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PubMed1983

Cathepsin B and prolyl endopeptidase activity in rat peritoneal and alveolar macrophages. Stimulation of peritoneal macrophages by saline lavage.

Cathepsin B and prolyl endopeptidase activity was determined in purified rat pulmonary and peritoneal macrophages and cathepsin B was determined in blood monocytes. The activity of cathepsin B in pulmonary macrophages was more than two times higher than in resident peritoneal macrophages and about eight times higher than in circulating monocytes. The simple process of peritoneal lavage with PBS induced an increase in cathepsin B activity in peritoneal macrophages that by 96 and 144 hr reached those levels observed in pulmonary macrophages. Both pulmonary and peritoneal macrophages contain prolyl endopeptidase activity. Repeated peritoneal lavage induced a significant increase in the activity of the enzyme, but not of the magnitude observed for cathepsin B. The data suggest that the transformation of monocytes into macrophages is associated with a significant increase in cathepsin B activity and that this increase is much greater in pulmonary than in peritoneal macrophages.

Animals↗
PubMed1980

Contrasting effects of activated and nonactivated macrophages and macrophages from tumor-bearing mice on tumor growth in vivo.

The effect of macrophages from normal and tumor-bearing mice on tumor growth was investigated with the use of an in vivo neutralization test. Macrophages from unstimulated and thioglycollate-stimulated peritoneal cavities (nonactivated macrophages) of normal mice enhanced growth of various syngeneic tumors [a 3-methylcholanthrene-induced transplantable fibrosarcoma from inbred C3HeB mice, a spontaneously originated transplantable melanoma (B16) from inbred C57BL/6 mice, and a radiation-induced lymphoma from inbred BALB/c mice]. This enhancing effect was not destroyed by irradiation of macrophages and was apparently mediated by macrophage secretory products. The effect appeared to be unrelated to immunosuppression and may have reflected direct stimulation of tumor cells. In contrast, Corynebacterium parvum-activated macrophages markedly inhibited tumor growth. Peritoneal macrophages from fibrosarcoma-bearing mice, which possessed tumor-inhibitory T-lymphocytes, enhanced tumor growth and abolished the effects of the tumor-inhibitory lymphocytes. Clearly, under certain conditions nonactivated macrophages interfered with the mechanisms of T-cell-mediated antitumor resistance in tumor-bearing mice.

Animals↗
PubMed1980

Role of accessory cells in B cell activation. I. Macrophage presentation of TNP-Ficoll: evidence for macrophage-B cell interaction.

The importance of cell interaction for thymic independent antigen responses has not been widely appreciated. The present report demonstrates, however, that macrophage-B cell interaction may be an important feature of B ce-l activation for the response to at least one polysaccharide thymic independent antigen, TNP-Ficoll. Experiments were performed demonstrating that a strict accessory cell requirement exists for the thymic independent response to soluble TNP-Ficoll, and that such accessory cells are both adherent and phagocytic, that is, macrophages. It was further demonstrated that macrophages could be pulsed with TNP-Ficoll and that these pulsed macrophages could activate B cells to respond, but only if the pulsed macrophages were viable. Thus, one function that macrophages can fulfill in responses to TNP-Ficoll is the specific function of antigen presentation. Such presentation of TNP-Ficoll by macrophages to B cells suggests that the antigen may not be activating B cells directly, and raises the possibility that the interaction of B cells and macrophages might be genetically restricted.

Animals↗
PubMed1982

Inhibition of macrophage-Trypanosoma cruzi interaction by concanavalin A and differential binding of bloodstream and culture forms to the macrophage surface.

The initial interaction between the surfaces of mouse peritoneal macrophages and Trypanosoma cruzi was examined using bloodstream (trypomastigote) and culture (epimastigote) forms of a predominantly reticulotropic strain of the parasite. Pretreatment with Con A resulted in a marked inhibition of macrophage binding of both forms of the parasite. Con A inhibition of epimastigote binding persisted for at least 4 hr after exposure to Con A whereas the trypomastigote-binding ability of macrophages showed a significant spontaneous recovery (57-79%) after 1 hr whether or not the parasites were present in the cell cultures during that time. Binding of Con A to the macrophage was required for inhibition of parasite attachment since incubation of Con A-treated cells with alpha-methyl mannoside prevented the inhibitory phenomenon when either epimastigotes or trypomastigotes were used. This monosaccharide had an inhibitory effect of its own which was not as marked as that produced by Con A and affected epimastigote but not trypomastigote binding to the phagocytic cells, thus representing an additional difference in the modes of interaction of these forms of the parasite with the macrophage surface. Furthermore, inhibition of either trypomastigote or epimastigote binding to macrophages was not caused by succinyl-Con A (which consists of two monomeric Con A subunits whereas Con A has four) unless the succinyl-Con A-treated macrophages were further incubated with anti-Con A antibodies. This observation suggests the importance of either molecular size or crosslinking of Con A subunits with consequent membrane rearrangement in causing the inhibitory phenomenon. The antibody preparation had no effect on macrophage binding of T. cruzi when tested by itself. These results highlight distinct characteristics of the binding of two forms of T. cruzi differing in their infective capacity to the surface of a host cell.

Animals↗
PubMedDate not supplied

[The characteristics of the estrogen reaction of the resident macrophages of the dermis and of the macrophages in an inflammatory focus in rats].

The method of morphometry was used to study specific features of the ultrastructure of derma resident macrophages in 2-weeks-old and mature rats and macrophages of an experimental inflammation focus caused by a subcutaneous introduction of a celloidin ball. Synthetic nonsteroid estrogen was injected subcutaneously to experimental animals: synestrol in dose 25 mg/kg of body mass 3 times a week. Animals not treated with the drug were taken as controls. Resident macrophages of the inflammation focus reacted to synestrol differently. The reaction of resident macrophages to synestrol depends on the age. Synestrol causes an increase of the summary section area of mature animals and slightly decreases the size of the lysosomal apparatus and intensity of the formation of microgrowings of the macrophage cytoplasm in young rats. Unlike the resident macrophages in which the apparatus of synthesis and secretion is not changed, the size of Golgi complex and the summary area of profiles of the granular endoplasmic reticulum in the cytoplasm of macrophages of the inflammation focus are increased under the influence of synestrol. All this seems to be a manifestation of the estrogen stimulation of secretory activity of the inflammation focus macrophages.

Aging↗
PubMed1997

IL-1 beta-converting enzyme (ICE) is present and functional in human alveolar macrophages: macrophage IL-1 beta release limitation is ICE independent.

Tissue macrophages readily produce intracellular pro-IL-1beta in response to stimuli such as LPS, but are limited in mature IL-1beta release compared with blood monocytes. The mechanism of this IL-1beta control may provide important insights into the physiology of IL-1beta at the tissue level. Since it has been hypothesized that IL-1beta processing by the IL-1beta-converting enzyme (ICE) regulates IL-1beta release, we compared human alveolar macrophages and human blood monocytes for relative ICE expression and activation. Using immunoblots and enzyme-linked immunoassay for ICE, we demonstrate that alveolar macrophages do not differ from blood monocytes in antigenic p45 ICE. Furthermore, an indirect assay for functional ICE documents similar ICE activities in both monocytes and alveolar macrophages, i.e., similar concentrations of soluble synthetic ICE inhibitor (IC50 values of 0.3 +/- 0.01 and 0.6 +/- 0.2 microM, respectively) are required to block mature IL-1beta generation. However, as has been reported for THP-1 myelomonocytic cells, neither alveolar macrophages nor blood monocytes contain directly quantifiable levels of functional ICE forms (p22/p20 and p10) when assayed by immunoblots or by a sensitive capture ELISA that uses an irreversible, biotinylated ICE inhibitor. These findings document that the macrophage limitation in mature IL-1beta release is not due to a lack of ICE or to an inability to activate ICE. Finally, using a staged release assay, the time to half-maximum mature IL-1beta release is significantly depressed in macrophages compared with that in monocytes. Taken together, these findings suggest that macrophage IL-1beta export is regulated independently of ICE activation.

Adenosine Triphosphate↗
PubMed1998

Macrophage-inflammatory protein-3 beta/EBI1-ligand chemokine/CK beta-11, a CC chemokine, is a chemoattractant with a specificity for macrophage progenitors among myeloid progenitor cells.

Chemoattractants are potential factors influencing cell migration. Stromal cell-derived factor-1, a CXC chemokine, is the only chemokine reported to have chemotactic activity for hemopoietic progenitor cells (HPC). We report in this work another chemokine of the CC subfamily, which is chemotactic for HPC. Macrophage-inflammatory protein (MIP)-3 beta/EBI1-ligand chemokine/CK beta-11 attracted bone marrow and cord blood CD34+ cells. In contrast to stromal cell-derived factor-1, which attracts multiple types of HPC, MIP-3beta attracted mainly CFU granulocyte macrophage, but not other HPC such as burst-forming unit erythrocyte or CFU granulocyte, erythrocyte, macrophage, and megakaryocyte. Chemoattracted CD34+ cells formed CFU granulocyte macrophage-like colonies, which were morphologically determined as large macrophages. These progenitors were selectively responsive to stimulation by macrophage CSF, demonstrating that MIP-3 beta attracts macrophage progenitors. Expression of CCR7, the receptor for MIP-3 beta, was detected at a mRNA level in the attracted CD34+ cells as well as input CD34+HPC. Expression of MIP-3 beta mRNA was not constitutive, but was inducible in bone marrow stromal cells by inflammatory agents such as bacterial LPS, IFN-gamma, and TNF-alpha. Taken together, our findings suggest that MIP-3 beta is expressed in the bone marrow environment after induction with certain inflammatory cytokines and LPS, and may play a role in trafficking of macrophage progenitors in and out of the bone marrow in inflammatory conditions.

Antigens, CD34↗
PubMed1992

Distinct in vivo functions of two macrophage subpopulations as evidenced by studies using macrophage-deficient op/op mouse.

The op/op mice totally lack macrophage growth factor colony-stimulating factor (CSF)-1 and thus, by definition are completely depleted of CSF-1-dependent functions of the macrophage cell lineage. Moreover, they possess a severe and generalized macrophage deficiency. However, residual macrophages of these mice should still have normal CSF-1-independent functions. Studies designed to elucidate this issue have revealed that op/op mice are capable of normal in vivo phagocytic function and demonstrate normal humoral and cellular response postimmunization with sheep red blood cells. However, release of monokines such as tumor necrosis factor and granulocyte CSF following administration of endotoxin is severely impaired in op/op mice as compared with littermate controls. These studies suggest that the CSF-1-dependent macrophage population (absent in the op/op mouse) is primarily responsible for regulatory functions of these cells mediated by monokines, while the CSF-1-independent macrophage population (present in the op/op mouse) is primarily responsible for the classical macrophage functions in immunity such as phagocytosis, antigen processing and presentation.

Animals↗
PubMed1991

Tumor-associated macrophages share in vitro growth characteristics with resident but not elicited macrophages.

Recent studies have shown that tissue macrophages are capable of proliferation and that this capability is enhanced by various cytokines, including macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Tumor-associated macrophages (TAM) have been demonstrated to proliferate in vitro, but no information is currently available on the ability of M-CSF and GM-CSF to enhance this response. To address this problem, limiting dilution analysis was utilized to examine the proliferative ability of macrophages isolated from two murine tumors of distinct origin following growth in secondary hosts. As a means of comparison, resident peritoneal macrophages (RPM) and thioglycolate-elicited macrophages (TEM) were also analyzed. Results indicate that a rare subset of TAM and RPM is capable of proliferation and that M-CSF and GM-CSF enhance the frequency of TAM and RPM which proliferate, but do not enhance the growth of TEM.

Animals↗
PubMed1997

Role of macrophage-colony-stimulating factor in regulating the accumulation and phenotype of tumor-associated macrophages.

In order to better define the role played by tumor-cell-derived macrophage-colony-stimulating factor (M-CSF) in regulating the recruitment and phenotype of tumor-associated macrophages, Polyoma large T-transformed fibroblastoid cell lines, derived from M-CSF-deficient osteopetrotic op/op mice and their phenotypically normal op/+ littermate controls, were inoculated into SCID (severe combined immunodeficiency) recipients and both the proportion and phenotype of the macrophages present within the tumors generated were determined. The results obtained indicate that, although tumors derived from M-CSF-deficient and M-CSF-producing tumor cell inoculate contain a similar proportion of macrophages, the macrophages isolated from tumors lacking M-CSF appear morphologically less mature and express lower levels of interleukin 1 beta, tumor necrosis factor alpha and FcR gamma II mRNA. Taken together, these data suggest that, although M-CSF does not appear to play a critical role in determining the macrophage content of these tumors, it does play a role in modulating the phenotype, and potentially the functional activity of the macrophages present within the tumor microenvironment.

Animals↗
PubMed1989

Lead inhibits oxidative metabolism of macrophages exposed to macrophage-activating factor.

The present experiments were designed to evaluate the effect of lead on the capacity of macrophages to respond to activating signals by increased respiratory-burst activity. When mouse peritoneal macrophages were exposed for 24 h to macrophage-activating factor (MAF) and/or bacterial lipopolysaccharide in the presence of lead acetate, a marked inhibition of their oxidative metabolism was observed. The hexosemonophosphate-shunt (HMPS) activity and the release of oxygen derivatives upon triggering by phorbol myristate acetate (PMA) were impaired. Treatment with the metal for 1 h led, however, to stimulation rather than inhibition of the PMA-triggered superoxide production, suggesting that the metal interfered with neither the triggering steps nor the activity of the NADPH oxidase. Moreover, the lead-induced inhibition of macrophage oxidative metabolism did not result from blockade of enzymes of the HMPS pathway. Glucose-6-phosphate dehydrogenase in macrophage extracts, as well as CO2 production from glucose, remained unaffected by the presence of lead, and extracts of lead-treated macrophages were as active as extracts from control cells in those two assays. Lead appeared to interfere with an early event in the MAF-induced activation process. In addition, lead decreased the uptake of 2-deoxyglucose by macrophages, suggesting that the metal might inhibit trans-membrane glucose-transport systems, a phenomenon that might explain in part the metabolic inhibition observed in lead-treated cells.

Animals↗
PubMed1999

Expression of CCR5 is increased in human monocyte-derived macrophages and alveolar macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis infection.

Human immunodeficiency virus (HIV) replicates more efficiently in Mycobacterium tuberculosis (MTB)-infected macrophages than in uninfected controls. We investigated whether this may be partly explained by changes in expression of CCR5 in the course of mycobacterial infection, as this molecule has been shown to be a coreceptor for HIV entry. Since the lung is the preferential organ of HIV replication in the course of tuberculosis, we preliminarily analyzed beta-chemokine receptor expression in alveolar macrophages from patients with active tuberculosis, using flow cytometry based on an MIP-1alpha ligand-biotin/avidin-FITC detection system. Increased MIP-1alpha receptor (MIP-1alphaR) expression in alveolar macrophages from infected patients was observed whereas no detectable expression could be revealed in uninfected controls. Since MIP-la can also bind CCR1 and CCR4, the presence of CCR5 mRNA was investigated in bronchoalveolar lavage (BAL) cells and detected in alveolar macrophages from tuberculosis patients only. The study was then extended to in vitro MTB-infected macrophages. Monocyte-derived macrophages (MDMs) were left to differentiate for 7 days before MTB H37Rv infection, and CCR5 expression was monitored, by using a specific monoclonal antibody, on days 1, 6, and 11 after infection. Increased CCR5 expression in MTB-infected macrophages was observed, with a peak on day 6 (64% in MTB-infected versus 33% in control cultures) and a decrease by day 11 (25% in MTB infected versus 13% in control cultures). These results show that CCR5 expression is enhanced in the course of in vitro MTB infection and during active pulmonary tuberculosis.

Cells, Cultured↗
PubMed1983

Chemical nature of the interaction between macrophage fusion factor and macrophage membranes.

Giant-cell formation induced by macrophage fusion factor (MFF) was not altered after pretreatment of macrophages with trypsin, chymotrypsin, pronase, neuraminidase, phospholipase C, or phospholipase D. Pretreatment of macrophages with either alpha-mannosidase or alpha-glucosidase completely inhibited giant-cell development, without altering macrophage viability. No alteration of giant-cell formation was observed when 0.1 M of L-fucose, N-acetyl-glucosamine, D-arabinose, D-xylose, melibiose, D-glucose, D-galactose, alpha-lactose, sucrose, D-fructose, or maltose was present during incubation of macrophages with MFF. Giant-cell formation was abolished when 0.1 M alpha-D-mannose was present during macrophage incubation with MFF. These results suggest that the protein moiety of MFF recognizes a specific receptor site on the macrophage membrane, one that is different from those described for other lymphokines and contains alpha-mannose.

Animals↗
PubMed2003

Recombinant Leishmania major secreting biologically active granulocyte-macrophage colony-stimulating factor survives poorly in macrophages in vitro and delays disease development in mice.

Leishmania is an intracellular pathogen that replicates inside macrophages. Activated macrophages produce a specific subset of cytokines that play an important role in the control of Leishmania infections. As part of our interest in developing suicide parasites that produce abortive infections for the purposes of vaccination, we engineered recombinant Leishmania major strains producing biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF). We showed that GM-CSF is being produced in the phagosomes of infected macrophages and that it can be detected in the culture supernatants of both infected macrophages and extracellular parasites. Our data support the notion that GM-CSF secreted by both developmental forms of recombinant L. major can activate macrophages to produce high levels of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and IL-18 and various chemokines including RANTES/CCL5, MIP-1alpha/CCL3, MIP-1beta/CCL4, MIP-2/CXCL2, and MCP-1/CCL2, which enhance parasite killing. Indeed, GM-CSF-expressing parasites survive poorly in macrophages in vitro and produce delayed lesion development in susceptible BALB/c mice in vivo. Selective killing of intracellular Leishmania expressing cytokine genes capable of activating cellular responses may constitute a promising strategy to control and/or prevent parasitic infections.

Animals↗
PubMed2005

Chronic ethanol ingestion in rats decreases granulocyte-macrophage colony-stimulating factor receptor expression and downstream signaling in the alveolar macrophage.

Although it is well recognized that alcohol abuse impairs alveolar macrophage immune function and renders patients susceptible to pneumonia, the mechanisms are incompletely understood. Alveolar macrophage maturation and function requires priming by GM-CSF, which is produced and secreted into the alveolar space by the alveolar epithelium. In this study, we determined that although chronic ethanol ingestion (6 wk) in rats had no effect on GM-CSF expression within the alveolar space, it significantly decreased membrane expression of the GM-CSF receptor in alveolar macrophages. In parallel, ethanol ingestion decreased cellular expression and nuclear binding of PU.1, the master transcription factor that activates GM-CSF-dependent macrophage functions. Furthermore, treatment of ethanol-fed rats in vivo with rGM-CSF via the upper airway restored GM-CSF receptor membrane expression as well as PU.1 protein expression and nuclear binding in alveolar macrophages. Importantly, GM-CSF treatment also restored alveolar macrophage function in ethanol-fed rats, as reflected by endotoxin-stimulated release of TNF-alpha and bacterial phagocytosis. We conclude that ethanol ingestion dampens alveolar macrophage immune function by decreasing GM-CSF receptor expression and downstream PU.1 nuclear binding and that these chronic defects can be reversed relatively quickly with rGM-CSF treatment in vivo.

Alcoholism↗
PubMed2001

Effects of macrophage-CSF on pulmonary-macrophage repopulation after bone marrow transplantation.

Pulmonary infections are important causes of morbidity and mortality in immunosuppressed patients after transplantation. After experimental irradiation and syngeneic bone marrow transplantation in mice, macrophages show reduced repopulation in the lung compared with that in other tissues. Macrophages are major microbicidal immune effector cells in host pulmonary defense. Therefore, we examined the role of locally applied cytokines for macrophage repopulation in the lung. An accelerated repopulation of macrophages in the lung was observed after intranasal application of macrophage-colony stimulating factor (M-CSF), but this effect was not enhanced by a combination of M-CSF with interleukin (IL)-3. Local proliferation contributed to this effect. Macrophages in the lung tissue of M-CSF-treated mice displayed greater secretion of IL-6, whereas M-CSF treatment did not enhance the gene expression of other macrophage-specific chemokines. The role of M-CSF treatment was determined in pulmonary murine cytomegalovirus infection using an irradiation/reconstitution model. The M-CSF treatment had no effect on virus load in the lung tissue. However, phosphate-buffered saline-treated mice seemed to develop stronger inflammation after viral infection than M-CSF-treated mice. We conclude that local M-CSF treatment modulates cellular inflammation in the lung during immunosuppression.

Administration, Intranasal↗
PubMed1994

Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by human immunodeficiency virus and reduces the activity of compounds that inhibit virus binding.

The effects of macrophage colony-stimulating factor (M-CSF) on CD4 receptor expression, susceptibility to human immunodeficiency virus type 1 (HIV) infection, and anti-HIV activity of dextran sulfate and soluble-CD4 were studied in cultured, human primary macrophages. M-CSF stimulated macrophage cells to express the CD4 receptor, and this resulted in an increase of both the number of CD4+ cells and the density of the receptor on the cell surface. M-CSF also significantly enhanced the susceptibility of macrophage cells to HIV infection. Interestingly, the anti-HIV activity of dextran sulfate and soluble-CD4 (two compounds that interfere with HIV-CD4 binding with different mechanisms) was reduced 100-fold and fivefold, respectively, in M-CSF-treated macrophages. Human blood concentrations of M-CSF are reported to be similar to those used in this work (1,000 U/mL); thus, it is conceivable that also in vivo this cytokine may modify the susceptibility of macrophages to HIV and the ability of dextran sulfate and soluble CD4 to inhibit HIV replication. These results suggest that the in vitro study in M-CSF-treated macrophages of promising drugs inhibitors of HIV-CD4 binding could provide further insights into the potential efficacy of these compounds in patients.

Antigens, CD↗
PubMed2003

Macrophage colony-stimulating factor-dependent macrophage proliferation is mediated through a calcineurin-independent but immunophilin-dependent mechanism that mediates the activation of external regulated kinases.

Calcineurin is constitutively expressed in bone marrow-derived macrophages. However, macrophage response to macrophage colony-stimulating factor (M-CSF) was not impaired by the use of either calcineurin inhibitors (W-13, chlorpromazine and trifluoperazine), calcium chelators (BAPTA-AM) or Ca2+ channel antagonists (verapamil, nifedipine and diltiazem). Inhibition of calcineurin expression by inhibitory antisense RNA treatment did not result in an inhibition of M-CSF-dependent proliferation. Only very high doses of cyclosporin A and FK506 inhibited macrophage proliferation induced by growth factors, such as M-CSF, granulocyte-macrophage (GM)-CSF or IL-3. This inhibitory action is mediated by the peptidylprolyl isomerase activity of the immunophilins, as demonstrated bythe use of specific inhibitors (rapamycin and sanglifehrin A). These isomerase inhibitors exerted a negative effect on a key element involved in macrophage proliferation, namely the M-CSF-dependent activation of the extracellular signal-regulated kinases (ERK). In summary, the data presented here provide new insights in the mechanism of macrophage proliferation, which may have relevant consequences. First, we showed that in M-CSF-dependent proliferation calcineurin is not involved, and second, that immunophilins play a key role and their activation blocks ERK activation.

Animals↗