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PubMed2002

Lack of association of the two polymorphisms in alpha-2 macroglobulin with Alzheimer disease.

Alzheimer disease is a complex neurodegenerative disorder that is characterized by cognitive decline and distinct neuropathology. The gene for alpha-2 macroglobulin (A2M) on chromosome 12 has two polymorphisms that, in some cases, are associated with Alzheimer disease. We examined these two polymorphisms in our families in the DNA Bank (a collection of DNA samples from families with Alzheimer disease in Texas). Using both association studies and sib transmission/disequilibrium tests, we found no association of the two polymorphisms with the disease in our collection. In addition, we did not find an association of the disease with the two polymorphisms in A2M in a small subset of National Institute of Mental Health (NIMH) families. Thus, our studies do not support the A2M polymorphisms as a risk factor for Alzheimer disease.

Adult↗

PubMed1995

Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein.

Both apolipoprotein E and its receptor, the low-density-lipoprotein receptor-related protein (LRP), are associated with senile plaques in Alzheimer's disease. We examined the relationship of other LRP-related molecules to senile plaques. LRP is a multifunctional receptor that binds and rapidly internalizes at least seven ligands: apolipoprotein E, activated alpha 2-macroglobulin, tissue and urokinase-type plasminogen activators, plasminogen activator inhibitor-1, lipoprotein lipase, and lactoferrin. Using immunohistochemistry, we showed that all of these ligands, representing a diverse group of otherwise apparently unrelated proteins, accumulate on senile plaques. We also studied expression of the receptor-associated protein, a physiological inhibitor of LRP, in the hippocampal formation from normal subjects and Alzheimer's disease patients. Receptor-associated protein colocalizes with LRP on neuronal soma, but not on neuronal processes or reactive astrocytes. It is not present on senile plaques. These results suggest that senile plaque-associated LRP can bind its ligands, but clearance of these compounds may be impaired in the vicinity of senile plaques.

Alzheimer Disease↗

PubMed1980

Synovial fluid in seronegative juvenile rheumatoid arthritis: studies of immunoglobulins, complements, and alpha 2-macroglobulin.

Synovial fluid of 20 children with seronegative juvenile rheumatoid arthritis (JRA) and 20 patients with other joint pathology was examined for levels of total hemolytic complement and selected components, immune complexes, and alpha 2-macroglobulin (alpha 2-M). When adjusted for total protein, synovial levels of total hemolytic complement, C3, C4, and alpha 2-M did not differ significantly in the two groups. The concentrations of IgM and IgG were elevated in the JRA synovial fluid, but immune complexes were not increased when compared with non-JRA group as determined by the Raji cell technique. alpha 2-M activity against substrates of C1 esterase was absent. therefore, evidence of specific increase in immune complexes and complement activation was sought but not found, suggesting that they may not be a major factor in the pathogenesis of seronegative, pauciarticular JRA.

Adolescent↗

PubMed1984

Degradation of a chromogenic substrate by alpha 2-macroglobulin from plasma of patients with rheumatoid arthritis.

We have shown previously that serum from patients with rheumatoid arthritis (RA) contains a polyclonal B cell activator that is associated with alpha 2-macroglobulin (alpha 2M). Some biologic effects of this activator appear to be due to a trypsin-like protease attached to alpha 2M. Therefore, in the present study, we used an anti-alpha 2M antibody solid-phase assay, with Chromozym-Try as a substrate, to determine the level of alpha 2M-protease complexes in plasma alpha 2M. We found higher levels of these complexes in RA patients than in 2 control groups. Since alpha 2M-protease complexes have been shown to induce RA-like inflammation in experimental animals and to be produced by lymphoid cells, we speculate that they may be involved in the pathogenesis of RA. However, the role of the other cells or enzyme systems in the formation of these complexes has not yet been ruled out. Results of these investigations could lead to another link between activation of the immune system and joint inflammation.

Adult↗

PubMed1986

Alpha 2-macroglobulin-proteinase complexes as correlated with alpha 1-proteinase inhibitor-elastase complexes in synovial fluids of rheumatoid arthritis patients.

The levels of alpha1-proteinase inhibitor-elastase and alpha 2-macroglobulin (alpha 2M)-proteinase complexes were measured in synovial fluids from arthritis patients by use of specific immunosorbent assays. Both types of proteinase inhibitor-proteinase complexes were significantly correlated with each other as well as with the total neutrophil count in synovial fluids of rheumatoid arthritis patients but were discordant in synovial fluids of patients with osteoarthritis. One synovial fluid sample showed active (inhibitory) alpha 2M as well as active collagenase. We purified alpha 2M from pooled synovial fluids obtained from patients with rheumatoid arthritis. This alpha 2M retained approximately 90% of its proteinase binding (inhibiting) capacity, compared with that of normal plasma alpha 2M. We found no evidence that alpha 2M was inactivated by means other than proteinases.

Arthritis, Rheumatoid↗

PubMed1987

Plasma from rheumatoid arthritis patients does not contain abnormally high levels of alpha 2-macroglobulin-proteinase complexes.

We measured the levels of alpha 2-macroglobulin (alpha 2M)-proteinase complexes in the plasma of 18 patients with classic rheumatoid arthritis, 11 age-matched patients with noninflammatory back pain and osteoarthritis, and 8 healthy volunteers. In contrast with previous reports, we found no evidence of alpha 2 M-proteinase complexes in the plasma samples from individuals in any of the groups. In our assays, all activity that might have been the result of the presence of such complexes in the plasma samples proved instead to be an artifact attributable to contamination of the anti-alpha 2M antibody immobilized on the AffiGel solid phase with a trypsin-like proteinase. When the contaminating activity was eliminated by pretreatment of the antibody with 1 mM diisopropyl fluorophosphate, no degradation of substrate was detected with any of the plasma samples. However, the ability of the solid-phase assay to detect and quantitate alpha 2M-proteinase complexes when they are present was confirmed in control experiments with plasma samples to which performed alpha 2M-trypsin complexes had been added, or in which alpha 2M-kallikrein complexes had been generated by activation of Hageman factor (coagulation factor XII). We therefore conclude that neither normal plasma nor that from rheumatoid arthritis patients contains measurable amounts of alpha 2M-proteinase complexes.

Arthritis, Rheumatoid↗

PubMed1991

Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic joints.

We studied the state of alpha 2-macroglobulin (alpha 2M), an important inhibitor of cartilage-degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive alpha 2M (i alpha 2M), which comprises alpha 2M complexed to proteinases and alpha 2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for i alpha 2M. In addition, levels of alpha 2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase-alpha 1-antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of i alpha 2M exceeded 1, indicating an intraarticular generation. Levels of i alpha 2M significantly correlated with neutrophil numbers (P less than 0.0005) and with levels of elastase-alpha 1-antitrypsin complexes and of lactoferrin (P less than 0.00001 for both). Moreover, part of i alpha 2M consisted of alpha 2M complexed to elastase-like and chymotrypsin-like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of i alpha 2M was approximately 10-fold larger than the amount complexed to these proteinases. In vitro inactivation of alpha 2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of alpha 2M, because eglin C completely abolished the inactivation of alpha 2M by cell-free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of alpha 2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of alpha 2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases.

Adolescent↗

PubMed1976

Preclinical warning of recrudescent mammary cancers by pregnancy-associated alpha-macroglobulin.

Nine of 30 mammary cancer patients developed metastases during 13-94 months after mastectomy. All 9 patients had elevated blood levels of pregnancy-associated alpha-macroglobulin (PAM) 1-21 months before conventional detection of metastases. Seven of the clinically well patients had PAM rises exceeding 90 per cent above the baseline and in 4 of these the PAM later fell to lower levels. PAM appears to have potential as an indicator of the growth of micrometastases.

Adult↗

PubMed1989

Uptake of alpha 2-macroglobulin-trypsin complex by human placenta is mediated by a microvillous membrane receptor.

The fate of native alpha 2-macroglobulin (alpha 2M) or its trypsin complex (alpha 2M-T) was studied in the isolated dually-perfused lobule of term human placenta. [125I]-alpha 2M added to the maternal circuit was unchanged during the course of the perfusion with minimal activity becoming associated with the placental tissue. Transfer of radioactivity into the fetal circulation accounted for only 0.07 per cent of the initial dose after 2 h. In contrast, [125I]-alpha 2M-T was rapidly taken up into the placental tissue (nearly 28 per cent of the initial dose during the 2-h perfusion) and breakdown products were released into both maternal and fetal circulations. At the end of 2 h, radioactivity levels on the fetal side were 13 times higher than those found with the native protein. These indications of a classical receptor-mediated uptake and breakdown pathway were confirmed in experiments in which the acidotrophic agent chloroquine was added to the maternal circuit prior to the alpha 2M-T. In the presence of chloroquine, tissue uptake was inhibited and the subsequent release of radioactive degradation products into the fetal circuit was similar to the levels seen with alpha 2M. Incubation of term trophoblast cells at 37 degrees C with [125I]-alpha 2M-T revealed over three-fold greater cell-associated activity than was found with the native protein. In another series of experiments, a purified microvillous membrane fraction was prepared from term placentae using buffers containing 1 mM iodoacetate. In the presence of this proteolytic enzyme inhibitor, binding studies showed a single class of low affinity receptors for the alpha 2M-T complex capable of binding 4.8 +/- 1.3 (SEM) micrograms of complex per mg of membrane protein. There was no binding of the native protein.

Cells, Cultured↗

PubMed1994

Cytokine and insulin regulation of alpha 2 macroglobulin, angiotensinogen, and hsp 70 in primary cultured astrocytes.

Acute-phase proteins and heat shock proteins (hsp) are upregulated following exposure to a number of conditions including bacterial infection, tissue injury, or stress. We show here that alpha 2 macroglobulin (alpha 2M), angiotensinogen (AOG), and hsp 70 are regulated by cytokines in primary cultures of astrocytes. In addition, we have found that insulin modulates the effect of cytokines on these proteins. In cells treated with lipopolysaccharide (LPS) conditioned Raw media, interleukin (IL)-6, or IL-1 beta for 24 h, there was a significant decrease of alpha 2M secretion below control levels. In the absence of insulin, however, similar treatments resulted in a significant increase in alpha 2M secretion. AOG secretion increased significantly following treatment with individual cytokines either in the presence or absence of insulin, but conditioned media did not cause a response in the absence of insulin. Hsp 73 concentrations also increased following treatment with conditioned media and IL-1 beta in the presence or absence of insulin. Following IL-6 treatment, however, hsp levels either decreased (- insulin) or did not change (+ insulin). To determine whether acute-phase proteins are regulated similarly to hsp, astrocytes were subjected to elevated environmental temperatures. Cells incubated at 43 degrees C for 90 min showed a marked increase in AOG secretion. However, alpha 2M and hsp 73 levels remained unchanged. In the absence of insulin, heat shock caused a significant increase of alpha 2M and AOG secretion. Thus, in astrocytes, alpha 2M is upregulated by cytokines and heat shock in the absence of insulin, while in the presence of insulin, cytokines function as negative regulators.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensinogen↗

PubMed1996

alpha2-Macroglobulin is mainly produced by cancer cells and not by hepatocytes in rats with colon carcinoma metastases in liver.

Localization and production of alpha2-macroglobulin (alpha2M), a multifunctional binding protein with protease and cytokine scavenging properties, was studied in situ in rat livers containing experimentally induced colon carcinoma metastases by means of immunocytochemistry and in situ hybridization methods. The study was performed to investigate whether alpha2M production by hepatocytes plays a role in the defense against the growth of metastases on the basis of its protease inhibiting capacity. It was found that colon cancer cells in all developmental stages of the metastases contained large amounts of messenger RNA (mRNA) of alpha2M but hardly any alpha2M protein. Cancer cells in culture contained large amounts of both mRNA and protein of alpha2M. In contrast, stromal cells and liver cells did not show positivity for alpha2M mRNA above background levels. The exception was a few layers of hepatocytes around the latest stage of metastases. Hepatocytes contained both alpha2M mRNA and protein only when Kupffer cells were present, indicating that alpha2M mRNA production was induced via Kupffer cells. On the other hand, alpha2M protein was found in high amounts in the sinusoids and stroma of all metastases, irrespective of their developmental stage. Increased levels of alpha2M could not be detected in serum in all but one rat tested (n=8). It is concluded that production of alpha2M by hepatocytes occurs only around the latest developmental stage of metastases and that alpha2M does not play a significant role in the defense against metastatic cancer growth in rat liver. In contrast, cancer cells produce and secrete large amounts of alpha2M, which seems to be linked with their tumorigenicity. We suggest that this alpha2M captures cytokines rather than proteases by complex formation. These complexes were observed using immunocytochemical staining for alpha2M protein indicating that it was captured by either stromal cells, sinusoidal cells, or hepatocytes that are in direct contact with cancer cells, Therefore, changes in serum levels of alpha2M were limited, indicating that these levels do not reflect local production and effects of alpha2M.

Animals↗

PubMed1984

Plasminogen activators, activation inhibitors and alpha 2-macroglobulin produced by cultured normal and malignant human cells.

In the present paper we have characterized the plasminogen activators (PA) synthesized by 25 different human cell lines. Technically easy methods were adopted for concentration and immunological characterization of the activators even in the presence of PA inhibitors. Most cell lines produced u-PA (mol. wt 55,000), melanoma and HeLa cells t-PA (mol. wt 66,000) and two carcinoma cell lines and normal skin fibroblasts produced no detectable PA. The classical 125I-fibrin method was compared to a caseinolytic assay and some of the discrepancies between results obtained with the two methods were shown to be due to cell-derived NaDodSO4-sensitive proteinase inhibitors in culture media. Additionally, synthesis and uptake by the cells of the wide-spectrum proteinase inhibitor alpha-2-macroglobulin ( alpha 2M ) were studied by radioimmunoassay and immunofluorescence. No production of alpha 2M could be measured in any of the malignant cell lines. In normal cells no correlation existed between the production of alpha 2M and the observed inhibition of PA activity, which indicates that other proteinase inhibitors are produced by the cells.

Cells, Cultured↗

PubMed1986

Human tumor cells synthesize and secrete alpha-2-macroglobulin in vitro.

In previous studies we showed that human sarcoma and melanoma cell lines synthesize and secrete into culture medium a glycoprotein, migrating in urea sodium dodecyl sulfate-polyacrylamide gel electrophoresis at Mr 140,000. It is not detected in cultures of the corresponding normal cells. Conditioned medium of the melanoma cell line HMB-2, producing among the cell lines tested the largest amounts of this glycoprotein, has now been used as a source for purification of the protein. NH2-terminal amino-acid sequence determination of the purified glycoprotein showed that it is identical to human alpha 2-macroglobulin (alpha 2M). Rabbit antibodies raised against the glycoprotein specifically reacted in immunoblotting and immunodiffusion tests with alpha 2M present in human plasma. Likewise, these antibodies immunoprecipitated from the conditioned media of 35S-methionine-labelled melanoma and osteosarcoma cell lines the protein which had a molecular weight corresponding to alpha 2M. alpha 2M was also synthesized and secreted by 2 strains of fetal lung fibroblasts but not by fetal skin fibroblasts or adult skin fibroblasts autologous to the osteosarcoma cell line.

Cells, Cultured↗

PubMed1988

Tumor-associated alpha-2-macroglobulin in human melanomas.

We and others have previously shown that human melanoma cell lines in culture synthesize alpha-2-macroglobulin (alpha 2M). We have now studied melanomas from 30 patients for the presence of alpha 2M using the peroxidase anti-peroxidase technique on histologic sections from paraffin-embedded tissues and primary antibody raised against tumor-associated alpha 2M in rabbits. alpha 2M was detected in 10 of the 30 melanomas studied. In all but 2 cases the presence of alpha 2M was restricted to solitary tumor cells or to solitary foci of tumor tissue. In one case of melanoma almost all tumor cells were positive for alpha 2M, while in the others between 20% and 50% of tumor cells were positive. In all but one of the melanomas, the positivity was characteristic of epithelioid or large-cell type or was confined to this component in melanomas with more than one cell type. In 4 positive cases, differences in the extent of alpha 2M-containing tumor tissue were observed between primary tumor and metastases or metastases from different localizations, with equivocal trend. Clinical follow-up of the melanoma patients suggested that alpha 2M-positively tends to correlate with an unfavorable prognosis.

Humans↗

PubMed1991

Counteracting effects of dexamethasone and alpha 2-macroglobulin on inhibition of proliferation of normal and neoplastic rat hepatocytes by transforming growth factors-beta type 1 and type 2.

Primary cultures of hepatocytes isolated from normal F-344 rats or from F-344 rats with hepatocellular carcinomas generated by a 2-step model of chemical carcinogenesis were used to determine if dexamethasone (DEX) or alpha 2-macroglobulin (alpha 2M) modify the ability of transforming growth factors-beta type I (TGF-beta I) and type 2 (TGF-beta 2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF-beta 1 and beta 2 were equivalently potent inhibitors of S-phase DNA synthesis in normal and neoplastic hepatocytes as determined by 3H-thymidine autoradiography. Both DEX (1 to 100 microM) and alpha 2M (50-200 microM) partially counteracted the mito-inhibitory effect of both TGF-betas on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive alpha 2M and were less able to overcome the inhibitory effect of TGF-beta than normal or surrounding hepatocytes. Purified bovine alpha 2M partially counteracted the inhibition of TGF-beta 1 or beta 2 of both surrounding and neoplastic hepatocytes. Both DEX and alpha 2M were more effective against the mito-inhibitory activity of TGF-beta 2. Our data suggest that alpha 2M released by DEX-treated normal hepatocytes contributes to the counteraction of the TGF-beta effect by DEX. Our results support the hypothesis that glucocorticoids and growth-factor-binding proteins may have important roles in modulating the effects of TGF-beta on normal hepatocyte proliferation and suggest that under some conditions hepatocellular neoplasms can be more sensitive than normal hepatocytes to inhibition of proliferation by TGF-beta.

Animals↗

PubMed1991

Proteinase-alpha 2 macroglobulin complexes are not increased in plasma of patients with cancer.

Alpha 2-macroglobulin, a major glycoprotein component of plasma, is unique in its capacity to bind and inhibit the proteolytic activities of all classes of proteinases. Since proteinases implicated in cancer dissemination (type-IV collagenase, plasminogen activator, cathepsins B) are normal constitutents of blood, we have explored the hypothesis that elevated tissue levels of activated proteinases bound to alpha 2M might be detected in plasma of patients with cancer. To test this premise, blood was collected from 149 subjects (33 healthy controls, 31 patients with infections and non-malignant diseases, 16 with myeloproliferative disease, 10 with gastrointestinal cancer, 7 with genito-urinary cancer, 16 with lung cancer, 14 with lymphoma, 11 with miscellaneous cancers and 11 with chronic lymphocytic leukemia and myeloma). Plasma was assayed for alpha 2M-proteinase complexes using a sandwich ELISA which employs a mouse monoclonal antibody (MAb) that binds to a neo-antigenic determinant on complexed alpha 2M and a rabbit polyclonal anti-native human alpha 2M antibody. The concentration of complexed alpha 2M in healthy controls was 14.2 +/- 9.8 micrograms/ml (mean +/- standard deviation). No significant differences in complexed alpha 2M were noted between normal and cancer groups (range 7.4-14.6 micrograms/ml). On the basis of these data, we propose that, in patients with cancer, activated proteinases are bound locally to inhibitors in the tissues and are not available to form complexes with plasma alpha 2M. An alternative explanation is that proteinases are not secreted in excess by cancer cells in vivo.

Adult↗

PubMed1993

Human plasma alpha 2-macroglobulin promotes in vitro oxidative stress cracking of Pellethane 2363-80A: in vivo and in vitro correlations.

It is hypothesized in this study that the phenomenon of environmental stress cracking (ESC) in polyetherurethane is caused by a synergistic action of biological components in the body fluids, oxidative agents, and stress. An in vitro system is designed to mimic the in vivo system; human plasma contains certain biological components that can act as a stress cracking promoter, while H2O2 (Co) solution provides an oxidative reaction comparable to that observed in the respiratory burst of adherent macrophages and foreign-body giant cells. It is demonstrated that the phenomenon of in vivo stress cracking in Pellethane 2363-80A is duplicated by an in vitro system that involves a pretreatment of prestressed specimens with human plasma at 37 degrees C for 7 days followed by oxidation in 10% hydrogen peroxide with 0.10M cobalt chloride at 50 degrees C for 10 days. The pretreatment with plasma has a synergistic effect with the oxidation by H2O2 (Co) treatment to produce ESC. A plasma component responsible for promoting stress cracking in Pellethane polyurethane is identified to be alpha 2-macroglobulin (alpha 2M).

Animals↗

PubMed2001

Inducible expression of the alpha2-macroglobulin signaling receptor in response to antigenic stimulation: a study of second messenger generation.

Thioglycollate (TG)-elicited murine, peritoneal macrophages express two receptors for activated forms of the proteinase inhibitor alpha2-macroglobulin (alpha2M*)--namely, the low density lipoprotein receptor-related protein (LRP) and the alpha2M signaling receptor (alpha2MSR). We now report that resident peritoneal macrophages express only 400+/-50 alpha2MSR receptors/cell compared to 5000+/-500 receptor/TG-elicited macrophage. By contrast, LRP expression is only 2-2.5-fold greater on elicited cells. The low level of alpha2MSR expression by resident cells is insufficient to trigger signal transduction in contrast to TG-elicited cells which when exposed to alpha2M* demonstrate a rapid rise in inositol 1,4,5-trisphosphate and a concomitant increase in cytosolic free Ca2+. We then studied a variety of preparations injected subcutaneously for their ability to upregulate alpha2MSR. Macroaggregated bovine serum albumin (macroBSA) injection upregulated alpha2MSR and triggered signaling responses by splenic macrophages. Nonaggregated BSA injection alone or in the presence of alum, by contrast, did not alter alpha2MSR expression. Recombivax (hepatitis B antigen adsorbed to alum) injection also upregulated alpha2MSR on splenic macrophages while the alum carrier had no effect. We conclude that macrophage alpha2M* receptors are inducible and their expression may be regulated, in part, by potential antigens.

Adjuvants, Immunologic↗