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PubMedDate not supplied

Utilization of macrophages in anticancer therapy: the macrophage network theory.

Appropriate and rational modulation of innate immunity may enhance the therapeutic efficacy of emerging immune therapies for treating cancer. One of the crucial cells of innate immunity is the macrophage. The purpose of this article was to review those issues that suggest ways of exploiting macrophage local functions in immune therapy, and to discuss the suitability of low molecular-weight lipopolysaccharides as potent modulators of macrophage functions for immune therapy of cancer.

Animals↗
PubMed2005

The effect of Helicobacter pylori infection on expression of macrophage migration inhibitory factor by T cells and macrophages in gastric mucosa.

BACKGROUND: Macrophage migration inhibitory factor (MIF) plays a pivotal role in inflammatory and immune-mediated diseases. However, its molecular function and role in gastrointestinal diseases has rarely been studied and thus warrants an in-depth investigation. This study was designed and conducted to determine MIF expression in Helicobacter pylori (H. pylori)-induced gastritis and the effect of H. pylori on MIF expression in monocytes in vitro. METHODS: Gastric specimens of 62 patients with chronic gastritis were obtained through endoscopic biopsies. Both gastric antrum and body were examined for histopathologic changes. Positive H. pylori was determined through rapid urease test and histopathological examination. A patient was classified as H. pylori positive if both tests showed positive results. The updated Sydney System was employed to assess the severity and activity of gastric inflammation. Double immunoassaying for MIF/T-cells (CD45RO) and MIF/macrophage (KP1), as well as in situ hybridization for the expression of MIF mRNA were used for the current analysis. THP-1, a monocyte cell line, was co-incubated with H. pylori strains (ATCC26695) and subsequently examined for the expression of MIF protein and mRNA by enzyme linked immunosorbent assay and retrospective transcription-polymerase chain reaction, respectively. RESULTS: Among 62 patients with chronic gastritis, significant increase in total T-cells, MIF+ T-cells, total macrophages, MIF+ macrophages and MIF mRNA+ cells was observed in 42 H. pylori positive patients compared to H. pylori negative patients. Moreover, the increase of the MIF mRNA+ cells was highly correlated with the severity of the disease (number of MIF mRNA+ cells/mm(2), mild: 2834 +/- 382, moderate: 3569 +/- 123, severe: 3881 +/- 118, P < 0.01). In vitro results showed that the expression of MIF protein and mRNA in monocytes was significantly increased after incubation with H. pylori strains. CONCLUSIONS: Overexpression of MIF is common in H. pylori-induced gastric inflammation, which suggests MIF may play an important role in the initiation and development of this disease.

Female↗
PubMed1990

Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages.

The alveolar macrophage (AM), as a representative human tissue macrophage, was used in an in vitro system to examine the anti-human immunodeficiency virus type-1 (HIV-1) activity of zidovudine (AZT) and granulocyte-macrophage colony-stimulating factor (GM-CSF). AMs were infected with the IIIB strain of HIV-1 and exposed to AZT (1 mumol/L), GM-CSF (30 U/mL), a combination of AZT (1 mumol/L)/GM-CSF (30 U/mL), or medium control. At 10 or 20 days post-infection, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear leukocytes (PBMLs) were added to the AM cultures as stimulated target cells. AZT effectively suppressed HIV replication and prevented transfer/amplification in target PBMLs as long as the drug was maintained in the medium. GM-CSF neither suppressed nor augmented HIV replication. The combination of AZT/GM-CSF was comparable with AZT alone in suppressing both the initial infection of AMs and the transfer to target PBMLs as long as the agents were maintained in the cultures. However, when the drugs were removed at the same time that PHA-stimulated PBMLs were added to the culture, the combination of AZT/GM-CSF was found to be more effective than AZT alone in preventing the transfer/amplification of HIV in the target lymphocytes. These results suggest that (1) AZT is effective in inhibiting HIV-1 infection in mononuclear phagocytes; (2) GM-CSF neither inhibits nor augments the replication of the IIIB strain of HIV in human AMs; and (3) the combination of AZT and GM-CSF may have an enhanced anti-HIV-1 activity compared with AZT alone. Clinical trials with the two agents in combination appear warranted.

Cells, Cultured↗
PubMed1989

Differential production of tumor necrosis factor, macrophage colony stimulating factor, and interleukin 1 by human alveolar macrophages.

Human alveolar macrophages (AMO) have been investigated for their ability to produce three monokines, tumor necrosis factor-alpha (TNF), macrophage colony stimulating factor (CSF-1), and interleukin 1-beta (IL-1). No TNF activity was found in supernatants of unstimulated AMO cultured for 20 h, although TNF mRNA was detected in the cells by Northern blot analysis. Stimulation of the cells with lipopolysaccharide (LPS) induced production and release of high levels of TNF into the culture supernatant. Increased levels of TNF mRNA were detectable at 90 min after LPS stimulation by dot blot analysis, reaching maximum expression between 4 and 8 h and declining thereafter. TNF activity peaked at approximately 8 h in the AMO supernatants. After 24 h TNF production had ended. Compared to autologous monocytes the AMO produced 5.7 times more TNF on a per cell basis (activity accumulated in 20 h supernatants). Uncultured AMO expressed CSF-1 mRNA which was translated into active protein recovered in supernatants upon culture in the absence of stimulus. The addition of LPS to AMO slightly reduced both mRNA levels and amount of factor in the supernatants. In contrast to the AMO, monocyte production of CSF-1 was enhanced by LPS. CSF-1 production by AMO continued for at least 48 h of culture. Spontaneous production of low amounts of IL-1 was found in one-third of the AMO samples, while low levels of IL-1 mRNA were present in all tested preparations. LPS stimulation induced increase in IL-1 mRNA within 90 min; mRNA levels peaked between 12 and 20 h and stayed high for at least 42 h. However, while all LPS-stimulated AMO expressed high levels of IL-1 mRNA biologically active IL-1 was again detected only in a fraction of the AMO supernatants. These results show that the production of monokines CSF-1, TNF, and IL-1 is differentially regulated by LPS in alveolar macrophages and has different responses as compared to monocytes. The longevity of the messages for each of the factors is possible indicators of the relative contribution of these factors to the response to endotoxin-induced injury and repair processes in the lung.

Adult↗
PubMed1988

Role of alveolar macrophages in tumor-bearing rats: tumoricidal properties of carrageenan-activated macrophages.

Tumor BN472, a malignant mammary adenocarcinoma, was subcutaneously transplanted into syngeneic female Brown Norway rats. Seven days after tumor inoculation, carrageenan-impregnated synthetic sponges were subcutaneously implanted in control and tumor-bearing rats. Another week later the animals were sacrificed and alveolar macrophages were harvested and tested for tumoricidal activity against a tissue culture line of BN472 cells and their capacity to phagocytose formaldehyde-treated sheep erythrocytes. The data demonstrate that carrageenan statistically significantly enhances the tumoricidal activity of alveolar macrophages in tumor-bearing rats. Phagocytic activity of the macrophages in these animals is not different from sham-operated control animals, whereas the phagocytic activity of tumor-bearing rats is statistically significantly decreased.

Animals↗
PubMed1981

Possible involvement of macrophage-mediated hepatocytotoxicity in chronic active hepatitis: the induction of liver cell injury by culture supernatant of MAF-activated macrophages.

When peripheral blood lymphocytes from patients with various types of hepatitis were stimulated in vitro with liver specific protein, lymphocyte transformation and MIF production were demonstrated in many cases, especially in chronic active hepatitis. The culture supernatant of these activated lymphocytes was also shown to contain MAF, a kind of lymphokine, which activated the peritoneal macrophages of guinea pigs. When the culture fluid of MAF-activated macrophages was added to isolated liver cells, a significant inhibition of their albumin biosynthesis was detected. The active principle which caused the impairment of liver function was fractionated by gel filtration using a Sephadex G-75 column, and it was found that the active material was a protein-like substance with a molecular weight of about 10,000-40,000. The results suggest the possibility that the soluble substance released from the activated macrophage may be involved at least partially in the immunological pathogenesis of chronic active hepatitis among many other immunological processes.

Adult↗
PubMed1982

Macrophages as effector cells of protective immunity in murine schistosomiasis. II. Killing of newly transformed schistosomula in vitro by macrophages activated as a consequence of Schistosoma mansoni infection.

Plastic adherent peritoneal cells from Schistosoma mansoni-infected mice have previously been shown to exhibit nonspecific tumoricidal activity in vitro. In this report we show that these same cell populations kill significant numbers of skin-stage schistosomula in vitro in the absence of added antibody. Larval killing by these activated cells could be enhanced by the use of suspension rather than monolayer cultures and by addition of heat-inactivated immune mouse serum to the cultures. Adherence of cells to schistosomula was also enhanced under the same conditions, suggesting that cell binding to the larvae might be critical in the development or expression of microbicidal activity. In support of this hypothesis, the same level of enhancement of cell binding and larval damage was observed upon substitution of concanavalin A for immune mouse serum. Killing of schistosomula appeared to be mediated solely by activated macrophages in the peritoneal cell suspensions from S. mansoni-infected mice, because partially purified preparations of eosinophils were virtually inactive in these assays. Likewise, inflammatory macrophages from uninfected mice were unable to kill schistosomula under the same conditions, emphasizing the importance of activation in the development of killing capability. The finding that macrophages activated as a consequence of S. mansoni infection are able to kill larval schistosomes in vitro suggests that these cells may play a role in concomitant immunity to schistosomiasis in vivo.

Animals↗
PubMed1995

Endogenous macrophage CSF production is associated with viral replication in HIV-1-infected human monocyte-derived macrophages.

Human monocyte-derived macrophages (MDM) cultured in medium containing macrophage (M) CSF are more susceptible to infection with HIV-1. M-CSF increases the frequency with which MDM become infected, the level of HIV mRNA expressed per infected cell, and the level of proviral DNA expressed per infected culture. Because of these effects of M-CSF on HIV-1 replication and the reported function of this factor as a survival and differentiation factor for human monocytes, we investigated whether HIV-1 could induce endogenous M-CSF production by MDM and the potential role of endogenous M-CSF on HIV-1 infection in these cells. MDM infected with HIV and maintained in the absence of exogenous M-CSF produced this cytokine endogenously at levels 5- to 24-fold higher than uninfected cells. In contrast, the proinflammatory cytokines IL-1, IL-6, and TNF-alpha and the growth factor granulocyte-macrophage CSF were not detected. The kinetics of M-CSF production following infection paralleled the kinetics of virus replication. Furthermore, enhanced production of M-CSF was dependent on viral entry and active replication of HIV-1. Thus, endogenous M-CSF production may contribute to the survival of HIV-infected MDM, enable them to function as a reservoir for HIV, and facilitate the spread of virus in vivo.

Blotting, Northern↗
PubMed1993

Granulocytic-macrophagic and macrophagic colony stimulating factors elicit colonies of mast cells in mouse bone marrow agar culture. An electron microscope study.

Granulocytic-macrophagic colony stimulating factor (GM-CSF) and macrophagic colony stimulating factor (M-CSF or CSF-1) stimulate bone marrow cells of mouse to produce in semisolid agar colonies in which mononuclear cells were reported to be macrophages. We verified in such colonies the ultrastructure of the mononuclear cells which had cytoplasmic granules of the mast cells and lacked lysosomes, therefore we considered them as mast cells. However, the granules content did not reach the degree of condensation typically found in granules of mouse peritoneal mature mast cells. The mast cells of colonies obtained in agar can be mast cells arrested at some point in the maturative process, mast cells of a yet unrecognized type or cells with mast cells ultrastructural features which behave as precursors for cells of myeloid lineage.

Agar↗
PubMed1996

Macrophage inflammatory protein-1alpha is induced by human immunodeficiency virus infection of monocyte-derived macrophages.

Disparate findings have been reported as to whether human immunodeficiency virus (HIV) affects cytokine production by macrophages (MA). We investigated production of different cytokines and of macrophage inflammatory protein (MIP)-1alpha by HIV-1Ba-L- or HIV-1Ada-infected blood-derived MA. Relative to controls, only MIP-1alpha levels increased twofold to > 10-fold in supernatants 2 to 3 weeks postinfection (PI), at the time of maximum virus production; levels of the other chemokines (RANTES, interleukin (IL)-8) and cytokines (IL-1alpha, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1) investigated were not affected. MIP-1alpha mRNA signal assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) was, however, only occasionally greater in cells from infected cultures relative to controls. MIP-1alpha levels in supernatants remained in the same range as in control cultures when more than 10 mmol/L Zidovudine was added 24 hours PI, which indicates involvement of virus replication in the effect. Anti-MIP-1alpha antibody labeling identified a 10% to 25% subset of MA, strongly expressing HLA-DR and CD4, and also stained by anti-IL-6 and anti-TNF-alpha antibodies. Two weeks PI, dual staining showed that the majority of the 5% to 20% cells that were p24+ belonged to the MIP-1alpha+ population, which may define a MA subset capable to better sustain HIV replication. MIP-1alpha induced by HIV replication in MA might play a role in the pathophysiology of HIV infection; in impaired hematopoiesis; or as a CD4+ and CD8+ lymphocyte chemoattractant, by recruiting either or both HIV-susceptible and cytotoxic T lymphocytes to virus replication sites.

Antiviral Agents↗
PubMed1997

[Plasma macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor and granulocyte colony-stimulating factor levels in continuous ambulatory peritoneal dialysis patients].

From a pathophysiological perspective, several studies have been performed on cytokines in chronic renal failure patients treated with continuous ambulatory peritoneal dialysis (CAPD). Because the peritoneal macrophages in CAPD patients produce some cytokines and the urinary secretion route for cytokines lost in those patients, CAPD patients are considered to have different plasma cytokine levels. Among the various cytokines, research on certain inflammatory cytokine levels has been reported. In studies of CAPD patients, peripheral blood and dialysate can be used as specimens. There are two methods of research. One involves determining the cytokine concentration in specimens and culture supernatant, while the other is to determine the mRNA expression of mononuclear cells in specimens and cultured mononuclear cells. The plasma levels of macrophage colony stimulating factor (M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were measured in CAPD patients without peritonitis. Plasma M CSF, GM CSF and G-CSF levels in CAPD patients were higher than those in healthy volunteers (p < 0.0001).

Adult↗
PubMed1998

A new cytokine-dependent monoblastic cell line with t(9;11)(p22;q23) differentiates to macrophages with macrophage colony-stimulating factor (M-CSF) and to osteoclast-like cells with M-CSF and interleukin-4.

Monocytes/macrophages exert a series of important functions in vivo. To facilitate detailed investigation of their functional capacity and the mechanism leading to their differentiation, several cell lines have been established from primary material. We present here a new human monoblastic cell line, designated UG3. UG3 cells are characterized by the following features. (1) UG3 cells harbor the t(9;11)(p22;q23) translocation that results in fusion of the MLL and the AF9 genes and produce the corresponding AF9-MLL and MLL-AF9 fusion transcripts. (2) UG3 cells rely on the presence of exogenous growth factors for viability and proliferation, such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), or macrophage colony-stimulating factor (M-CSF). (3) When cultured in the presence of G-CSF, UG3 cells differentiate along the granulocytic lineage, as evidenced by segmentation of nuclei and positive staining for neutrophilic alkaline phosphatase and peroxidase. (4) When cultured in the presence of GM-CSF or M-CSF, UG3 cells differentiate into mature macrophages while preserving surface expression of CD14 and CD68 and also start to release cytokines into cell-culture supernatants. Under these culture conditions, UG3 cells also take up acetylated LDL. (5) When cultured in the presence of M-CSF and IL-4, UG3 cells differentiate into osteoclast-like multinucleated giant cells capable of bone resorption and display tartrate-resistant acid phosphatase (TRAP) activity. UG3 cells thus provide features to qualify them as a useful model to further investigate the mechanism underlying these processes and also to further elucidate the functional role of mature monocytes/macrophages or osteoclasts.

Adult↗
PubMed1999

Selective expansion of alveolar macrophages in vivo by adenovirus-mediated transfer of the murine granulocyte-macrophage colony-stimulating factor cDNA.

Based on the hypothesis that genetic modification of freshly isolated alveolar macrophages (AM) with the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA would induce AM to proliferate, this study focuses on the ability of adenoviral (Ad) vectors to transfer and efficiently express the murine (m) GM-CSF cDNA in murine AM with consequent expansion in the number of AM in vitro and in vivo. To demonstrate that an Ad vector can effectively transfer and express genes in AM, murine AM recovered by bronchoalveolar lavage from the lung of Balb/c mice were infected with an Ad vector coding for green fluorescent protein (GFP) in vitro and expressed GFP in a dose-dependent fashion. Infection of AM with an Ad vector containing an expression cassette coding for mGM-CSF led to GM-CSF expression and to AM proliferation in vitro. When AM infected with AdGFP were returned to the respiratory tract of syngeneic recipient mice, GFP-expressing cells could still be recovered by bronchoalveolar lavage 2 weeks later. In vitro infection of AM with AdmGM-CSF and subsequent transplantation of the genetically modified AM to the lungs of syngeneic recipients led to GM-CSF expression in vivo. Strikingly, the AM recovered by lavage 5 weeks after transplantation demonstrated an increased rate of proliferation, and the total number of alveolar macrophages was 1. 9-fold greater than controls. Importantly, the increase in the numbers of AM was selective (ie, other inflammatory cell numbers were unchanged), and there was no modification to the lung architecture. Thus, it is feasible to genetically modify AM with Ad vectors and to use this strategy to modify the behavior of AM in vivo. Based on the importance of AM in the primary defense of the respiratory epithelial surface, this strategy may be useful in enhancing pulmonary defenses in immunodeficiency states.

Adenoviridae↗
PubMed1979

IgG-binding sites on macrophage cell membrane. I. Identification of two distinct Fc receptors on mouse peritoneal macrophages.

Evidence is presented concerning the existence on mouse peritoneal macrophages of two separate and distinct Fc receptors, one for cytophilic monomeric IgG (mIgG) and the other for polymeric IgG. The latter Fc receptor recognizes both heat-aggregated IgG and antigen-complexed IgG. The major findings of our studies are: (a) the different susceptibility of the two Fc receptor types by pronase, trypsin or phospholipase C; (b) the independent modulation of these two binding sites on the cell membrane; (c) the inability of mIgG to inhibit the binding of particulate antigen-complexed IgG ligand; (d) the ability of mIgG molecules which are devoid of the cytophilic property to attach to the macrophage surface upon their polymerization induced by heating or antigen. The results are discussed in terms of "cytophilic" and "opsonic" Fc receptor types which may provide different functional abilities for normal macrophages.

Animals↗
PubMed1987

Immunohistochemical characterisation of macrophages in human liver and gastrointestinal tract: expression of CD4, HLA-DR, OKM1, and the mature macrophage marker 25F9 in normal and diseased tissue.

This report describes the immunocytochemical characterisation of macrophages in sections of human liver, gastrointestinal tract, and associated lymphoid tissue and the inflammatory lesions of Crohn's disease. 25F9 is an antigen reported to be induced during the maturation of blood monocytes in vitro. The antigen was concentrated in cytoplasmic vesicular structures of isolated gastrointestinal macrophages. Similar labelled cells were observed in the apical regions of lamina propria in both small and large intestine in vivo. Their numbers and size were greatly increased in specimens of colon from patients with melanosis coli. Mucosal inflammatory lesions in specimens from patients with Crohn's disease did not contain 25F9-positive cells. The antigen was absent from giant cells and epithelioid cells in granulomata but was expressed on histiocytes in submucosal microgranulomata. In lymphoid organs, 25F9-positive cells were found in germinal centres, in the dome region of Peyer's patch, and in the medulla, but were largely excluded from T cell areas. In reactive nodes from Crohn's disease patients, the number of labelled cells in germinal centres and T cell areas was greatly increased. 25F9 was absent from the majority of typical liver Kupffer cells, but was expressed on cytoplasmic granules in a minor subpopulation of larger, more rounded cells in the liver. The results suggest that 25F9 is a marker for endocytosis rather than maturation. In parallel sections, resident macrophages of both liver and gastrointestinal tract labelled with Leu 3a/OKT4 (CD4) and with OKIa (HLA-DR antigen) but did not express OKM1 (type III complement receptor). By contrast, OKM1 was present on inflammatory cells, epithelioid cells, and giant cells in mucosal lesions of Crohn's disease.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1998

Reduced expression of the macrophage scavenger receptors in macrophage-like cell mutants resistant to brefeldin A.

Brefeldin A (BFA)-resistant mutants, JB15, JB23 and JB33, were isolated from mutagenized murine macrophage-like (J774) cells and their modified low density lipoprotein (LDL) metabolism was studied. When JB23 cells, the most resistant clone, were incubated with acetylated LDL, intracellular accumulation of cholesteryl esters (CE) was reduced by 31% as compared with J774 cells. The cell-association of 125I-acetyl-LDL with, and subsequent endocytic degradation by JB23 cells were reduced by 40-60% compared with J774 cells. Western and Northern blot analyses showed that the protein and mRNA levels of the macrophage scavenger receptors (MSR) were reduced by 68% and 55% respectively in JB23 cells as compared with those in J774 cells. These results indicate that a putative BFA-target molecule(s) might regulate MSR gene expression as well as macrophage-derived foam cell formation.

Animals↗
PubMed1996

CNS microvascular pericytes express macrophage-like function, cell surface integrin alpha M, and macrophage marker ED-2.

CNS pericytes are an integral part of the blood-brain (BBB), but their function is not well understood. We questioned whether primary cultured CNS pericytes have immune potential. Primary cultured pericytes exhibit phagocytic activity when exposed to fluorochrome-conjugated polystyrene beads and antibody-coated zymosan. Maximum phagocytic activity occurred by 3 hr. Pericytes were found to express the macrophage markers ED-2 and the integrin subunit CD11b (alpha M) in culture as well as on isolated microvessels. Pericytes did not express the macrophage marker ED-1. We confirm the heterogeneity of cultured CNS pericytes with regard to expression of alpha-smooth muscle actin. In conclusion, pericytes express macrophage surface antigens and have the ability to perform at least some immune function. CNS pericytes may therefore have a role in neuroimmune networks at the BBB.

Animals↗