human placental syncytiotrophoblast in vitro.

We have investigated the binding and internalization of alpha2-macroglobulin and serum albumin by human placental syncytiotrophoblast cells in vitro. The time course (obtained at 4 degrees C) of alpha2-macroglobulin binding indicated that an equilibrium was reached after 4 h. The binding of 125I-labelled alpha2-macroglobulin to syncytiotrophoblast cells was competitively reduced in the presence of excess unlabelled alpha2-macroglobulin. When the concentration-dependence of binding was examined over a wide concentration range, non-linear regression analysis yielded a Kd of 6.4 nM. In the case of albumin, binding was weak and ligand dissociated from the cell surface during aqueous washing making it impractical to analyze the binding reaction. In other experiments, syncytiotrophoblast cells were incubated with 125I-labelled alpha2-macroglobulin at 37 degrees C. Under these conditions, trypsin-resistant cell-associated radioactivity increased with time consistent with ligand internalization. 125I-labelled-ligand was internalized with a t1/2 of about 5 min. After a lag period some radioactivity was released back into the incubation medium. When measured at times up to 210 min, this was found to consist of mostly TCA-precipitable material that had been lost from the cell surface. However, when the incubation was extended to 24 h, almost 15% of the initial cell-associated radioactivity was released to the extracellular medium as TCA-soluble material, consistent with a slow rate of ligand degradation. The specific binding of 65Zn-labelled alpha2M was similar to that of the 125I-labelled ligand and trypsin-resistance measurements provided evidence of alpha2M-mediated 65Zn uptake. These results support a role for syncytiotrophoblast in the metabolism of alpha2-macroglobulin during pregnancy and are also consistent with a role for alpha2-macroglobulin in the maternal-fetal transport of zinc.

Cells, Cultured↗

PubMed1998

Rat hepatic stellate cell expression of alpha2-macroglobulin is a feature of cellular activation: implications for matrix remodelling in hepatic fibrosis.

1. Hepatic stellate cells are key mediators of hepatic fibrosis. We have studied hepatic stellate cell expression of the collagenase and general protease inhibitor alpha2-macroglobulin after activation in tissue culture and in response to certain cytokines. 2. Hepatic stellate cells isolated by Pronase-collagenase digestion were activated by culture on uncoated plastic. By Northern analysis hepatic stellate cells undergoing activation (5 days) expressed alpha2-macroglobulin mRNA and alpha2-macroglobulin could be immunolocalized to hepatic stellate cells from 5 to 15 days of culture. 3. By ELISA of cell culture supernatants hepatic stellate cell secretion of alpha2-macroglobulin was found to increase from 2. 78+/-1.13 ng x ml-1 x microgram-1 DNA per 24 h at 5 days of culture (n=8) to 13.55+/-4.64 ng x ml-1 x microgram-1 DNA per 24 h at 15 days of culture (n=7). Stimulation of hepatic stellate cells with interleukin-6 at 5 days caused a significant increase in alpha2-macroglobulin expression as did exposure to Kupffer-cell conditioned medium. However, exposure of hepatic stellate cells to interleukin-1, transforming growth factor-beta1 and tumour necrosis factor-alpha had no significant effect. 4. During profibrotic liver injury plasma alpha2-macroglobulin levels were found to increase to between 850% and 250% of the control value (100%) after bile duct ligation (72 h to 13 days respectively), and to 1166% and 1106% of the control value during progressive CCl4-induced fibrosis (24 h to 4 weeks respectively). 5. These data suggest that hepatic stellate cells are a potential source of the potent protease inhibitor alpha2-macroglobulin, expression of which may inhibit matrix remodelling during progressive fibrosis.

Animals↗

PubMedDate not supplied

[The role of macroglobulin family proteins in the regulation of inflammation].

The macroglobulin family represents a group of universal regulators involved into control of the inflammatory response to external and internal pathogens. Alpha-2-macroglobulin (MG), the major protein in the family, has 3 different binding sites and high affinity to an endocytosis receptor that allows MG to participate in recognition and phagocytosis of the foreign agents. The macroglobulin family proteins are most powerful apoptosis inhibitors: they bind autoaggressive hydrolases accumulating during inflammation. MG is the main transporter of cytokines and growth factors controlling the inflammatory response. At the same time, the macroglobulins are negative reactants of an acute phase of inflammation and the decrease of their synthesis at later stages is necessary for stimulation of collagenosis processes, coagulation, activation of thymulin, stimulating NK. At septic inflammation binding of macroglobulins to exotoxins can localize inflammation, and initiate systemic inflammatory response. Macroglobulin damage sharply reduces their subsequent utilization; this provokes accumulation of makroglodulin-proteinase complexes in biological fluids and may cause immune inflammation.

Apoptosis↗

PubMed1984

Experimental synovitis induced by intraarticular administration of alpha 2-macroglobulin-proteinase complexes.

Rheumatoid synovial collagenase was prepared from tissue cultures from rheumatoid arthritis patients, obtained after synovectomy. Alpha 2-macroglobulin was isolated from human plasma and complexed with collagenase or trypsin. Formation of both types of complexes was proven by sodium dodecyl sulfate and rate electrophoresis. Normal rabbits were injected intraarticularly into the right knee, on days 0, 3, and 6, with either alpha 2-macroglobulin-collagenase or alpha 2-macroglobulin-trypsin complexes. Control injections of alpha 2-macroglobulin, trypsin, or rheumatoid synovial collagenase were applied to the left knee joint cavity. Groups of rabbits were killed 18 hours, 1 week, or 3 weeks after the last injection, and cellular exudation into synovial fluid and morphologic alterations of synovium were investigated. Joints injected with alpha 2-macroglobulin showed no synovitis, while joints injected with collagenase showed an experimental synovitis. Alpha 2-macroglobulin-proteinase complexes, however, induced a synovitis, which was more severe than that occurring after injection of proteinases only. In the early stages, synovium showed perivascular accumulation of inflammatory cells, infiltration with neutrophils, proliferation of synovial cells, and exudation of inflammatory cells into synovial fluid. Later stages were characterized by infiltration with mononuclear cells and fibroplasia.

Animals↗

PubMed2004

Proteomic analysis of adipocyte differentiation: Evidence that alpha2 macroglobulin is involved in the adipose conversion of 3T3 L1 preadipocytes.

Adipogenesis is an important aspect of energy homeostasis. Here we have used a differential proteome mapping strategy to identify intracellular proteins that are differentially expressed during adipose conversion of 3T3 L1 preadipocytes. Two-dimensional gel electrophoresis analysis identified 8 proteins that are induced following hormone-evoked differentiation. In addition, we found that a alpha2 macroglobulin fragment was abundantly present in 3T3 L1 preadipocytes, but was virtually undetectable in fully differentiated adipocytes. Metabolic radiolabeling with (35S)methionine and Northern blot analysis indicated that the intracellular alpha2 macroglobulin fragment in preadipocytes was derived from the extracellular culture medium, not de novo synthesis. Incubation of preadipocytes with an antialpha2 macroglobulin polyclonal antibody caused depletion of the intracellular alpha2 macroglobulin fragments, and also enhanced spontaneous adipose conversion. These results suggest that intracellular alpha2 macroglobulin fragment inhibits adipocyte differentiation, and that hormone treatment induces differentiation at least in part by suppression of intracellular alpha2 macroglobulin activity in 3T3 L1 preadipocytes.

3T3 Cells↗