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PubMed1984

Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea.

Purified polysaccharides (EPS) prepared from the plant Echinacea purpurea are shown to strongly activate macrophages. Macrophages activated with these substances develop pronounced extracellular cytotoxicity against tumor targets. The activation is brought about by EPS alone and is independent of any cooperative effect with lymphocytes. Also the production and secretion of oxygen radicals and interleukin 1 by macrophages is increased after activation with EPS. Cells of the macrophages lineage seem to be the main target for the action of these polysaccharides. EPS has no effect on T lymphocytes. B lymphocytes show a comparatively modest proliferation after incubation with E. purpurea EPS. Thus, these compounds, which are at least in tissue culture completely nontoxic, may be suited to activate in vivo cells of the macrophage system to cytotoxicity. They may therefore be of relevance in tumor and infectious systems.

Adjuvants, Immunologic↗
PubMed2000

Antifungal activity of splenic, liver and pulmonary macrophages against Candida albicans and effects of macrophage colony-stimulating factor.

Disseminated infections due to Candida albicans are frequently encountered in immunocompromised patients. We compared the antifungal activities of macrophages residing in spleen, liver and lungs of rabbits against blastoconidia and pseudohyphae of C. albicans. Splenic adherent cells (SAC), Kupffer cells (KC) and pulmonary alveolar macrophages (PAM) all ingested blastoconidia efficiently. SAC caused significantly more damage to unopsonized pseudohyphae compared with KC (P < 0.01) or PAM (P < 0.001). Incubation of SAC with 15 ng ml(-1) of recombinant human macrophage colony-stimulating factor (M-CSF) at 37 degrees C for 2 days significantly enhanced phagocytosis (P = 0.02) and killing (P = 0.05) of blastoconidia. In contrast, M-CSF had no effect on phagocytic activities of KC or PAM against blastoconidia or on damage caused by any of the macrophages to pseudohyphae of C. albicans. Thus, although all three resident macrophage types ingest blastoconidia efficiently, they differ in their capacity to cause damage to pseudohyphae and in their responsiveness to M-CSF for antifungal activation. M-CSF augments the capacity of SAC to ingest and kill blastoconidia and may therefore have a role in the treatment and prevention of hematogenously disseminated candidiasis.

Animals↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor promotes the proliferation of human alveolar macrophages in vitro.

The effects of granulocyte-macrophage (GM-CSF) or macrophage-CSF on in vitro proliferation of human alveolar macrophages (AM) were evaluated. AM of healthy volunteers incubated with recombinant human GM-CSF revealed incorporation of [3H]thymidine in vitro. The maximum incorporation was observed at 20 U/ml of GM-CSF on day 3. The proportion of proliferating cells incubated with 20 U/ml of GM-CSF from day 3 to day 4 was 8 to 11% of the total, whereas 3 to 5% of cells proliferated without GM-CSF. The number of cell nuclei increased 1.30- to 1.68-fold in the initial 7 days during incubation with 20 U/ml of GM-CSF, whereas there was a 1.07- to 1.13-fold increase without GM-CSF. Conditioned media obtained by the incubation with human lung tissue exhibited similar effects as recombinant human GM-CSF on macrophages. The effects were completely abrogated by antibody against human GM-CSF. Immunohistochemically, GM-CSF was detected in lung cells including AM, alveolar epithelium, alveolar interstitial cells, and endothelial cells. In contrast, recombinant macrophage-CSF did not induce the proliferation of human AM, although it has been known to promote the proliferation of murine AM. These observations suggest that GM-CSF plays an important role among the regulatory factors that locally support the population of AM in human lungs.

Adult↗
PubMed1994

In vivo modulation of macrophage tumoricidal activity by oral administration of the liposome-encapsulated macrophage activator CGP 19835A.

The present study evaluated the in vivo biological activity of synthetic muramyl tripeptide, CGP 19835A, when encapsulated into phosphatidylcholine liposomes (POPC-19835A) and administered as an p.o. immunomodulator to BALB/c mice. Liposomes were rapidly absorbed in the intestine and reached the systemic circulation within 4 h. Alveolar macrophages harvested from the lungs of mice 24 h after a single p.o. feeding of POPC-19835A were tumoricidal toward syngeneic murine renal cell carcinoma target cells. Repeated daily feedings with POPC-19835A generated sustained activation of the alveolar macrophages. Activation of peritoneal macrophages to the tumoricidal state required at least three daily feedings of POPC-19835A. In vitro studies demonstrated the release of tumor necrosis factor alpha and interleukin 6 by macrophages activated by POPC-19835A in the presence of gamma-interferon. Interleukin 1 and nitric oxide were not induced in macrophages by this liposomal preparation. Daily administration of POPC-19835A after i.v. injection of renal cell carcinoma tumor in BALB/c mice inhibited the development of experimental lung metastasis and confirmed the potential role of long-term therapy with this new p.o. immunomodulator.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1995

Absence of CSF-1 in macrophage-deficient op/op mice has differential effects on macrophage colony stimulating activity (M-CSA) released by various organs and cells.

The absence of detectable levels of CSF-1 in op/op mice results in a marked deficiency of macrophage colony-stimulating activity (M-CSA) in both the unstimulated and postendotoxin sera of these animals. These deficiences are not secondary to the presence of an inhibitor of macrophage formation. In contrast, various organs, particularly the organs of endotoxin-treated op/op mice, released amounts of M-CSA comparable to those of normal mice. Similarly, mitogen-stimulated lymphoid cells from op/op mice released either similar or increased amounts of M-CSA compared to mitogen stimulated +/+ lymphoid cells. On the other hand, conditioned media from cultures of fibroblastoid cells obtained from primary and secondary cultures of op/op organs were nearly totally devoid of M-CSA. However, incubation of these op/op fibroblasts with endotoxin in vitro induced the easily and readily detectable levels of M-CSA. These data suggest that CSF-1 is most likely a major source of M-CSA in serum and postendotoxin serum, while its contribution to soluble M-CSA in other organs may be only partial. In addition, in specific circumstances, the induced release of other macrophage growth factors may partially compensate for CSF-1 deficiency. Furthermore, it appears that the generalized macrophage deficiency in op/op mice cannot be fully explained by the deficiency of soluble M-CSA (soluble CSF-1) and argues for an in vivo role of membrane-bound CSF-1. These data may be interpreted as supporting a model in which the regulation of CSF-1-dependent and CSF-1-independent macrophage production is carried out by partly unrelated mechanisms.

Animals↗
PubMed1992

Differential production of granulocyte-macrophage colony-stimulating factor by macrophages from mice susceptible and resistant to Leishmania mexicana amazonensis.

The present results demonstrate that macrophages from mice susceptible to infection with Leishmania mexicana amazonensis sustain a higher production of granulocyte-macrophage colony-stimulating factor (GM-CSF) throughout the in vitro infection than macrophages from a resistant strain. Resident macrophages from BALB/c and C57B1/10 mice were infected with promastigotes of L. mexicana amazonensis and the amount of biologically active GM-CSF was measured in the supernatants collected at different times of infection. Measurements were made by bone marrow and GM-CSF/interleukin-3 addicted cell proliferation. Because GM-CSF is a disease-exacerbating cytokine, its differential production by infected macrophages may be one of the mechanisms defining resistance or susceptibility to a leishmanial infection.

Animals↗
PubMed1999

Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas.

Activated Kupffer cells and macrophages accumulate in necrotic areas in the liver. Osteopontin, an extracellular matrix with RGD sequence, has been shown to act as a chemokine that can induce monocyte migration. The possibility that osteopontin can play a role in infiltration of both cells into hepatic necrotic areas was investigated in rats. Northern blot analysis revealed that osteopontin mRNA expression was minimal in Kupffer cells and hepatocytes immediately after isolation from normal rats, but slight in hepatic stellate cells assumed nearly quiescent in function after 3 days of culture on plastic dishes. When rat received carbon tetrachloride, liver necrosis developed between 1 and 3 days following the intoxication. In these rats, osteopontin mRNA expression assessed by quantitative competitive RT-PCR was increased in the liver later than 1 day with its peak at 2 days following the intoxication. Kupffer cells and hepatic macrophages and hepatic stellate cells isolated from such liver showed marked expression of osteopontin mRNA on Northern blotting. Immunohistochemical examination disclosed that osteopontin was stained in macrophages including Kupffer cells and stellate cells in the necrotic areas. On electron microscopy, osteopontin stains were present in the Golgi apparatus in these cells. Recombinant human osteopontin promoted migration of Kupffer cells isolated from normal rats and cultured in a Transwell cell culture chamber in a dose-related manner. We conclude that activated Kupffer cells and hepatic macrophages and stellate cells express osteopontin. These cells might contribute to the infiltration of Kupffer cells and macrophages into hepatic necrotic areas by expressing osteopontin.

Animals↗
PubMed1998

Macrophage-derived cytokines in the follicular fluids of women with infertility due to immunological causes. Elevated levels of interleukin 6 and low levels of granulocyte-macrophage colony-stimulating factor.

The cytokines are (glyco)proteins secreted by lymphoid and non-lymphoid cells which modulate several biological responses including the ovarian function. Interleukin (IL)-1 and tumour necrosis factor (TNF)-alpha suppress 17beta-estradiol (E2) and progesterone release from granulosa and luteal cells in vitro. TNF-alpha affects negatively folliculogenesis and ovarian maturation. Additional in vivo evidence for a role of this macrophage-derived cytokine came from our recent observation that women with infertility due to immunological causes have elevated intrafollicular fluid levels of TNF-alpha and decreased levels of E2 compared to women with a tubal factor of infertility. Because the macrophages are a primary component of the intrafollicular compartment, the present study was undertaken to evaluate whether other macrophage-derived cytokines are also released in the human follicular fluid. To accomplish this, we measured the levels of IL-1beta, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the follicular fluids of two groups of infertile women undergoing to an in vitro fertilization program. The first group of women had a significant titre of anti-spermatozoon antibodies in the serum and/or the mucus as the only cause of infertility, whilst the second group of women was infertile because of non patent fallopian tubes. Intrafollicular cytokines levels were measured by solid-phase ELISA and steroid concentrations by radioimmunoassay. Whilst IL-1beta, IL-6, IL-10, and GLM-CSF were all measurable in the follicular fluid of both groups of women, the levels of IL-6 were found to be significantly more elevated and those of GM-CSF lower in patients with infertility due to immunological causes as compared to those with tubal infertility. The former had also decreased intrafollicular E2 levels and increased progesterone concentrations. No difference was seen in the follicular fluid levels of testosterone and androstenedione. In conclusion, several macrophage-derived cytokines are present in the follicular fluids of infertile women. Patients with infertility due to immunological causes had higher levels of IL-6 and lower concentrations of GM-CSF as compared to patient with a tubal factor of infertility. We speculate that this abnormal cytokine profile may contribute to the altered intrafollicular steroid milieu.

Adult↗
PubMed1997

Macrophage colony-stimulating factor accelerates wound healing and upregulates TGF-beta1 mRNA levels through tissue macrophages.

Macrophage colony-stimulating factor (M-CSF) is produced by many cell types involved in wound repair, yet it acts specifically on monocytes and macrophages. The monocyte-derived cell is thought to be important in wound healing, but the importance of the role of tissue macrophages in wound healing has not been well defined. Dermal ulcers were created in normal and ischemic ears of young rabbits. Either rhM-CSF (17 microg/wound) or buffer was applied to each wound. Wounds were bisected and analyzed histologically at Days 7 and 10 postwounding. The amounts of epithelial growth and granulation tissue deposition were measured in all wounds. The level of increase of TGF-beta1 mRNA level in M-CSF-treated wounds was examined using competitive RT-PCR. M-CSF increased new granulation tissue formation by 37% (N = 21, P < 0.01) and 50% (P < 0.01) after single and multiple treatments, respectively, in nonischemic wounds. TGF-beta1 mRNA levels in rhM-CSF-treated wounds increased 5.01-fold (N = 8) over vehicle-treated wounds under nonischemic conditions. In contrast, no effect could be detected in ischemic wounds treated with rhM-CSF, and these wounds only showed a 1.66-fold increase in TGF-beta1 mRNA levels when compared to ischemic wounds treated with vehicle alone. GAPDH, a housekeeping gene, showed no change. As mesenchymal cells lack receptors for M-CSF, the improved healing of wounds treated with topical rhM-CSF must reflect a generalized enhancement of activation and function of tissue macrophages, as demonstrated by upregulation of TGF-beta. The lack of effect under ischemic conditions suggests that either macrophage activity and/or response to M-CSF is adversely affected under those conditions; this may suggest the pathogenesis of impaired wound healing at the cellular level.

Animals↗
PubMed1990

Anti-macrophage CR3 antibody blocks myelin phagocytosis by macrophages in vitro.

Myelin phagocytosis in Wallerian degeneration of peripheral nerves depends on invasion of nerves by non-resident macrophages. The present study was done to clarify the role of the macrophage complement receptor type 3 (CR3) in myelin removal. Myelin phagocytic capacity of invading macrophages was abolished by treatment of cultured nerves and macrophages with anti-CR3 antibody or by serum complement depletion with cobra venom factor. This indicates that myelin phagocytosis is mediated by the macrophage CR3.

Animals↗
PubMed2004

Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages.

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.

Calcium Channel Blockers↗
PubMed1984

Incorporation of palmitic acid or oleic acid into macrophage membrane lipids exerts differential effects on the function of normal mouse peritoneal macrophages.

Normal mouse peritoneal macrophages were enriched with either palmitic acid (16:0) or oleic acid (18:1). Normal or oleic acid-enriched macrophages showed 3-4-fold greater erythrophagocytic capacity as compared to palmitic acid-enriched macrophages. Staphylococcus aureus uptake was only moderately decreased in palmitic acid-enriched macrophages. Fatty acid modifications did not influence the ability of macrophages to kill intracellular bacteria or to generate superoxide anions after stimulation with phorbol myristate acetate or opsonized zymosan.

Animals↗
PubMed1984

Inhibition of macrophage DNA synthesis by immunomodulators. II. Characterization of the suppression by muramyl dipeptide or lipopolysaccharide [3H]thymidine incorporation into macrophages.

Guinea pig peritoneal exudate macrophages actively incorporated [3H]thymidine into trichloroacetic acid-insoluble fraction in vitro. The incorporation of [3H]thymidine was almost completely inhibited by aphidicolin, an inhibitor of DNA polymerase alpha and an autoradiograph showed heavy labeling in nuclei of 15% of macrophage populations. These results indicate that the observed thymidine incorporation was due to a nuclear DNA synthesis. The [3H]thymidine incorporation was markedly suppressed when macrophages were activated by immunoadjuvants such as muramyl dipeptide (MDP) or bacterial lipopolysaccharide (LPS). The suppression of [3H]thymidine incorporation by MDP was neither due to the decrease in thymidine transport through the cell membrane, nor due to dilution by newly synthesized "cold" thymidine. An autoradiograph revealed that MDP markedly decreased the number of macrophages the nuclei of which were labeled by [3H]thymidine. These results suggest that the suppression of [3H]thymidine incorporation by the immunoadjuvants reflects a true inhibition of DNA synthesis. The inhibition of DNA synthesis by MDP was also observed in vivo. Further, it was strongly suggested that the inhibition was not caused by some mediators, such as prostaglandin E2, released from macrophages stimulated by the immunoadjuvants but caused by a direct triggering of the adjuvants at least at the early stage of activation. Cyclic AMP appears to be involved in the inhibitory reaction.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Biochemical models of interferon-gamma-mediated macrophage activation: independent regulation of lymphocyte function associated antigen (LFA)-1 and I-A antigen on murine peritoneal macrophages.

IFN-gamma can induce the expression of both class II histocompatibility antigens (Ia) and the lymphocyte function associated (LFA)-1 antigen on murine peritoneal macrophages. We have examined the molecular changes which lead to altered expression of these two cell surface proteins to determine whether they are regulated by similar or independent mechanisms. While I-A antigen expression can be induced or enhanced by treatment of macrophages with either phorbol diesters and/or the Ca2+ ionophore A23187, these agents had no effect upon expression of LFA-1 under similar conditions. Macrophages from the A/J strain mouse exhibit a deficiency in their sensitivity to IFN-gamma which is seen in our studies as an inability of IFN-gamma to elevate I-A antigen expression. However, expression of I-A could be modulated in these cells by treatment with either phorbol diesters or A23187. In contrast, IFN-gamma could induce LFA-1 antigen on A/J derived macrophages and this was not affected by either phorbol or A23187. Thus these two antigens, despite coordinate expression in response to IFN-gamma in normal mouse strains, are clearly regulated independently. These results suggest that IFN-gamma generates at least two independent molecular events in macrophages which ultimately modulate the expression of cell surface proteins important to the performance of activated functions.

Animals↗
PubMed1989

Macrophage colony-stimulating factor enhances monocyte and macrophage antibody-dependent cell-mediated cytotoxicity.

In vitro culture of either human peripheral blood monocytes or murine peritoneal macrophages for 72 hr in the presence of macrophage colony-stimulating factor (M-CSF) dramatically increased their subsequent ability to mediate antibody-dependent cellular cytotoxicity (ADCC). The M-CSF-treated cells were more effective in ADCC at lower effector to target cell ratios and in the presence of lower concentrations of tumor-specific monoclonal antibody than the untreated control cells. Two other hematopoietic cytokines, granulocyte-macrophage colony-stimulating factor and interleukin-3, reported to enhance other macrophage effector functions were ineffective in promoting the development of ADCC by cultured human monocytes. All three hematopoietic growth factors were capable of enhancing the ability of the cultured monocytes to secrete TNF alpha; however, TNF alpha is unlikely to be an important cytotoxic factor in ADCC because neutralizing antibodies against TNF alpha had no affect on ADCC in vitro. Further, much higher concentrations of M-CSF were required to augment monocyte TNF alpha release (20-100 ng/ml) than ADCC capacity (1-10 ng/ml). These results suggest that M-CSF administration might prove effective in increasing the tumoricidal activities of tumor-specific monoclonal antibodies by enhancing the capacity of monocytes and macrophages to mediate ADCC.

Animals↗
PubMed1988

Monomeric and dimeric IgG1 as probes for assessing high-affinity and low-affinity receptors for IgG on human monocyte-derived macrophages and on activated macrophages.

From a panel of IgG1 myeloma proteins, only one was found to interact with human monocyte FcR in a manner similar to that of polyclonal IgG. This protein was used in binding studies involving human macrophage Fc receptors. A monomeric fraction depleted of dimeric and polymeric IgG1 was crosslinked with bis-diazonium benzidine, and a fraction highly enriched in cross linked IgG1 dimers was radiolabeled. Labeled monomeric and dimeric IgG were allowed to interact with monocytes that had matured to macrophages in vitro. The association with macrophages at 4 degrees C, in the presence of cytochalasin B, reached a plateau after 6 hr. The dissociation induced by excess unlabeled IgG followed similar kinetics as the association, but 20-30% of the bound IgG could not be dissociated. Under equilibrium conditions, evidence for a single FcR population binding monomeric IgG was obtained, the Kd being in the range of 12-42 nM. In contrast, the binding of dimeric IgG was more consistent with a model assuming two populations of binding sites when appropriate curve-fitting calculations were applied. The high-affinity FcR population had a Kd in the range of 0.8-3.5 nM, whereas the Kd of the low-affinity FcR population was in the range of 28-85 nM. When macrophages had been pre-treated with recombinant interferon-gamma, the expression of high-affinity sites was increased by a factor of 1.5-3, but the number of low-affinity sites was not augmented. Cytofluorographic analyses confirmed the increased expression of high-affinity FcR, binding fluoresceinating murine IgG2a. The expression of CD16, a low-affinity FcR expressed on neutrophils, NK cells and macrophages, as well as the expression of the complement receptor type III was little influenced by the rIFN-gamma pretreatment.

Antibody Affinity↗
PubMed2000

Immunolocalization of macrophage adhesion molecule-1 and macrophage inflammatory protein-1 in schistosomal soluble egg antigen-induced granulomatous hyporesponsiveness.

This work studied the histopathological changes and the changes in the expression of macrophage adhesion molecule-1 (Mac-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) in a murine model of soluble egg antigen (SEA) - induced granulomatous hyporesponsiveness. Histopathological results of hepatic sections in an SEA group showed early acceleration of ova destruction and markedly diminished granuloma cellularity with eosinophils and macrophages still being the predominant cells. Later, giant cells and pigmented macrophages that were scattered among granuloma cells and in intimate contact with the deposited eggs were more predominant in the SEA group than in the infected control group. Concurrently, the counts of Mac-1 positive cells were significantly increased in liver sections of the SEA group than the infected control group during the course of infection. MIP-1alpha showed early higher counts followed by lower counts in the later stages of infection on granuloma cells in the SEA group than the infected control group. During the course of infection, similar distribution of Mac-1 and MIP-1alpha was present in both groups. This study suggests that sensitization with SEA probably leads to enhancement of phagocytic activity of macrophages via increasing expression of Mac-1 and hence engulfment of ic3b coated schistosomal products such as ova. It leads to rapid destruction of ova and hence decreases the host inflammatory response to infection and amelioration of hepatic pathology which would be a promising approach in reduction of host morbidity and mortality.

Animals↗
PubMed1982

Interaction of Lotus-tetragonolobus Lectin (LTL) and an MIF-like factor with guinea-pig macrophages. I. Effects on macrophage migration inhibition and receptor-binding studies.

Purified Lotus-tetragonolobus lectin (LTL) was studied for its interaction with guinea-pig peritoneal macrophages in the migration-inhibition and spreading-inhibition assay. LTL was found capable of inhibiting macrophage migration in a dose-response relationship similar to that of an MIF-life factor present in rat Zajdela-hepatoma ascites, whereas macrophage spreading was less affected. Mitogenic activity of the fucolectin could be excluded. Both the LTL and MIF-like factor seem to come into action by means of alpha-L-fucopyranosyl residues-containing macrophage surface receptors. Both substances act synergistically in inhibiting migration of macrophages. Since binding studies with 125I-LTL demonstrated competition with the MIF-like factor, it is suggested that the latter and LTL share a common surface receptor, and that optimal occupation densities are required for the realization of the inhibitory effect. Possibly, LTL acts in a monomeric form in the migration inhibition assay.

Animals↗