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PubMed1985

Augmentation of macrophage complement receptor function in vitro. V. Studies on the mechanisms of ligation of macrophage Fc receptors required to trigger macrophages to signal T lymphocytes to elaborate the lymphokine that activates macrophage C3 receptors for phagocytosis.

We previously described a unique lymphokine that activates macrophage C3 receptors for phagocytosis. The lymphokine is generated when T lymphocytes receive a signal from macrophages that have ingested IgG-coated material. In the present work, we examined the mechanisms by which macrophage Fc receptors must be engaged for macrophages to signal lymphocytes to elaborate the lymphokine. We found that ingestion mediated by any of the three classes of murine macrophage Fc receptors was sufficient to trigger macrophages, and that engagement of macrophage Fc receptors by immobilized immune complexes was effective as well. We also found that ligation of Fc receptors by an anti-Fc receptor IgG antibody or by its F(ab')2 or Fab fragments also triggered macrophages. The ability of monovalent ligation of the receptor to elicit biologic activity suggests that this system may be of value in elucidating general mechanisms by which ligand binding of receptors is transduced into biologic effects.

Animals↗
PubMed1994

Effects of macrophage colony-stimulating factor (M-CSF) on the development, differentiation, and maturation of marginal metallophilic macrophages and marginal zone macrophages in the spleen of osteopetrosis (op) mutant mice lacking functional M-CSF activity.

Immunohistochemical techniques using an anti-mouse panmacrophage monoclonal antibody and anti-mouse monoclonal antibodies specific for marginal metallophilic macrophages or marginal zone macrophages were used to detect red pulp macrophages, marginal metallophilic macrophages, and marginal zone macrophages in the spleen of op/op mice. In the mutant mice, the red pulp macrophages were reduced to about 60% of those in the normal littermates and the marginal metallophilic macrophages and marginal zone macrophages were absent. After administration of recombinant human macrophage colony-stimulating factor (rhM-CSF), numbers of red pulp macrophages increased rapidly, reaching levels found in normal littermates 1 week later. In contrast, the marginal metallophilic macrophages as well as the marginal zone macrophages appeared slowly after rhM-CSF administration and their numbers were less than half of the baseline level of normal littermates even at 12 weeks of administration. The distribution of marginal metallophilic macrophages and marginal zone macrophages appearing after M-CSF administration was irregular in the spleen of the op/op mice. These splenic macrophage subpopulations differed in their responses to rhM-CSF, suggesting that distinct mechanisms may be involved in their development and differentiation. The splenic red pulp macrophages present in unmanipulated op/op mice are an M-CSF-independent macrophage population. Although the marginal metallophilic macrophages and marginal zone macrophages are thought to be M-CSF-dependent, their development and differentiation appear to be influenced by locally produced M-CSF or other cytokines.

Animals↗
PubMed1989

Differences in the induction of macrophage cytotoxicity by the specific T lymphocyte factor, specific macrophage arming factor (SMAF), and the lymphokine, macrophage activating factor (MAF).

Specific T cell factors, such as specific macrophage arming factor (SMAF), are involved in the initiation of the immune response. Induction of SMAF-producing T lymphocytes in vivo and of SMAF production by T lymphocytes in vitro is dependent on the presence of intact tumor cells, and is independent of antigen presentation by macrophages. SMAF renders peritoneal macrophages cytotoxic for tumor cells. The armed peritoneal macrophages expressed a specific cytotoxicity. However, antigen-presenting cells can trigger lymphokine-producing T lymphocytes. These T lymphocytes produce lymphokines (e.g. macrophage activating factor (MAF] that activate macrophages. The MAF-activated macrophages express a non-specific tumoricidal activity. In the present study, we investigated the difference in the induction of macrophage cytotoxicity by SMAF and MAF. The following differences were found: 1) SMAF renders peritoneal resident macrophages cytotoxic, whereas MAF could only render peritoneal exudate macrophages cytotoxic. 2) SMAF requires only a 4-h incubation with macrophages, whereas MAF activates macrophages optimally after 12 h. 3) SMAF-armed macrophages recognize only the specific target cell(s), and thus, the cytotoxicity is specific in its expression. MAF activated macrophages were non-specifically cytotoxic. 4) Lipopolysaccharide (LPS) in the culture medium did not enhance the cytotoxicity of SMAF-armed macrophages. In contrast, MAF induced tumoricidal activity was enhanced by adding LPS to the culture medium. 5) After adsorption chromatography with anti-murine interferon-gamma (IFN-gamma), the arming capacity of SMAF supernatant was not reduced, whereas the activating capacity of the MAF supernatant was significantly reduced or abrogated. After immunization of mice with allogeneic tumor cells, SMAF-producing lymphocytes were detected in the draining lymph nodes already 4 days after immunization and up to 12 days. Lymphocytes with the capacity to produce MAF were present in the draining lymph nodes 14-24 days after immunization. Our data indicate that the T cell factors SMAF and MAF can both render macrophages cytotoxic, but act in a different way and during different stages of the cellular immune response against allogeneic tumor cells.

Animals↗
PubMed1984

Augmentation of macrophage complement receptor function in vitro. IV. The lymphokine that activates macrophage C3 receptors for phagocytosis binds to a fucose-bearing glycoprotein on the macrophage plasma membrane.

Macrophage receptors for the third component of complement (C3) are normally immobilized and unable to diffuse within the cell's plasma membrane and, even though they promote avid particle binding, are unable to promote phagocytosis of C3-coated particles. We have previously identified a lymphokine that activates macrophage C3 receptors for phagocytosis and have found that it acts by freeing the receptors so that they can diffuse within the macrophage plasma membrane. It seemed likely to us that the initial lymphokine-macrophage interaction would occur at the macrophage surface, perhaps via a specific lymphokine receptor. Since the binding of many ligands to cells is mediated by cell surface glycoproteins, we examined the protein and sugar requirements for murine peritoneal macrophages to respond to the lymphokine. Macrophages treated with the neutral protease Dispase lost the ability to respond to the lymphokine, and inclusion of L-fucose in the incubation medium containing lymphokine and macrophages inhibited markedly the macrophages' response to the lymphokine, suggesting that the lymphokine exerts its effects by first binding to fucose residues on a glycoprotein receptor on the macrophage surface. Further evidence for the essential role of macrophage surface fucose was obtained by demonstrating that pretreatment of macrophages with either fucosidase or gorse lectin, a fucose-binding lectin, strikingly disabled the cells from responding to the lymphokine. All treatments that prevented lymphokine activation of macrophage C3 receptors for phagocytosis also prevented lymphokine-induced C3 receptor mobility. These results strongly suggest that the lymphokine binds to a fucose-bearing macrophage surface glycoprotein, perhaps a specific lymphokine receptor. They also strengthen our hypothesis that, for a receptor to be able to promote phagocytosis, it must be able to diffuse within the macrophage plasma membrane.

Animals↗
PubMed2002

Lymph node macrophages, but not spleen macrophages, express high levels of unmasked sialoadhesin: implication for the adhesive properties of macrophages in vivo.

Sialoadhesin is a macrophage-restricted adhesion molecule that recognizes N-acetylneuraminylalpha2-3galactose structure. We prepared a multivalent neoglycoprotein probe carrying this oligosaccharide and characterized the binding activity of sialoadhesin on native rat macrophages. Macrophages from mesenteric and axillar lymph nodes exhibited 36-fold higher activity than those from the spleen. The K(d) values of the probe binding to macrophages of the two organs were indistinguishable (1-2 nM), whereas the B(max) value of lymph node macrophages was markedly higher than that of splenic macrophages. Western blot analysis revealed that the quantity of sialoadhesin present in lymph node macrophages was 25-fold higher than in splenic macrophages. High cell surface expression of sialoadhesin on lymph node macrophages was also shown by flow cytometry. To examine the "masking" of sialoadhesin by endogenous sialoglycoconjugates, we treated macrophages with sialidase before measuring the probe binding. After sialidase treatment, the binding activity of splenic macrophages increased fourfold, whereas that of lymph node macrophages did not increase. In conclusion, we have identified macrophages expressing high levels of unmasked sialoadhesin in lymph nodes. The unmasked forms on these macrophages are available for sialoadhesin-dependent adhesive functions, unlike the masked forms on the majority of splenic macrophages.

Animals↗
PubMed1988

Analysis of Ia antigen expression in macrophages derived from bone marrow cells cultured in granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor.

Bone marrow cells from C3H/HeJ mice were cultured in recombinant granulocyte-macrophage-CSF (rGM-CSF) or recombinant or purified (natural) preparations of macrophage-CSF (CSF-1) for 7 days, the adherent macrophages removed enzymatically, recultured in the absence of growth factor, and examined for their differentiative and functional characteristics. Expression of Ia Ag differed markedly in these two populations. Antibody plus complement-mediated cytotoxicity indicated that the percent of Ia-positive macrophages was low (approximately 15 to 20%) in both populations. Treatment of cultures with rIFN-gamma increased the percentage of Ia-positive cells in both populations; however, more CSF-1-derived macrophages were induced to become Ia positive than rGM-CSF-derived macrophages. In contrast, total Ia expression and Ia density per cell, as measured by ELISA and quantitative immunofluorescence, respectively, showed that medium-treated rGM-CSF-derived macrophages exhibited greater total Ia expression and higher Ia density per cell than CSF-1-derived macrophages. Treatment of CSF-1-derived macrophages with rIFN-gamma increased total Ia expression per culture to the levels exhibited by rGM-CSF-derived cells, although the density of Ia Ag per cell remained lower than in rGM-CSF-derived cells (medium or rIFN-gamma-treated). Northern blot and slot blot analysis of cytoplasmic RNA extracted from freshly harvested rGM-CSF- or CSF-1-derived cells indicated that the differences seen in basal Ia expression were also reflected at the level of steady-state, Ia-specific mRNA. The functional capacity of these two macrophage populations to stimulate Ag-specific T cell proliferation was also assessed. rGM-CSF- or CSF-1-derived macrophages were first cultured in the absence or presence of rIFN-gamma, Ag-pulsed, and irradiated before co-culture with Ag-primed, purified T cells. Ag-induced T cell proliferation was significantly greater in rGM-CSF- than in CSF-1-derived macrophages. Treatment of either population with rIFN-gamma had only a minimal effect on the ability of either macrophage population to stimulate Ag-specific T cell proliferation. These findings suggest that the development of mature macrophages from bone marrow progenitors under the influence of either GM-CSF or CSF-1 may, in part, underlie the functional heterogeneity of different macrophage populations.

Animals↗
PubMed1989

Binding of activated macrophages to tumor cells through a macrophage lectin and its role in macrophage tumoricidal activity.

A 45-60 kDa Gal/GalNAc-specific macrophage lectin was found to participate in the interaction between tumor cells and tumoricidal macrophages activated by an antitumor streptococcal preparation, OK-432, and in the tumoricidal activity of the activated macrophages. The binding between OK-432-elicited activated macrophages and murine mastocytoma P-815 cells was inhibited on preincubation of the macrophages with a neoglycoprotein (Gal-BSA) or a complex-type glycopeptide (unit B) which was a specific inhibitor of the macrophage lectin. This binding of the macrophages to P-815 cells was also inhibited on the addition of anti-macrophage lectin antiserum. Contrary to the case of OK-432-elicited macrophages, the binding of thioglycolate-elicited (responsive) macrophages to P-815 cells was inhibited only a little by Gal-BSA and unit B, and not inhibited by the antiserum. Furthermore, the tumoricidal activity of the activated macrophages was inhibited by the addition of the anti-macrophage lectin antiserum. These results suggest that the binding of activated macrophages to tumor cells through the Gal/GalNAc-specific macrophage lectin is an important part of the tumor cell killing mechanism.

Animals↗
PubMed1997

Macrophage differentiation and expression of macrophage colony-stimulating factor in murine milky spots and omentum after macrophage elimination.

To elucidate the differentiation mechanisms of macrophages in the murine omentum, we studied the repopulation of these cells and the expression of macrophage colony-stimulating factor (M-CSF) in the milky spots and omental tissues in mice depleted of macrophages following administration of liposome-encapsulated dichloromethylene diphosphonate (clodronate). The macrophages in the omentum were spindle or dendritic in shape, expressed several macrophage-specific antigens and Ia antigen, and phagocytized intraperitoneally injected carbon particles. In the milky spots, macrophages and macrophage precursors were detected, and the number of precursors increased after elimination of macrophages by intraperitoneal injection of liposome-encapsulated clodronate. Macrophage precursors in the milky spots proliferated, moved to the omentum, and transformed into dendritic-shaped macrophages. Expression of M-CSF mRNA extracted from the milky spots was markedly enhanced at 2 and 3 days after macrophage depletion. Localization of M-CSF protein and mRNA was observed in the stromal cells of the milky spots. In osteopetrosis (op/op) mutant mice that are defective in the production of functional M-CSF omental macrophages were absent. These results indicate that M-CSF locally produced in the milky spots plays an important role in providing a microenvironment for development and differentiation of omental macrophages.

Animals↗
PubMed1988

Bone marrow progenitors cultured in the presence of granulocyte-macrophage colony-stimulating factor versus macrophage colony-stimulating factor differentiate into macrophages with distinct tumoricidal capacities.

Bone marrow-derived cells from C3H/HeJ mice were cultured in the presence of recombinant murine granulocyte-macrophage colony-stimulating factor (rGM-CSF) or highly purified murine macrophage colony-stimulating factor (CSF-1) for 7 days. Following this 7-day culture period, mature macrophages were harvested and replated at precise densities in the absence of exogenous rGM-CSF or CSF-1, and assayed in a two-signal tumoricidal assay. Cultures were stimulated with medium only or with combinations of recombinant interferon-gamma (rIFN-gamma) as the "priming" signal, and/or butanol-extracted lipopolysaccharide (But-LPS) as the "triggering" signal for 24 hr. At this time, 51Cr-labeled, P815 tumor target cells were added, and the percent tumor cell cytotoxicity was determined after 16 hr. Macrophages derived under the influence of rGM-CSF exhibited significant tumoricidal capacity with medium alone (16 +/- 5%). The addition of "priming" signal only (i.e., rIFN-gamma, 10.0 U/ml) significantly increased tumoricidal capacity to 31 +/- 9%. Treatment with But-LPS alone did not alter the basal tumoricidal activity of rGM-CSF-derived macrophages. Combinations of rIFN-gamma (10.0 U/ml) and But-LPS (0.5-5.0 micrograms/ml) generated highly tumoricidal macrophages (50-60% tumor cell cytotoxicity). In contrast, medium-treated CSF-1-derived macrophages exhibited a significantly lower basal level of tumor cytotoxicity (6 +/- 3%). Unlike rGM-CSF-derived macrophages, treatment of CSF-1-derived macrophages with high concentrations of rIFN-gamma alone did not increase significantly the level of cytotoxicity above that of medium-treated cultures. However, CSF-1-derived macrophages responded to the highest concentrations of But-LPS (5.0 micrograms/ml) to increase tumoricidal activity from 6 +/- 3% to 17 +/- 5%. Optimal tumoricidal activity (44 +/- 17%) was observed when CSF-1-derived macrophages were treated simultaneously with high concentrations of both rIFN-gamma and But-LPS. Thus, macrophages derived from bone marrow progenitors in either rGM-CSF or CSF-1 exhibited tumoricidal capacities that differed in basal activity as well as in their requirements for and sensitivities to "priming" and "triggering" signals.

Animals↗
PubMed1996

Effects of macrophage colony-stimulating factor on macrophages and their related cell populations in the osteopetrosis mouse defective in production of functional macrophage colony-stimulating factor protein.

The development of macrophage populations in osteopetrosis (op) mutant mice defective in production of functional macrophage colony-stimulating factor (M-CSF) and the response of these cell populations to exogenous M-CSF were used to classify macrophages into four groups: 1) monocytes, monocyte-derived macrophages, and osteoclasts, 2) MOMA-1-positive macrophages, 3) ER-TR9-positive macrophages, and 4) immature tissue macrophages. Monocytes, monocyte-derived macrophages, osteoclasts in bone, microglia in brain, synovial A cells, and MOMA-1- or ER-TR9-positive macrophages were deficient in op/op mice. The former three populations expanded to normal levels in op/op mice after daily M-CSF administration, indicating that they are developed and differentiated due to the effect of M-CSF supplied humorally. In contrast, the other cells did not respond or very slightly responded to M-CSF, and their development seems due to either M-CSF produced in situ or expression of receptor for M-CSF. Macrophages present in tissues of the mutant mice were immature and appear to be regulated by either granulocyte/macrophage colony-stimulating factor and/or interleukin-3 produced in situ or receptor expression. Northern blot analysis revealed different expressions of GM-CSF and IL-3 mRNA in various tissues of the op/op mice. However, granulocyte/macrophage colony-stimulating factor and interleukin-3 in serum were not detected by enzyme-linked immunosorbent assay. The immature macrophages differentiated and matured into resident macrophages after M-CSF administration, and some of these cells proliferated in response to M-CSF.

Animals↗
PubMed1997

Involvement of mannose receptor in cytokine interleukin-1beta (IL-1beta), IL-6, and granulocyte-macrophage colony-stimulating factor responses, but not in chemokine macrophage inflammatory protein 1beta (MIP-1beta), MIP-2, and KC responses, caused by attachment of Candida albicans to macrophages.

The production of chemotactic cytokines (chemokines) and other cytokines by macrophages in response to fungal infection is thought to be critical during the course of candidiasis. However, the mechanism of cytokine synthesis by macrophages in response to fungi is not well understood. Therefore, the response of macrophages to Candida albicans was examined in terms of receptor-mediated chemokine and other cytokine mRNA induction. Attachment of C. albicans to murine thioglycollate-elicited peritoneal macrophages induced increased mRNA levels of the cytokines interleukin-1beta (IL-1beta), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein 1beta (MIP-1beta), MIP-2, and KC (a member of the platelet factor 4 neutrophil chemoattractant family), as determined by quantitative reverse transcription-PCR. However, treatment of macrophages with alpha-methyl-D-mannoside significantly reduced the cytokine GM-CSF response to C. albicans but did not affect the chemokine MIP-2 response. Antisense oligodeoxynucleotide (ODN) to mannose receptor (MR) mRNA inhibited the expression and function of MR in macrophages as determined by Western blot analysis and 125I-labeled mannose-bovine serum albumin (BSA) binding, and also inhibited the elevation of cytokine IL-1beta, IL-6, and GM-CSF mRNA levels induced by C. albicans attachment. Elevation of chemokine MIP-1beta, MIP-2, and KC mRNA levels induced by C. albicans was not affected in macrophages whose MR expression was suppressed by antisense ODN treatment. Furthermore, IL-4 treatment of macrophages, which up-regulated MR expression as determined by Western blot analysis and fluorescein isothiocyanate-labeled mannose-BSA uptake, enhanced the level of cytokine GM-CSF mRNA induced by C. albicans but not the level of the chemokine MIP-2 mRNA. These results indicate that selected cytokine responses of macrophages to C. albicans are mediated by MR, while some chemokine responses may be mediated by other receptors.

Animals↗
PubMedDate not supplied

Regulation of tumor necrosis factor-alpha receptors on macrophages: differences between primary macrophages and transformed macrophage cell lines.

Macrophages are a pivotal cell in the production of a variety of cytokines. In addition, macrophages express receptors on their surface which allows them to act as target cells for cytokines. The regulation of both cytokine production and cytokine receptor expression in macrophages may play a key role in modulating the processes of inflammation, injury, and repair. In this report we have studied the regulation of macrophage receptors for tumor necrosis factor-alpha (TNF alpha) on rat bone marrow-derived macrophages, rat alveolar macrophages, human monocyte-derived macrophages, and the human monocyte-like cell line, U937, by a variety of immunomodulatory and inflammatory agents. U937 cells and rat and human macrophages bound TNF alpha in a saturable process, with an affinity in each cell type of approximately 1 nM. Following incubation with phorbol myristate acetate for 60 min, TNF alpha binding to all cells was decreased. Interleukin-1 treatment increased TNF alpha binding to human and rat macrophages. Interferon-gamma treatment decreased receptor activity in both human and rat macrophages, but increased TNF alpha binding to U937 cells. Treatment of human and rat macrophages with endotoxin resulted in a rapid loss of TNF alpha binding, while endotoxin treatment increased receptor expression in U937 cells. In all cases, receptor regulation was the result of a change in receptor number. Finally, following intraperitoneal injection of endotoxin, TNF alpha receptor expression was down-regulated on alveolar lavage cells from rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Mycobacteria-macrophage interactions. Macrophage phenotype determines the nonopsonic binding of Mycobacterium tuberculosis to murine macrophages.

During tuberculosis, host defenses may be determined, in part, by the capacity of resident, elicited, and activated macrophages to bind and ingest Mycobacterium tuberculosis. We have investigated the mechanism by which macrophages bind M. tuberculosis and other mycobacteria in a serum-free system. The extent of binding of M. tuberculosis to macrophages was dependent on the phenotype of the macrophage; thioglycollate-elicited and immune-activated macrophages bound mycobacteria poorly, whereas resident macrophages bound mycobacteria efficiently. Within 'freshly' explanted macrophage populations (from 2 to 24 h in vitro) poor binding of mycobacteria correlated with poor binding of C3bi-coated particles, but not with variations in the level of complement receptor 3 (CR3) expression. Induction of C3bi-coated particle binding in thioglycollate-elicited macrophages by PMA was not accompanied by enhanced M. tuberculosis binding. Inhibition of M. tuberculosis binding by resident macrophages could only be achieved using a mAb recognizing an epitope within CR3 distinct from that which recognizes C3bi. Our results suggest that nonopsonic binding of M. tuberculosis is mediated by a site within CR3, which is distinct from the C3bi binding site. In addition, we show a variation in the capacity of different macrophage phenotypes to bind mycobacteria nonopsonically. These data suggest that heterogeneity in macrophage-mediated clearance of M. tuberculosis may be a significant factor in the progression of tuberculosis.

Animals↗
PubMed1992

Different accessory function for TH1 cells of bone marrow derived macrophages cultured in granulocyte macrophage colony stimulating factor or macrophage colony stimulating factor.

The ability of macrophages to stimulate immune responses is heterogeneous and may have influence on the type of the developing immune response. Therefore, in an attempt to define different functional states of mouse macrophages, we made use of the two macrophage growth factors: macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF). Generation of macrophages from freshly isolated bone marrow cells in the presence of GM-CSF results in a population expressing profound antigen presenting function for mouse TH1 cells, resulting in strong lymphokine production and proliferation of the T cells. Furthermore, high amounts of a novel soluble cytokine active on mouse TH1 cells are generated during the interaction of TH1 cells with macrophages elicited with GM-CSF. In contrast, macrophages grown from bone marrow cells for at least 14 days in the presence of M-CSF express only minimal antigen-presenting function for TH1 cells. Treatment of such macrophages for 24 h with either IFN-gamma or GM-CSF allows the distinction between two further functional states. Those treated with IFN-gamma efficiently presented antigen towards TH1 cells. The T cells produced large amounts of lymphokines and proliferate well. However, synthesis of the novel soluble cytokine (active on TH1 cells) was not detectable. The generation of this mediator requires a short-term treatment with GM-CSF of macrophages developed in the presence of M-CSF prior to their interaction with TH1 cells.

Animals↗
PubMedDate not supplied

Production of a macrophage growth factor(s) by a goldfish macrophage cell line and macrophages derived from goldfish kidney leukocytes.

We recently established a spontaneously proliferating macrophage cell line from the goldfish (GMCL), and in this report demonstrate the production of a macrophage-specific growth factor(s) (MGFs) by these cells. The supernatants from GMCL cultures induced proliferation and differentiation of macrophage-like cells from kidney hematopoietic tissues of goldfish. Kidney leukocytes cultured at 6.25 x 10(4)cells/ml in the presence of GMCL-derived MGFs proliferated during two weeks of cultivation, whereas those cultured without the MGFs did not. Leukocytes cultured at higher densities (2.5 x 10(5) cells/ml) proliferated in the absence of exogenous growth factor, but not to the same extent as those stimulated with GMCL-derived MGFs, suggesting that kidney leukocytes may produce endogenous MGFs. At higher cell density (1 x 10(6) cells/ml), kidney leukocytes multiplied extensively over a two-week cultivation period in the absence of exogenous GMCL-derived MGFs. The supernatants from these cultures restored the proliferative ability of leukocytes cultured at low densities, providing direct evidence of MGFs production by kidney leukocytes. The predominant cell-type in cultures grown in the presence of GMCL or kidney leukocyte-MGFs was the macrophage based on the following criteria: (1) non-specific esterase staining; (2) morphologic similarity to GMCL; (3) phagocytosis of the bacterium, A. salmonicida; (4) production of reactive oxygen and nitrogen intermediates in response to stimulation with macrophage activating factors and/or bacterial lipopolysaccharide; and (5) flow cytometric analyses. Both in vitro-derived kidney macrophage (IVDKM) and GMCL cultures contained three distinct populations of cells, (determined by flow cytometry), suggesting that these macrophage cultures are comprised of cells arrested at distinct differentiation junctures in macrophage development. Production of MGFs by macrophages and kidney leukocytes may play an important role in regulating macrophage hematopoiesis in fish.

Animals↗
PubMed1996

Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor.

We investigated the regulation of elastase activity in murine peritoneal macrophages by different cytokines and bacterial LPS. Thioglycolate-elicited mouse peritoneal exudate macrophages secrete a metalloproteinase that degrades elastin. Incubation of peritoneal exudate macrophages with LPS and IFN-gamma significantly inhibited the production of elastase by a mechanism independent of nitric oxide, superoxide, and hydrogen peroxide. The cytokines IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, TGF-alpha and -beta, basic fibroblast growth factor, monocyte chemotactic factor-1, and granulocyte CSF (G-CSF) had no significant effect on the production of elastase by macrophages. In contrast, granulocyte-macrophage CSF (GM-CSF) increased the production of elastase in a dose-dependent manner, and with macrophage CSF (M-CSF) inhibited it. Elastin zymography demonstrated that the modulation of elastolytic activity in macrophages was associated with changes in the level of metalloelastase protein. The stimulation of elastase activity by GM-CSF and the inhibition of elastase activity by LPS, IFN-gamma, and M-CSF occurred at the level of transcription. LPS and M-CSF also augmented the expression level of tissue inhibitors of metalloproteinase mRNA. The increased mRNA steady state level of murine macrophage elastase induced by GM-CSF resulted from both increased transcription and enhanced stability. The modulation of metalloelastase activity in macrophages by IFN-gamma, M-CSF, and GM-CSF suggests that these molecules may control the degradation of elastin fibers in lungs or blood vessels.

Animals↗
PubMed1991

The role of macrophages in experimental arthritis induced by Streptococcus agalactiae sonicate: actions of macrophage colony-stimulating factor (CSF-1) and other macrophage-modulating agents.

Intraperitoneal injection of Streptococcus agalactiae sonicated cells into Wistar rats causes a chronic relapsing polyarthritis resembling human rheumatoid arthritis. We report evidence favoring a role for macrophages in the pathology of this disease. S. agalactiae injected ip induced a high level of tumor necrosis factor release by peritoneal macrophages isolated subsequently, and had a similar effect when added to control peritoneal macrophages in culture. Ia antigen was induced on macrophages in both the peritoneum and affected joints following S. agalactiae injection. The role of macrophages in the disease process was studied by treating animals prior to S. agalactiae injection with varying concentrations of bacterial lipopolysaccharide (LPS), silica, and carrageenan, agents known to have a biphasic effect on macrophage function. They aggravated the pathology at low doses but prevented the disease at high doses. The most specific alteration of macrophage levels was achieved by injection of recombinant human macrophage colony-stimulating factor (CSF-1). Treatment with CSF-1 early in the disease lead to significant worsening of the pathology. Administration of CSF-1 after 2 weeks reactivated the disease and extended the chronic phase. These data in combination with previous findings are consistent with nonimmune, macrophage-mediated pathology for this model of arthritis. The results have implications for therapeutic application of CSF-1.

Animals↗
PubMed1998

Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma.

We determined the effect of inhaled corticosteroid, budesonide, on the release of the anti-inflammatory cytokine, interleukin-10 (IL-10), and of pro-inflammatory cytokines, macrophage inflammatory protein-1alpha (MIP-1alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF), from blood monocytes and alveolar macrophages of mild asthmatic subjects in a double-blind, cross-over, placebo-controlled study. Budesonide reduced bronchial hyperresponsiveness and improved baseline FEV1. Alveolar macrophages were obtained by bronchoalveolar lavage performed at the end of each treatment phase. IL-10 from blood monocytes was not altered, but both IL-10 mRNA and protein expression from alveolar macrophages stimulated by lipopolysaccharide and IL-1beta were increased after corticosteroid therapy. By contrast, alveolar macrophages released significantly less MIP-1alpha, IFN-gamma, and GM-CSF after steroid treatment. In comparison to alveolar macrophages from normal nonasthmatic volunteers, those from asthmatic patients released more MIP-1alpha, IFN-gamma, and GM-CSF but lower amounts of IL-10 particularly at baseline and after IL-1beta stimulation. The ability of steroids to inhibit pro-inflammatory cytokines but to enhance the anti-inflammatory cytokine such as IL-10 may contribute to their beneficial actions in asthma. Asthma is characterized by alveolar macrophages exhibiting both an enhanced capacity to release pro-inflammatory cytokines and a reduced capacity to produce IL-10.

Administration, Inhalation↗