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PubMed1992

Mechanisms in intimal monocyte-macrophage recruitment. A special role for monocyte chemotactic protein-1.

This article briefly addresses the role of the monocyte-macrophage in atherogenesis and the potential mechanisms participating in intimal blood monocyte recruitment. The obligatory components of the recruitment process, i.e., contact with the vascular endothelium, attachment, and migration into the subendothelial space, are addressed with reference to the influence of blood flow, plasma proteins (particularly low density lipoprotein), and inflammatory mediators and cytokines. The potentially important role of monocyte chemotactic protein-1 in regulating monocyte recruitment in plaque pathogenesis is discussed.

Arteriosclerosis↗
PubMed1992

The monocyte interleukin-2 receptor light chain: production of cell-associated and soluble interleukin-2 receptor by monocytes.

Stimulation with lipopolysaccharide (LPS) initiated monocytes to produce interleukin-2 receptor light chain (p55 IL-2R). After stimulation with LPS for 48 hr, considerable quantities of soluble IL-2R were found in the supernatants of monocytes, exceeding even the amount of soluble IL-2R produced by activated T lymphocytes. Cell-associated p55 IL-2R was also increased during the first 24 hr of stimulation, after which time it remained constant. Fractionation of cells and analysis of cytoplasm, mitochondria, plasma membranes and nuclei for the presence of p55 IL-2R revealed that the main portion of receptor was present in the cytoplasm. This led to the conclusion that in monocytes cell-associated p55 IL-2R is not necessarily attached to membranes but is present in a soluble form in the cytoplasm, presumably freshly produced with the aim of being secreted. Stimulation of monocytes with pure recombinant interferon-gamma did not lead to augmentation of p55 IL-2R, as shown by enzyme-linked immunosorbent assay, binding of antibodies directed against the receptor (anti-Tac, CD25) and analysis of p55 IL-2R gene expression.

Antibodies↗
PubMed1990

Relative inefficiency of soluble recombinant CD4 for inhibition of infection by monocyte-tropic HIV in monocytes and T cells.

Macrophages are major viral reservoirs in the brain, lungs, and lymph nodes of HIV-infected patients. But not all HIV isolates infect macrophages. The molecular basis for this restrictive target cell tropism and the mechanisms by which HIV infects macrophages are not well understood: virus uptake by CD4-dependent and -independent pathways have both been proposed. Soluble rCD4 (sCD4) binds with high affinity to gp 120, the envelope glycoprotein of HIV, and at relatively low concentrations (less than 1 microgram/ml) completely inhibits infection of many HIV strains in T cells or T cell lines. HTLV-IIIB infection of the H9 T cell line was completely inhibited by prior treatment of virus with 10 micrograms/ml sCD4: no p24 Ag or HIV-induced T cell syncytia were detected in cultures of H9 cells exposed to 1 x 10(4) TCID50 HTLV-IIIB in the presence of sCD4. Under identical conditions and at a 100-fold lower viral inoculum, 10 micrograms/ml sCD4 had little or no effect on infection of monocytes by any of six different HIV isolates by three different criteria: p24 Ag release, virus-induced cytopathic effects, and the frequency of infected cells that express HIV-specific mRNA. At 10- to 100-fold higher concentrations of sCD4, however, infection was completely inhibited. Monoclonal anti-CD4 also prevented infection of these same viral isolates in monocytes. The relative inefficiency of sCD4 for inhibition of HIV infection in monocytes was a property of the virion, not the target cell: HIV isolates that infect both monocytes and T cells required similarly high levels of sCD4 (100 to 200 micrograms/ml) for inhibition of infection. These data suggest that the gp120 of progeny HIV derived from macrophages interacts with sCD4 differently than that of virions derived from T cells. For both variants of HIV, however, the predominant mechanism of virus entry for infection is CD4-dependent.

CD4 Antigens↗
PubMed1989

Regulation of granulocyte- and monocyte-colony stimulating factor mRNA levels in human blood monocytes is mediated primarily at a post-transcriptional level.

Human blood monocytes secrete a number of cytokines following activation including two hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) and monocyte/macrophage-colony stimulating factor (M-CSF). The genes for these two factors can be both coordinately and independently expressed. Treatment of monocytes with phorbol myristic acid or cycloheximide induces both genes, while lipopolysaccharide selectively and transiently induces G-CSF transcripts. Interleukin-3 or granulocyte/monocyte-colony stimulating factor selectively induce M-CSF transcripts. Using nuclear run-on transcription assays and Northern blot analysis of actinomycin D-treated cells to estimate mRNA half-life, we show that the induction of both genes is due to mRNA stabilization. In resting monocytes, the levels of transcripts for both G-CSF and M-CSF are very low. Following stimulation with phorbol myristic acid, cycloheximide, lipopolysaccharide, or interleukin-3 the estimated transcription rate of both genes does not increase. However, the half-life of M-CSF mRNA increases to approximately 2 h, whereas G-CSF mRNA half-life increases to as long as 4 h. Thus, the control of CSF gene expression in monocytes is likely to involve more than one post-transcriptional mechanism.

Colony-Stimulating Factors↗
PubMed1986

Effector mechanisms of human monocyte-mediated tumor cytotoxicity in vitro: parameters of induction of cytotoxins from peripheral blood monocytes isolated by counterflow elutriation.

Human peripheral blood monocytes, isolated in high purity by centrifugal counterflow elutriation from normal donors, were stimulated in vitro to release cell toxins, herein termed human monocyte toxin(s) (HMT). Bacterial lipopolysaccharide, the lipophilic 6-O-stearoyl derivative of muramyl dipeptide, and 4 beta-phorbol-12 beta-myristate-13 alpha-acetate served as effective induction signals. Induction involved a sequence of transcription, translation, and secretion, all necessary for HMT synthesis and release into the supernatant as determined by blocking of these functions with the drugs actinomycin D, cycloheximide, and monensin, respectively; HMT levels reached a peak within 4-6 h and thereafter declined. The levels of HMT produced varied considerably from donor to donor; one parameter causing this variability appeared to be the plateletapheresis history of the donor. Monocytes from donors subjected to pheresis for the first time were responsive to induction signals immediately after adherence and could not be brought to a higher state of priming for HMT production by further in vitro culture for up to 9 days, with or without recombinant human gamma-interferon. In contrast, monocytes from donors who had recently undergone pheresis (up to 1 wk earlier) were poorly responsive initially to triggering with lipopolysaccharide; however, these cells could be brought to a highly primed state for HMT production by a combination of culture in vitro for several days and a subsequent 24-h exposure to recombinant gamma-interferon (0.1-1.0 units/ml). These primed cells could then be effectively triggered by lipopolysaccharide to release HMT. HMT was found to be cytotoxic (cytostatic/cytolytic) for human and murine tumor cells in vitro.

Animals↗
PubMed1986

Effector mechanisms of human monocyte-mediated tumor cytotoxicity in vitro: biochemical, functional, and serological characterization of cytotoxins produced by peripheral blood monocytes isolated by counterflow elutriation.

Human peripheral blood monocytes, isolated in high purity by centrifugal counterflow elutriation from normal donors, release cell toxins, herein termed human monocyte toxins (HMTs) upon further stimulation in vitro. The principal form of HMTs produced by these human peripheral blood monocytes has been subjected to biochemical, functional, and serological characterization. By molecular sieving on Sephacryl S-200, HMTs can be resolved into two molecular weight classes. The larger, termed alpha, has a molecular weight of about 120,000, and the smaller, termed beta, has a molecular weight of about 65,000. The beta class is by far the most predominant species and has been further characterized. Chromatofocusing of beta-HMT indicates a slightly acidic nature, since this species is eluted at pH 5.8. Functional characterization of beta-HMT suggests that it is not a trypsin-like protease, since neither alpha,N-tosyl-L-lysylchloromethylketone nor alpha,N-tosyl-L-arginyl methyl ester are capable of causing significant inhibition of the cell-lytic activity of the molecule. Furthermore, cell lysis induced by beta-HMT appears to be independent of oxygen-dependent mechanisms, since catalase is incapable of blocking lysis, and since hydrogen peroxide and superoxide anion are not produced in detectable amounts during lysis. Finally, beta-HMT does not appear to be an arginase, since it is active in arginine-containing medium and further addition of arginine to the assay medium does not inhibit lysis significantly. beta-HMT is serologically related to recombinant human tumor necrosis factor (rHuTNF), since its cell lytic activity can be blocked by a rabbit antiserum against rHuTNF. However, much higher levels of this antiserum are required to achieve neutralization than are required to neutralize a comparable number of cell lytic units of rHuTNF. Furthermore, the results of preliminary immunoprecipitation experiments using the rabbit anti-rHuTNF antiserum suggest that a peptide in the Mr 60,000-70,000 range is recognized by this serum, whereas no signal at Mr 17,000 corresponding to rHuTNF is detectable. Thus, human peripheral blood monocytes can be triggered to release cell toxins, the principal form of which, beta-HMT, appears to be functionally distinct from the cytotoxic proteases reported in the murine system and appears to be molecularly distinct from, but serologically related to rHuTNF.

Chromatography, Gel↗
PubMed1983

Killing of Listeria monocytogenes by human neutrophils and monocytes, but not by monocyte-derived macrophages.

Acquired resistance to listeriosis is thought to require immunological activation of mononuclear phagocytes to an enhanced microbicidal state. In this study we found that both neutrophils and mononuclear phagocytes from nonimmunized human donors killed Listeria monocytogenes in vitro as well as they killed Salmonella typhimurium and Escherichia coli. Bactericidal activity was detectable using both adherent cell and cell suspension bactericidal assays; however, bactericidal activity was greater when the suspension assay was used. Perhaps more surprising, freshly-obtained monocytes were more bactericidal than were monocytes cultured in vitro for 5-7 days, even though monocytes cultured in vitro acquire many characteristics of mature macrophages. These data suggest that newly emigrated monocytes and neutrophils may be particularly effective cell types in resistance to listeriosis.

Adult↗
PubMed1983

Characterization of hydrogen peroxide-potentiating factor, a lymphokine that increases the capacity of human monocytes and monocyte-like cell lines to produce hydrogen peroxide.

A study was made of a lymphokine produced by human T lymphocytes that mediates activation of human monocytes and monocyte-like cell lines, measured by increased production of H2O2. The lymphokine was produced either by stimulation of human nonadherent peripheral blood mononuclear cells with concanavalin A (Con A) or by stimulation of a human T cell line, HSB2, with Con A and phorbol myristic acetate (PMA). When incubated with freshly isolated peripheral blood monocytes for 48 to 72 hr, the H2O2-potentiating factor (HPPF) stimulated increased production of H2O2, measured in a PMA-triggered assay for H2O2 secretion. Because variations occurred in the response of normal blood donors to the HPPF, human monocyte-like cell lines were used as homogeneous and consistently responsive targets for the lymphokine to facilitate biochemical characterization studies of the factor. Two cell lines were studied: HL60, a human promyelocytic cell line, and U937, a human histiocytic cell line. When target cells of either type were incubated in the presence of the HPPF for 48 to 72 hr, they produced increased amounts of H2O2 in a dose-dependent fashion. H2O2 levels were assessed by means of a microassay that measures peroxide-mediated oxidation of phenol red after an oxidative burst triggered with PMA. By using this assay, HPPF was found to have an apparent m.w. of 54,000 and an isoelectric point of 5.5. The bouyant density was determined to be 1.307, indicating that HPPF is a protein. The utilization of cell lines for both the production and assay of HPPF should facilitate the purification of this lymphokine and the subsequent evaluation of its relationship to other lymphokines known to affect macrophage microbicidal and tumoricidal function.

Adjuvants, Immunologic↗
PubMed1980

Modulation of human monocyte functions by Fc fragments of IgG: a comparison to other monocyte 'activators'.

Human monocytes were maintained in tissue culture and the effect of various stimuli on their morphology and capacity to synthesize and secrete total protein, lysozyme, acid phosphatase, prostaglandin E and the second component of complement were determined. Human monomeric IgG, Fab fragments and albumin had no effect on the secretion of these products. However, addition of Fc fragments significantly decreased the synthesis of both lysosomal enzymes and the second component of complement and increased production of prostaglandin E. The addition of Con A to the monocyte monolayers resulted in a similar response. Latex particles slightly increased the secretion of acid phosphatase and C2, but had no effect on lysozyme secretion. Fc fragments also stimulated protein synthesis by monocyte monolayers cultured in serum-free medium. These 'activators' and endotoxin- or antigen-activated mononuclear cell supernatants (AMNS) resulted in varying degrees of increased spreading and adherence of the monocytes. The results of these studies suggest that the molecular species inducing the 'activated state' qualitatively and quantitatively determines the characteristics of the secretory response.

Acid Phosphatase↗
PubMed1994

Tumor-derived monocyte chemoattractant protein-1 induces intratumoral infiltration of monocyte-derived macrophage subpopulation in transplanted rat tumors.

By immunohistochemistry using anti-rat macrophage monoclonal antibodies RM-1, ED1, ED2, ED3, TRPM-3, and Ki-M2R, we studied transplanted rat tumors of 9L (rat gliosarcoma), Ad-2 (rat mammary carcinoma), and MT-P (rat malignant fibrous histiocytoma) cell lines to examine the distribution pattern of macrophages within and around the tumors. Most tumor-associated macrophages expressed RM-1, ED1, and Ia antigens, indicating activated macrophages. Based on differences in their immunophenotypical expression, these macrophages were distinguished into two major subpopulations. One expressed TRPM-3 and/or ED3, and the other was positive for ED2 and Ki-M2R. The former was considered to be monocyte-derived macrophages, whereas the latter showed the immunophenotype of tissue-fixed, resident macrophages. Infiltration and distribution patterns in the two macrophage subpopulations differed in the three different tumors. Monocyte-derived, activated macrophages infiltrated into 9L- and Ad-2-transplanted tumors, which markedly produced monocyte chemoattractant protein-1 (MCP-1). Additionally, numerous ED2- and Ki-M2R-positive macrophages were observed within the Ad-2-transplanted tumors, and some of them expressed TRPM-3. However, there were few macrophages in the MT-P-transplanted tumors that showed no MCP-1 production. In transplanted tumors of four MT-P/MCP-1 cell lines established by transfecting a rat MCP-1 gene expression vector (pCEP4/MCP-1) into the MT-P cell line, different levels of MCP-1 production were detected, which correlated well with the numbers of intratumorally infiltrated TRPM-3-positive macrophages. In contrast, ED2- and Ki-M2R-positive macrophages were not detected in any MT-P/MCP-1-transplanted tumors. MT-P/MCP-1-transplanted tumors exhibited lower growth rate than parental MT-P-transplanted tumors. These results indicate that tumor-derived MCP-1 induces intratumoral infiltration of monocyte-derived macrophages, but not macrophages with the immunophenotype of tissue-fixed, resident type. The former population of macrophages seems to have a suppressive effect on the growth of tumors.

Animals↗
PubMed1998

Modulation of iron metabolism in monocytic THP-1 cells and cultured human monocytes by the acute-phase protein alpha1-antitrypsin.

The reticuloendothelial (RE) system plays an important role in the changes in iron metabolism associated with the anemia of chronic disease (ACD). We previously reported that the acute-phase protein alpha1-antitrypsin (alpha1-AT) reduced growth and proliferation in cells of the erythroid cell system by interfering with transferrin (Tf)-mediated iron uptake. The regulation of iron metabolism in cells of the RE system is distinctly different from that in other cell systems; moreover, monocytes and macrophages play an essential part in the regulation of the production and clearance of alpha1-AT. In the present study we examined the effect of alpha1-AT on cells of the monocyte-macrophage lineage. Alpha1-AT completely inhibited the binding of Tf to its receptor (TfR) on THP-1 human myelomonocytic cells and cultured human monocytes. Results of equilibrium saturation and kinetic studies indicated that this inhibition was competitive. No other acute-phase protein demonstrated the same inhibitory potency. Furthermore, alpha1-AT almost completely prevented internalization of the Tf-TfR complex in a dose-dependent manner. Interestingly, and in sharp contrast to the results of our studies with erythroid cells, this inhibition did not reduce the growth and proliferation of THP-1 cells. Furthermore, alpha1-AT significantly increased the concentration of intracellular ferritin in THP-1 cells and monocytes, whereas the number of TfR remained unchanged. Because alpha1-AT showed no enhancing effect on ferritin transcription and translation, we believe that an as-yet unidentified posttranslational mechanism may be responsible for this phenomenon. In addition, our results indicate that the increase in ferritin concentration caused by alpha1-AT is mediated independently of iron supply, as has previously been shown for several proinflammatory cytokines. These data provide further evidence that alpha1-AT is a mediator of the alterations in iron metabolism characteristic of ACD.

Cell Division↗
PubMed1986

WEHI 164 sarcoma cells rendered resistant to monocyte-released cytotoxin are also resistant to monocyte-induced cytolysis.

WEHI 164 sarcoma cells cultured with monocyte-released cytotoxin (CF) for 4 weeks became resistant to CF-induced cytolysis and were concomitantly rendered resistant to monocyte-induced cytolysis. The resistant cell line (R-WEHI 164) has been stable with respect to resistance to monocyte- and CF-induced lysis for more than 7 months. WEHI 164 and R-WEHI 164 cells adsorbed CF and no significant difference in CF adsorption was observed. The results indicate that CF may be an effector molecule in monocyte-mediated cytolysis.

Adsorption↗
PubMed2006

Monocyte-specific Bcl-2 expression attenuates inflammation and heart failure in monocyte chemoattractant protein-1 (MCP-1)-induced cardiomyopathy.

OBJECTIVE: Infiltrating inflammatory cells within the myocardium have been shown to be apoptotic, but the significance of apoptotic inflammatory cells to the development of cardiomyopathy remains undefined. Transgenic mice with cardiac-specific expression of MCP-1 exhibit extensive apoptosis of infiltrating mononuclear cells and develop heart failure. Here, we tested the hypothesis that in vivo selective inhibition of apoptosis of infiltrating mononuclear cells would preserve cardiac structure and function and improve survival in this murine model. METHODS: Mice with cardiac-specific expression of MCP-1 and monocyte-specific expression of Bcl-2 were generated by cross-breeding MCP-1 transgenic mice with hMRP8-Bcl-2 mice that over-express Bcl-2 in the monocytes. Structural and functional parameters and the inflammatory response of the heart were evaluated and compared between the wild-type and transgenic mice. RESULTS: Expression of Bcl-2 in monocytes results in superior preservation of myocardial structure, cardiac function and a significant prolongation of survival of MCP-1 transgenic mice. The beneficial effects of monocyte-specific Bcl-2 expression are associated with inhibition of apoptosis of infiltrating mononuclear cells, normalization of circulating C-reactive protein levels, attenuation of cellular infiltrates, macrophage activation and production of proinflammatory cytokines, tumor necrosis factor (TNF-alpha), interleukin (IL)-1 beta and IL-6 in the hearts. CONCLUSIONS: These results demonstrate that apoptosis of infiltrating mononuclear cells plays a detrimental role in the development of heart failure in this murine model, suggesting that modulation of apoptosis of infiltrating mononuclear cells may be of clinical benefit in heart failure.

Animals↗
PubMed2000

Quantitative deficiency of monocyte-specific esterase (MSE) mRNA in monocyte esterase deficiency (MED).

Cytochemical staining of monocyte-specific esterase (MSE) is widely used for identification of the monocytic lineage in leukaemias. Deficiency of this enzymatic activity occurs as a familial trait and the deficiency has been shown to occur with greater frequency in patients with lymphoproliferative or gastrointestinal malignant neoplastic diseases than in normal blood donors. Reverse transcriptase polymerase chain reaction (RT-PCR), sequencing and quantification by Northern blot analysis was conducted on the MSE mRNA of 12 subjects with monocyte esterase deficiency (MED) and seven MSE-positive subjects to examine whether mutations were present or whether the defect was quantitative. Mutations were not found in the mRNA sequences. However, MED subjects had significantly less MSE mRNA than MSE-positive subjects (P = 0.001). These findings show that deficiency of monocyte esterase activity in MED is not as a result of the presence of inactive isoenzymes and may be owing to an abnormality in the regulation of mRNA production.

Anemia, Hemolytic, Autoimmune↗
PubMed1990

Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.

Systemic infusion of low concentrations of tumor necrosis factor/cachectin (TNF) into mice that bear TNF-sensitive tumors leads to activation of coagulation, fibrin formation, and occlusive thrombosis exclusively within the tumor vascular bed. To identify mechanisms underlying the localization of this vascular procoagulant response, a tumor-derived polypeptide has been purified to homogeneity from supernatants of murine methylcholanthrene A-induced fibrosarcomas that induces endothelial tissue factor synthesis and expression (half-maximal response at approximately 300 pM), and augments the procoagulant response to TNF in a synergistic fashion. This tumor-derived polypeptide was identified as the murine homologue of vascular permeability factor (VPF) based on similar mobility on SDS-PAGE, an homologous NH2-terminal amino acid sequence, and recognition by a monospecific antibody to guinea pig VPF. In addition, VPF was shown to induce monocyte activation, as evidenced by expression of tissue factor. Finally, VPF was shown to induce monocyte chemotaxis across collagen membranes and endothelial cell monolayers. Taken together, these results indicate that VPF can modulate the coagulant properties of endothelium and monocytes, and can promote monocyte migration into the tumor bed. This suggests one mechanism through which tumor-derived mediators can alter properties of the vessel wall.

Amino Acid Sequence↗
PubMed1995

Comparison of activity of peripheral monocytes and splenic macrophages in the monocyte monolayer assay.

Functional assays intended to reflect the haemolysis in vivo have been performed with peripheral monocytes, occasionally only with peritoneal macrophages or monocyte-like cell lines. Although the splenic macrophages presumably play the major role in immune red cell destruction, the functional assays have not been done with these cells because of their relative inaccessibility. In this study, the activity of peripheral monocytes and splenic macrophages was compared using the monocyte monolayer assay (MMA), and no substantial differences were found.

Anemia, Hemolytic↗
PubMed1989

A case of acute monocytic leukemia with lysozyme-positive leukemic monocytes and normal serum lysozyme levels.

We report a case of acute monocytic leukemia with normal serum lysozyme but with immunoperoxidase positivity for lysozyme in the leukemic blasts. The diagnosis of acute monocytic leukemia was made on the basis of cellular morphology, immunocytochemistry and cytochemistry. Discrepancy between serum lysozyme and intracytoplasmic lysozyme has not previously been reported in the literature. Levels of serum lysozyme may be misleading in cases of acute monocytic leukemia (FAB classification M5).

Adult↗
PubMed1984

Alkaline phosphatase-positive leukemic monocytes in a child with acute monocytic leukemia.

A subpopulation with alkaline phosphatase activity and neutrophilic granules was found in leukemic monocytes from a child with acute monocytic leukemia (M5B). Almost all leukemic cells were strongly positive for nonspecific esterase and phagocytized opsonized zymosans. These findings suggest that the subpopulation are chimeric cells with characteristics of both monocytic and neutrophilic cell lines. The leukemogenesis in this patient might involve the simultaneous expression of differentiation genes otherwise restricted to either cell lineage.

Alkaline Phosphatase↗