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PubMed1986

Mechanism of macrophage reversal of Friend erythroleukemia: macrophage regulation of normal and leukemic erythropoiesis.

The acute erythroleukemia induced in mice by the anemia-inducing strain of the Friend virus complex is caused to regress by normal macrophages. We examined the possibility that reversal of leukemia is related to a macrophage regulatory function in erythropoiesis. We found that the ability of macrophages to induce leukemia regression correlates with nonimmunological, in vivo suppression of normal and susceptible leukemic erythroid progenitors. The macrophage effect on erythropoiesis appears to be due to changes in a humoral regulator, related to but independent of erythropoietin. The results suggest a novel regulatory system for erythropoiesis, operative in vivo, and involving macrophages as accessory or suppressor cells. This regulation appears to be disrupted in erythroleukemic mice, but can be restored, and the disease can be made to regress by treatment with normal macrophages.

Animals↗
PubMed1987

Macrophage colony-stimulating factor enhances the expression of Fc receptors on murine peritoneal macrophages.

Experiments were performed to test the postulate that macrophage colony-stimulating factor (M-CSF) modulates the expression of specific membrane structures on mature murine macrophages. Resident peritoneal macrophages were incubated with M-CSF for 48-72 hr and analysed for Fc receptor and Ia antigen expression. M-CSF treatment of macrophages increased the expression of Fc receptors two- to three-fold over that of unstimulated macrophages. The effect was detected at 1 U/ml of M-CSF, with maximal expression between 100 and 500 U/ml. The specificity of the enhancement was indicated by two sets of experiments. Purified rabbit anti-M-CSF IgG, but not normal rabbit IgG, inhibited the M-CSF-mediated Fc receptor enhancement. Also, a highly purified M-CSF preparation, which was essentially free of endotoxin and interferon, was active in these assays. M-CSF augmented both major types of IgG Fc receptors, FcR I (recognizing IgG 2a) and FcR II (recognizing IgG 2b/IgG1). A second membrane marker, the Ia antigen, was induced by recombinant IFN-gamma (rIFN-gamma) but not by M-CSF. These results indicate that M-CSF is an inducer of two classes of IgG Fc receptors on mature tissue macrophages.

Animals↗
PubMed1979

Macrophage stimulation by bacterial lipopolysaccharides. III. Selective unresponsiveness of C3H/HeJ macrophages to the lipid A differentiation signal.

Peritoneal macrophages from the endotoxin-unresponsive C3H/HeJ substrain of mice were entirely refractory to activation in vitro by protein-free LPS, a defect that was not overcome by co-culture of spleen cells from the responder C3H/St substrain with LPS resistant C3H/HeJ macrophages. The defect in responsiveness appears confined to the lipid A activation signal since C3H/HeJ macrophages were fully activated after in vitro treatment by lipid A protein (LAP)--LPS complex, isolated LAP, and BCG. Moreover, after exposure to allogeneic tumor cells in vivo, C3H/HeJ macrophages were cytotoxic for tumor target cells in vitro. By contrast, macrophages from the responder C3H/St strain were fully activated by protein-free LPS to become cytolytic for tumor cells in vitro. C3H/HeJ macrophages, therefore, exhibit a highly selective defect characterized by unresponsiveness to the lipid A activation signal of protein-free LPS and resistance to the toxic effects of high concentrations of LPS that were lethal to the responder C3H/St strain.

Animals↗
PubMed1985

Long-term culture of human bone marrow macrophages: macrophage development is associated with the production of granulomonopoietic enhancing activity (GM-EA).

We describe a liquid culture system allowing the long-term maintenance and differentiation of human marrow monocytes into well-developed, lipid-containing macrophages, and we show that these cells produce a regulating activity that enhances the colony formation induced by granulocyte-macrophage colony-stimulating factors (GM-CSF). Adherent, low density (less than 1.074 g/cm3) human marrow cells were used as a source of monocytic cells. Of 12 different culture conditions tested, alpha-medium supplemented with 20% horse serum and incubation at 37 degrees C provided the best conditions for macrophage development, adipogenesis, and long-term culture. Neither insulin (1 to 10 micrograms/ml) nor hydrocortisone (10(-6) M) improved the lipid accumulation in cultures containing horse serum. Trypsin was employed to remove fibroblasts without detaching monocytic cells from the marrow-derived adherent cell layers. Marked structural and functional changes characterized the transformation of monocytes into lipid-containing macrophages. Cell enlargement up to seven or eight times by 21 to 28 days of culture was associated with an increase in small and medium-sized lipid granules, as well as in acid phosphatase and nonspecific esterase activities. Ultrastructurally, there was an increase in the number of mitochondria, Golgi apparatus, lysosomes, rough endoplasmic reticulum, and lipid inclusions, which remained of small size and did not coalesce to form larger inclusions. The absolute quantity of Fc receptors, Ia antigens, and antigens recognized by monoclonal antibodies 61D3 and 63D3 also increased as a function of cell size. As marrow monocyte-macrophage differentiation proceeded, a rapid decline in GM-CSF production was accompanied by an increase in an activity that by itself had no capacity to stimulate colony formation in CFU-GM cultures devoid of GM-CSF, but did enhance the colony formation induced by optimal concentrations of GM-CSF. Neither the enhancing activity nor its production was related to the horse serum present in the culture supernatants. The morphology of colonies enhanced by this activity was different from the morphologic spectrum in non-enhanced cultures. This granulomonopoietic enhancing activity (GM-EA) represents another positive feedback regulator of hematopoiesis derived from cells of the monocyte-macrophage system.

Adult↗
PubMed1983

Superoxide anion and hydrogen peroxide release by macrophages from mice treated with Nocardia rubra cell-wall skeleton: inhibition of macrophage cytotoxicity by a protease inhibitor but not by superoxide dismutase and catalase.

Peritoneal macrophages obtained from male BALB/c mice intraperitoneally injected with Nocardia rubra cell-wall skeleton (N-CWS) showed abundant superoxide anion and hydrogen peroxide release in response to opsonized zymosan used as a trigger. These N-CWS-induced macrophages also showed marked cytolytic activity against syngeneic Meth A fibrosarcoma targets. To examine the possible role of superoxide anion and/or hydrogen peroxide in the lysis of Meth A cells, N-CWS-induced macrophages were assayed with Meth A targets in the presence of superoxide dismutase, catalase, or both. However, addition of these agents to the assays, in doses which abolished detectable superoxide anion and/or hydrogen peroxide release from the effector cells, had no inhibitory effects on the cytotoxicity of N-CWS-induced macrophages. In contrast, both a protease inhibitor and actinomycin D could inhibit the cytolysis of Meth A targets by N-CWS-induced macrophages. These data raise the possibility that protease(s) rather than oxygen intermediates might be involved in the cytotoxicity of N-CWS-induced macrophages against tumor cells.

Animals↗
PubMed1983

Role of ADP-ribosyl transferase in differentiation of human granulocyte-macrophage progenitors to the macrophage lineage.

Nuclear adenosine diphosphate-ribosyl (ADP-ribosyl) transferase is a chromatin-bound enzyme catalyzing the transfer of ADP-ribose from NAD+ to chromatin proteins. The physiologic function of this covalent modification of chromatin has not been fully established, but roles in both DNA repair and in differentiation have been proposed. We demonstrate that three specific inhibitors of ADP-ribosyl transferase (5-methylnicotinamide, 3-methoxybenzamide, 3-aminobenzamide) inhibit differentiation of human granulocyte-macrophage progenitor cells to the macrophage lineage. Differentiation to the neutrophil-granulocyte lineage is much less affected. The inhibition of macrophage differentiation seems to relate to the ability of these compounds to inhibit ADP-ribosyl transferase. A structural analogue (3-methoxybenzoic acid), which is not inhibitory for the enzyme, did not inhibit macrophage differentiation. Additional evidence for a role of ADP-ribosyl transferase in the differentiation of granulocyte-macrophage progenitors was obtained from experiments in which enzyme activity levels were measured in permeabilized marrow cells. Marrow cell ADP-ribosyl transferase activity increased after 3-hr stimulation by the differentiation/proliferation stimulus--granulocyte-macrophage colony-stimulating activity (GM-CSA). Unstimulated marrow cells showed low or undetectable levels of enzyme activity.

Benzamides↗
PubMed1984

Antitumor activity of macrophages in lung cancer patients with special reference to location of macrophages.

Antitumor activity of macrophages from the peripheral blood, pleural cavity, and alveoli of 35 patients with primary lung cancer was examined. Cytostatic activities of peripheral blood monocytes and alveolar macrophages from either tumor-bearing or non-tumor-bearing segments declined in association with metastasis to regional lymph nodes, an increase in tumor size, and the development of pleural invasion. However, no such correlation could be observed between the cytostatic activity of pleural cavity macrophages and the degree of pleural invasion. The cytostatic activity of pleural cavity macrophages was found to be suppressed when the pleural invasion extended beyond the visceral pleura to the neighboring lobe or chest wall. On the other hand, the cytostatic activity of pleural cavity macrophages was markedly augmented when pleural invasion was limited to within the visceral pleura, although it was low in patients with no visceral pleural invasion. These results suggest that the pleural cavity is isolated from sites of systemic immunological response and that systemic immunological response does not strongly affect pleural cavity macrophages.

Cell Line↗
PubMed1984

Lymphocyte-induced macrophage cytotoxicity. Production of specific macrophage arming factor by sensitized Lyt 1+2+ T-lymphocytes.

T cells obtained from C57BL (H-2b) mice, that were immunized against allogeneic SL2 (H-2d) tumor cells, were able to produce a factor with the capacity to render macrophages cytotoxic. The factor producing T cells were of the Lyt 1+2+ phenotype. The factor was only produced by the T cells after triggering in vitro by SL2 cells or other cells with H-2d antigens. The macrophages armed with the factor only killed tumor cells with H-2d antigens. The factor was absorbed from the supernatant by macrophages and by cells bearing H-2d antigens but not by other cells. This showed that the factor has an affinity for macrophages and the specific sensitizing alloantigen. Therefore, the specificity of the lymphocytes is the same as the specificity of the factor and the factor-armed macrophages. The factor produced by the Lyt 1+2+ T cells is therefore the specific macrophage arming factor.

Animals↗
PubMed1983

New histochemical method for measuring intratumoral macrophages and macrophage recruitment into experimental metastases.

A new double-label histochemical method is described which permits accurate quantitation of macrophage recruitment into neoplastic lesions in situ. Intratumoral macrophages are identified by their capacity to ingest colloidal iron particles from the interstitial fluid. Since colloidal iron is retained in a stable form within these cells for a considerable time, new macrophages that emigrate into the tissue after injection of the colloidal iron are identified by their ability to ingest a second colloid (lanthanum) which can be reliably distinguished from the initial iron label. Preexisting (colloidal iron label) and newly recruited macrophages (lanthanum label) are identified in serial sections by histochemical methods using hydrogen peroxide oxidation to detect iron (blue reaction product) and cleavage of phosphate esters to demonstrate lanthanum (magenta reaction product). The macrophage content and macrophage recruitment were found to vary substantially in individual metastases within the same host.

Animals↗
PubMed1980

Macrophage accumulation in murine ascites tumors. I. Cytoxan-induced dominance of macrophages over tumor cells and the anti-tumor effect of endotoxin.

The host cellular response to i.p. growth of the SA-1 spindle cell sarcoma was studied in semisyngeneic AB6F1 hybrid mice. At progressive stages of tumor growth mice were sacrificed, their ascites were collected, and changes in the numbers of tumor cells, macrophages, lymphocytes, and granulocytes were determined. It was found that macrophages were the predominant host cell that accumulated locally in response to tumor growth. Cytoxan treatment caused a 90% reduction in tumor cells without affecting the accumulation of macrophages. Six days after treatment with cytoxan, macrophages exceeded all other cell types present in the peritoneal cavity and outnumbered tumor cells by 20:1. However, in spite of this macrophage dominance, the tumor cells ultimately regrew to kill the host. Ascites tumors could be completely regressed, however, by following cytoxan treatment with an appropriately timed intratumor injection of endotoxin. The relatively long delay before endotoxin caused the tumor to regress suggests that endotoxin acted by stimulating the generation of anti-tumor immunity, rather than by directly augmenting the tumoricidal activity of macrophages.

Animals↗
PubMed1981

The response of isolated rabbit hepatic macrophages (H-M macrophage) to lipopolysaccharide (LPS).

In order to evaluate the possible role of the hepatic macrophage (H-M macrophage) in lipopolysaccharide-induced shock and disseminated intravascular coagulation (DIC), a technique has been developed for the isolation and maintenance in culture of rabbit H-M macrophage. Characterization of the resultant cell population by morphology, nonspecific esterase staining, phagocytosis of latex beads, by presence of Fc and C3b membrane receptors confirms a pure population of M macrophage without outgrowth of other cell types for up to 10 days in culture. The exposure in vitro of the H-M macrophage to LPS (either Salmonella minnesota R595 or Escherichia coli 0111:B4) stimulates a selective increase in activity of several cellular enzyme: LDH, lysozyme, plasminogen activator, and a procoagulant factor, with minimal changes in acid phosphatase and beta-glucuronidase detected. Concomitantly, both in vivo and in vitro treatment with LPS produces an apparent direct cellular toxicity. The combined effect of toxicity and selective stimulation and release of mediators in LPS-stimulated H-M macrophage may play a central role in the endotoxemic shock syndrome.

Animals↗
PubMed1995

Monocyte chemoattractant protein-1 stimulates tumor necrosis and recruitment of macrophages into tumors in tumor-bearing nude mice: increased granulocyte and macrophage progenitors in murine bone marrow.

Monocyte chemoattractant protein-1 (MCP-1) belongs to the newly recognized "chemokine" superfamily of activation-inducible cytokines. We report here that MCP-1 gene-transferred mouse myeloma cells modulate tumor necrosis in myeloma-bearing nude mice. We established an MCP-1-producing myeloma cell line (X63-MCP-1) by transfection with human MCP-1 cDNA as well as interleukin-8-producing X63 cells (X63 IL-8). Each cell line showed the same growth characteristics in vitro, and 1 x 10(7) cells per mouse were injected into the peritoneal cavity resulting in the formation of tumors. Hematologic studies, including peripheral white blood cell counts and differentiation, showed no differences among the groups. They formed tumors in the same manner, which we observed from weeks 2.5 to 9. MCP-1 mice showed more tumor necrosis and infiltration of the macrophages into the tissue surrounding the tumor. In situ hybridization, using a partial cDNA as a probe, showed that macrophages contained MCP-1 mRNA. Bone marrow cell colony-forming assay showed a greater number of both granulocyte and macrophage colonies in MCP-1 mouse femur than in those of controls or interleukin-8 mice. MCP-1 has no direct stimulatory activity on stem cells, but longer exposure to MCP-1 in vivo might stimulate both granulocyte and macrophage progenitors and recruitment of macrophages into tumors, and it might explain the antitumor activity of macrophages in tumor-bearing nude mice.

Animals↗
PubMed1996

Interleukin 12 primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2.

Interleukin-12 (IL-12) is a recently described immunoregulatory cytokine with potent therapeutic activity in various preclinical models of infectious or malignant disease. As part of our ongoing evaluation of potential mechanisms accounting for the potent antitumor activity of IL-12, we have investigated the influence of IL-12 administration on total serum nitrate/nitrite (NO(x)(-)) levels and the production of nitric oxide (NO) by peritoneal macrophages from normal and tumor-bearing mice. We report here that IL-12 administration to either normal or tumor-bearing mice for periods of time ranging from 7-19 days induced progressive increases in serum NO(x)(-) levels and primed peritoneal macrophages for NO production on subsequent exposure to lipopolysaccharide or IL-2 ex vivo. Treatment of resident peritoneal macrophages or the macrophage cell line ANA-1 with IL-12 alone or IL-12 in combination with various other stimuli failed to induce NO production, suggesting that the effects of IL-12 occurred via an indirect mechanism. Furthermore, we have shown that not only was the production of NO by macrophages from untreated long-term, tumor- bearing mice suppressed compared with control mice treated with vehicle or IL-12, but also that IL-12 administration overcame this suppression and delayed tumor growth. Lastly, we have shown that administration of weekly pulses of IL-2 in combination with IL-12 additively enhanced the priming of macrophages for NO production ex vivo and delayed tumor growth far more effectively than either agent alone. These observations and reports in the literature regarding the potential influence of NO on development of the immune response and on the regulation of tumor growth and vascularization suggest that NO may play a significant role in the antitumor activity of IL-12 and IL-2.

Animals↗
PubMed1989

Regulation of murine macrophage function by IL-4. I. Activation of macrophages by a T-T cell hybridoma is due to IL-4.

A T-cell hybridoma produced by fusion of concanavalin A-stimulated murine splenocytes produced a factor (MAFH) capable of activating tumoricidal capacity by responsive murine peritoneal macrophages. Macrophages treated with the MAFH required an additional trigger signal of bacterial lipopolysaccharide (LPS) for maximal activity. In contrast to interferon-gamma (IFN gamma), which induced tumoricidal activity against all tumor cells tested, MAFH only induced macrophage-mediated kill of the BI6P51 and 168 lines, and not of the P815 or B16BL6 lines. An identical pattern of tumoricidal activity was obtained by treating macrophages with recombinant interleukin-4 (IL-4). The active moiety of MAFH appeared to be IL-4 as (i) monoclonal antibody against IL-4 blocked MAFH, but not IFN gamma, activity, and (ii) the T-cell hybridoma contained large amounts of mRNA for IL-4 and no detectable mRNA for IFN gamma (as determined by Northern dot analysis). The pattern of tumoricidal activity observed may be due to an IL-4 mediated enhancement of tumor necrosis factor production by LPS-triggered macrophages.

Animals↗
PubMed1984

Activation of macrophages by lymphokines from T-cell clones: evidence for different macrophage-activating factors.

The data reported in this paper demonstrate that macrophage-activating factors (MAFs) are a heterogeneous group of T-cell-derived lymphokines. Two long-term T-cell clones, Cl 96 and PK 7.1.2E8, were potent sources of MAFs (MAF96 and MAF7.1.2E8). These MAFs could be distinguished by differential activation of macrophages. Activation of resident murine macrophages with MAF7.1.2E8 enhanced RNA and glycoprotein synthesis, hexosemonophosphate shunt (HMPS) activity, release of oxygen metabolites (O-2 and H2O2), pinocytosis and tumor cytostasis, whereas no effect on schistosomula killing and tumor cytolysis could be observed. In contrast, MAF96 enhanced glycoprotein synthesis, HMPS activity, release of oxygen metabolites and prostaglandin E, schistosomula killing, and tumor cytostasis and cytolysis, while RNA synthesis and pinocytosis were decreased. These findings show that MAFs from both T-cell clones share some properties but markedly differ in others. In addition, the macrophage-activating properties of MAF96 but not of MAF7.1.2E8 could selectively be inhibited by a rabbit anti-lymphokine antiserum. This demonstrates a serological difference between MAF activities from both clones. Although at optimal concns both MAFs were active in the absence of lipopolysaccharide (LPS), the activity of suboptimal doses of MAF96 but not of MAF7.1.2E8 could be enhanced by LPS. These findings show that different MAFs from T-cell clones may be useful to clarify molecular mechanisms of macrophage activation.

Animals↗
PubMed1992

Production of macrophage colony-stimulating factor by astrocytes and brain macrophages.

Morphological hallmarks of inflammatory and degenerative diseases of the brain are hypertrophy of astrocytes and accumulation of macrophages recruited from circulating blood monocytes and/or from resident macrophages, the so-called microglial cells. Recently, production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by astrocytes has been suggested to contribute to the macrophage response. Here we report that in addition to GM-CSF, murine astrocytes also produce macrophage (M)-CSF upon stimulation with tumor necrosis factor alpha, interleukin-1 and lipopolysaccharides. The bioactivity detected in supernatant of astrocytes was characterized using the M-CSF-dependent cell line M-NFS-60 and neutralizing anti-M-CSF antibodies. RNase protection analysis showed M-CSF mRNA already in unstimulated astrocytes without striking up-regulation by the stimuli. Thus, in astrocytes the expression of the M-CSF gene is predominantly regulated at the posttranscriptional level.

Animals↗
PubMed2003

Human lung fibroblasts inhibit macrophage inflammatory protein-1alpha production by lipopolysaccharide-stimulated macrophages.

We investigated the effect of interaction between lung fibroblasts and macrophages on macrophage inflammatory protein 1alpha (MIP-1alpha) production by macrophages. In a co-culture system consisting of WI-38 lung fibroblasts layered over THP-1 macrophages stimulated with lipopolysaccharide (LPS), MIP-1alpha production by THP-1 was significantly lower in co-culture with WI-38 than in THP-1 alone. Treatment with conditioned medium generated from WI-38 (CM-WI-38) suppressed MIP-1alpha production and mRNA expression in THP-1 cells. Such inhibitory effect of CM-WI-38 on MIP-1alpha production was abrogated by treatment with indomethacin, NS-398 (a specific COX-2 inhibitor), or anti-prostaglandin E(2) antibody. Furthermore, even in a transwell filter system separating both types of cells, co-culture-induced reduction of MIP-1alpha production was observed. Therefore, soluble factors such as prostaglandin E(2) released from lung fibroblasts are responsible for the co-culture-induced inhibition of macrophage-derived MIP-1alpha production, suggesting that immune and inflammatory cell interactions can contribute to the modulatory mechanisms involved in the regulation of the inflammatory or fibrotic process.

Cell Communication↗
PubMed1990

Granulocyte-macrophage and macrophage colony-stimulating factors activate intramacrophage killing of Leishmania mexicana amazonensis.

Leishmania organisms are important pathogens, causing diseases worldwide. Standard therapies are often toxic and are not always effective. The effect of recombinant human granulocyte-macrophage and macrophage colony-stimulating factors (GM-CSF and M-CSF) on intramacrophage survival of Leishmania mexicana amazonensis (Lma) were compared with those of interferon-gamma (IFN-gamma). Macrophages previously infected with Lma were treated with or without GM-CSF and M-CSF. Compared with no cytokine treatment, treatment with GM-CSF (0.1-100 ng/ml) or M-CSF (1:3.5 X 10(6) - 1:3.5 X 10(3) dilutions) caused a significant dose-dependent reduction in intracellular parasites, 427 +/- 20 (mean +/- SE) Lma/100 macrophages. GM-CSF or M-CSF in combination with IFN-gamma resulted in more effective inhibition of intracellular parasites. Thus, the cytostatic activity appears to require interaction between cytokines, macrophages, and amastigotes. These cytokines are potential therapeutic agents for visceral leishmaniasis.

Animals↗