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At least 217 records · Page 12Linked to original sources
PubMed1992

Increasing the dietary (n-3) to (n-6) polyunsaturated fatty acid ratio increases tumor necrosis factor production by murine resident peritoneal macrophages without an effect on elicited peritoneal macrophages.

Tumor necrosis factor (TNF), prostaglandin (PG) E2 and 6-keto-PGF1 alpha production by murine peritoneal macrophages was monitored following in vitro stimulation with lipopolysaccharide. Macrophages were obtained from mice fed diets containing increasing ratios of (n-3) to (n-6) fatty acids by addition of (n-3) polyunsaturated fatty acids (PUFA) to the (n-6) fatty acids in the diet, or by substituting (n-3) PUFA for the (n-6) fatty acids in the diet. Increasing the dietary (n-3) to (n-6) fatty acid ratio from 0 to 1 increased both cell-associated and secreted TNF production by resident peritoneal macrophages but did not affect TNF production by macrophages elicited with Complete Freund's Adjuvant (CFA). With increasing dietary (n-3): (n-6) ratio there was a decrease in the prostaglandin production by resident peritoneal macrophages, which may partly explain the increased TNF production. The CFA-elicited macrophages produced less prostaglandin than the resident macrophages, and the lower prostaglandin production may partly explain the lack of effect of dietary (n-3) PUFA on TNF production by CFA-elicited macrophages. Increasing the TNF production by resident macrophages with dietary (n-3) PUFA may be beneficial in enhancing antitumor actions and antipathogenicity; by not increasing the high TNF production of inflammatory macrophages, (n-3) PUFA may protect against undesirable systemic inflammatory effects of overproduction.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Aleutian mink disease parvovirus infection of mink peritoneal macrophages and human macrophage cell lines.

Aleutian mink disease parvovirus (ADV) mRNAs are found in macrophages in lymph nodes and peritoneal exudate cells from ADV-infected mink. Therefore, we developed an in vitro infection system for ADV by using primary cultures of mink macrophages or macrophage cell lines. In peritoneal macrophage cultures from adult mink, virulent ADV-Utah I strain showed nuclear expression of viral antigens with fluorescein isothiocyanate-labeled ADV-infected mink serum, but delineation of specific viral proteins could not be confirmed by immunoblot analysis. Amplification of ADV DNA and production of replicative-form DNA were observed in mink macrophages by Southern blot analysis; however, virus could not be serially propagated. The human macrophage cell line U937 exhibited clear nuclear expression of viral antigens after infection with ADV-Utah I but not with tissue culture-adapted ADV-G. In U937 cells, ADV-Utah I produced mRNA, replicative-form DNA, virion DNA, and structural and nonstructural proteins; however, virus could not be serially passaged nor could [3H]thymidine-labeled virions be observed by density gradient analysis. These findings indicated that ADV-Utah I infection in U937 cells was not fully permissive and that there is another restricted step between gene amplification and/or viral protein expression and production of infectious virions. Treatment with the macrophage activator phorbol 12-myristate 13-acetate after adsorption of virus reduced the frequency of ADV-positive U937 cells but clearly increased that of human macrophage line THP-1 cells. These results suggested that ADV replication may depend on conditions influenced by the differentiation state of macrophages. U937 cells may be useful as an in vitro model system for the analysis of the immune disorder caused by ADV infection of macrophages.

Aleutian Mink Disease Virus↗
PubMed1997

Murine macrophage elastolytic activity induced by Aspergillus fumigatusstrains in vitro: evidence of the expression of two macrophage-induced protease genes.

The interaction between Aspergillus fumigatus conidia and murine macrophages of various origins was investigated. Cocultures were carried out between A. fumigatus strains and freshly isolated murine pulmonary alveolar macrophages or two murine macrophage cell-lines: murine alveolar cell-line MALU and murine astrocytoma cell-line J774. By measuring the variation of elastolytic activity in the coculture supernatants with two elastin substrates, we demonstrated that either viable or fixed A. fumigatus or C. albicans yeasts or nonspecific particles induced significant macrophage elastolytic activity. The effect of A. fumigatus supernatant or the purified A. fumigatus galactomannan suggested also the possible involvement of this polysaccharide in macrophage-protease gene expression, release, and activity in invasive aspergillosis. The effect of inhibitory compounds demonstrated the potential implication of a macrophagic metalloprotease and a macrophagic cysteine protease. RNA analysis allowed us to demonstrate the induction of expression of two macrophagic protease genes in stimulated macrophages. Two distinctive mechanisms appeared to be implicated in macrophage protease induction: nonspecific phagocytosis in the earliest times of the coculture and (or) specific galactomannan recognition after its gradual release by the mycelium.

Animals↗
PubMed1995

Repression of the macrophage scavenger receptor in macrophage-smooth muscle cell heterokaryons.

Macrophage scavenger receptors mediate the uptake of chemically modified LDL in an unregulated manner, leading to massive intracellular accumulation of lipid and thus a foamy cellular morphology. In atherosclerotic lesions, foam cells originate not only from macrophages but also from smooth muscle cells, yet smooth muscle cells do not normally express scavenger receptors, and when exposed to chemically modified LDL in vitro, lipid accumulation does not occur. The mechanism of conversion of smooth muscle cells into foam cells in the arterial wall is thus still under discussion. To investigate whether direct interaction between macrophages and smooth muscle cells may be involved and to explore the effects of components of the two cell types on the expression of scavenger receptors, we report here experiments using somatic cell hybrids formed by fusion of the two cell types. Immunofluorescent labeling and confocal microscopic techniques were applied to investigate and measure (1) lipid accumulation (using Nile Red staining), (2) the binding and uptake of acetylated LDL (using 1,1'-dioctadecyl-1-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate-labeled acetylated LDL), and (3) receptor expression (assessed using a specific anti-receptor antibody) in smooth muscle cell-macrophage heterokaryons, macrophage-macrophage homokaryons, smooth muscle cell-smooth muscle cell homokaryons, and unfused macrophages and smooth muscle cells. The results demonstrate that scavenger receptor expression becomes repressed in macrophage-smooth muscle cell heterokaryons but not in macrophage-macrophage homokaryons. One possible explanation for the observed repression would be the existence of a negative regulatory cytoplasmic factor produced by smooth muscle cells.

Animals↗
PubMed1998

Role of macrophage glycosaminoglycans in the cellular catabolism of oxidized LDL by macrophages.

Macrophage binding sites for oxidized LDL (Ox-LDL) include class A scavenger receptors (SR-As), the CD-36 molecule, and an additional but hitherto unidentified binding site. Because cell-surface glycosaminoglycans (GAGs) were previously shown to be involved in the cellular uptake of native LDL and lipoprotein(a), several strategies to assess the participation of heparan sulfate (HS) and chondroitin sulfate (CS) in macrophage catabolism of Ox-LDL were used. First, incubation of J-774 A.1 macrophage-like cells with either heparinase or chondroitinase, or with both enzymes together, reduced the binding, uptake, and degradation of 125I-Ox-LDL by 20% to 45%, in comparison with control nontreated cells, while catabolism of 125I-labeled acetylated LDL (Ac-LDL) and native LDL were unaffected. Second, the proteoglycan (PG) cellular content was increased by cell enrichment with exogenous GAGs or by using human monocyte-derived macrophages from two patients with Sanfilippo mucopolysaccharidosis, which are characterized by cellular HS accumulation. In these macrophages, cellular uptake of 125I-Ox-LDL increased, while catabolism of 125I-Ac-LDL and native LDL were unaffected. Experiments using conditioned media from control, heparinase-digested, or chondroitinase-digested macrophages indicated that neither secreted GAGs nor released digestion products played any role in Ox-LDL catabolism. To evaluate potential interactions between cell-surface GAGs and known receptors for Ox-LDL, we used excess unlabeled Ac-LDL to block SR-As or anti-CD-36 antibodies to block CD-36, and then examined the catabolism of 125I-Ox-LDL by GAG-enriched or -depleted macrophages. Both excess unlabeled Ac-LDL and anti-CD-36 antibodies reduced 125I-Ox-LDL catabolism, but only excess unlabeled Ac-LDL completely abolished the increase in 125I-Ox-LDL catabolism on GAG enrichment of the cells, indicating a cooperation between exogenous GAGs and cell-surface SR-As in the catabolism of OX-LDL. Moreover, the addition of GAGases to macrophages that were preincubated with anti-CD-36 antibodies and excess Ac-LDL further reduced macrophage degradation of Ox-LDL in comparison with cells that were pretreated only with anti-CD-36 antibodies and Ac-LDL, indicating a more complex role for endogenous GAGs. Overall, these studies demonstrate a substantial contribution of macrophage-associated GAGs in the catabolism of Ox-LDL, which is mediated in part by a cooperation between GAGs and cell-surface SR-As.

Acetylation↗
PubMed1999

Influence of macrophages and macrophage-modified collagen I on the adhesion and proliferation of vascular smooth muscle cells in culture.

The adhesion, proliferation and morphology of rat vascular smooth muscle cells (VSMC) in cocultures with macrophages or in cultures on type I collagen modified by activated macrophages were evaluated. In the first set of experiments, rat alveolar macrophages were added to 24-hour-old VSMC cultures. Between days 2 and 5 after VSMC seeding, the population densities and doubling times of cells were similar in both VSMC-macrophage and pure VSMC cultures. However, from day 5, the cocultures proliferated about two times more rapidly and on day 7, they reached higher cell population density by 40%. The pure macrophage cultures did not proliferate. In the second set of experiments, rat alveolar macrophages were activated by non-toxic TiO2 dust to produce reactive oxygen species and incubated for 120 min with collagen I. The collagen was then adsorbed on plastic culture dishes and seeded with VSMC. The collagen exposed for 10 min only, the unmodified collagen and pure culture dishes were used as control growth supports. On all four tested substrates, the number of initially adhered cells was similar, but on the collagen modified for 120 min, the cells were less spread. Moreover, on day 2 to 3 after seeding, some cells on this collagen became vacuolated and detached spontaneously from the growth support. The remaining VSMC, however, rapidly proliferated, so that on day 9, the cell population density on 120-min-modified collagen was similar as on both control collagens and significantly higher compared to that on uncoated dishes. Our results suggest that 1. The delayed growth-stimulating effect of macrophages on VSMC-macrophage mixed population is probably due to autocrine production of mitogens by both cell types rather than due to an acute effect of short-living oxygen radicals released from macrophages immediately after adding to VSMC cultures. 2. The effect of collagen I exposed to activated macrophages for 120 min is slightly cytotoxic, which could, however, stimulate a release of mitogens from damaged as well as surviving VSMC.

Animals↗
PubMed1976

Correlation of antitumor chemoimmunotherapy with bone marrow macrophage precursor cell stimulation and macrophage cytotoxicity.

The present investigations have assessed the effects of prolonged cyclophosphamide (CY) and Corynebacterium (CP) treatment on the production of bone marrow macrophage precursors [colony-forming cells (CFC)] and on the cytotoxicity of macrophages comprising colonies produced by the CFC. The findings have been correlated with tumor growth in animals receiving the immunochemotherapy. In addition, studies have been directed toward ascertaining whether the administration of CP with CY might lessen the myelosuppressive effects of the latter. Following each consecutive weekly dose of CY (even after as many as 11), there was a significant depression in the number of bone marrow cells (BMC's) but, by the next injection, marrow cellularity had returned to normal. When the number of BMC's was reduced, the proportion of the remaining cells, which consisted of CFC, was increased. Upon reconstitution of the marrow, the proportion of CFC returned to the level of the controls. The total number of CFC in marrow was at no time following CY therapy significantly less than the number in marrow of untreated mice. The addition of CP to the treatment regimen with CY resulted in an absolute as well as relative increase in CFC at all times during administration of the combined therapy, i.e., when there was a depression in total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total BMC's had been neither increased nor prevented from decreasing, by CP administration, indicating that the use of total cellularity as an index of the CP marrow-sparing effect is without merit. The present results relative to cytotoxicity of macrophages derived from the CFC concur with and extend our previous findings indicating that the cytotoxic property of macrophages originates in its ancestral stem cell or CFC and that factors responsible for increasing the CFC population do not selectively stimulate precursor cells responsible for production of the cytotoxic macrophage. Although the proportion of cytotoxic macrophages was not altered by CP when administered with CY, the absolute number of such cells was increased. Since the increase in macrophage colony production and, consequently, in cytotoxic macrophages correlates with increased inhibition of tumor growth when CP was used with CY, it is suggested that macrophage precursors are the cells of primacy in CP immunopotentiation. Their stimulation, resulting in enhanced cytotoxic macrophage formation, could be responsible for the inhibition of tumor growth observed in our model system. The findings also suggest that when myelosuppression is a limiting factor in the use of a chemotherapeutic agent, the concomitant use of CP may be advantageous.

Animals↗
PubMed1988

Macrophage-derived cytokines amplify immune complex-triggered O2-. responses by rat alveolar macrophages.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are monocyte macrophage-derived hormonelike regulatory proteins that participate in many physiologic and pathophysiologic processes. Several proinflammatory activities have been attributed to these cytokines, but their importance in anatomically compartmentalized inflammatory processes is unclear. The current in vitro studies have been designed to examine modulatory influences of these cytokines on O2-. responses of rat phagocytes implicated as effector cells in immune complex mediated lung injury. Purified human IL-1, recombinant human TNF (rTNF), and culture supernatant from zymosan-activated alveolar macrophages significantly amplified O2-. responses of immune complex-stimulated alveolar macrophages but did not enhance the responses of neutrophils. Equivalent concentrations of IL-1, rTNF, and alveolar macrophage culture supernatant had no direct stimulatory effect on alveolar macrophages as measured by O2-. production. Culture media from unstimulated alveolar macrophages exerted negligible effects on O2-. generation by immune complex-activated alveolar macrophages. These data indicate that O2- responses of immune complex alveolar macrophages can be enhanced by the presence of IL-1, TNF, or media from activated macrophages. It is possible that macrophage products may greatly amplify tissue injury through the enhancement of oxygen radical production.

Animals↗
PubMed1979

Fc-receptor-bearing macrophages isolated from hypersensitivity and foreign-body granulomas. Delineation of macrophage dynamics, fc receptor density/avidity and specificity.

Foreign-body and delayed hypersensitivity granulomas were induced in mice; and the dynamics of macrophages isolated from dispersed, 1--4-week-old lesions was delineated. The size and histologic complexity of the lesions increased as shown: adjuvant greater than schistosome egg greater than methylated bovine serum albumin greater than bead. Esterase staining, spreading on glass, and the percentage of Fc-receptor--bearing macrophages present in the various granulomas reflected the same gradient. The Fc receptors were examined by rosetting with rabbit-antibody--SRBC complex (EA). Whereas more than 90% of the population of macrophages of the dermal adjuvant granuloma contained undiminished numbers of receptor-bearing macrophages throughout the 4 weeks, the percentage of macrophages that displayed receptors in pulmonary foreign-body (40%) and delayed hypersensitivity granulomas (70%) peaked at 1 week and subsequently declined. The EA rosetting of the foreign-body and delayed hypersensitivity granuloma macrophages was strongly inhibited by monomeric IgG2a-specific and weakly by aggregated IgG2b-specific mouse myeloma proteins. Also, macrophages of the delayed hypersensitivity granulomas rosetted in higher percentages with SRBCs coupled with monomeric IgC2a than with those coupled with aggregated IgG2b myeloma proteins. Macrophages of the foreign-body lesion did not react with aggregated IgG2b--SRBC. Rosetting with monomeric IgG2a--SRBC or aggregated IgG2b--SRBC could not be cross-inhibited by the myeloma proteins. Both the monomeric IgG2a--SRBC and aggregated IgG2b--SRBC complexes were readily phagocytized. Trypsin treatment of the macrophages inhibited rosetting with EA or myeloma-protein--coupled SRBCs. The display of Fc receptors on the granuloma macrophages seems to be related to the etiology of the lesion and the intensity and duration of the inflammatory reaction.

Animals↗
PubMed1985

On the origin of peritoneal resident macrophages. II. Recovery of the resident macrophage population in the peritoneal cavity and in the milky spots after peritoneal cell depletion.

A kinetic study of the resident macrophage population in the peritoneal cavity and in the milky spots was done in mice depleted of peritoneal cells by repeated peritoneal washing. According to the distribution of the peroxidatic activity, four types of peritoneal macrophages could be distinguished. The size of each of these subpopulations depends on the length of the interval after peritoneal-cell depletion. Tritiated thymidine experiments revealed in the peritoneal cavity and in the milky spots local DNA synthesis by resident and PO-negative macrophages but not by monocytes or exudate macrophages and exudate/resident macrophages. The relationships between the various types of macrophages are discussed. No evidence was found for a relationship between resident macrophages and monocytes or macrophages with PO-positive granules. The PO-negative macrophage population was suggested to be heterogeneous, part of it being derived from monocytes and part having a relationship with the resident macrophages.

Animals↗
PubMed1980

Macrophage functional heterogeneity in vivo. Macrolocal and microlocal macrophage activation, identified by double-staining tissue sections of BCG granulomas for pairs of enzymes.

BCG lesions were produced in the skin of rabbits, and biopsies were performed at 7, 21, and 42 days, when they were developing, maximal in size, and almost healed, respectively. Tissue sections were prepared and stained histochemically for several enzymes. The percentage of cells stained for a given enzyme and the distribution of such cells within lesions of various ages were determined. Seven-day BCG lesions contained few esterase- and beta-galactosidase-positive macrophages, but 21-day lesions contained many, especially in the viable and nonviable tuberculous granulation tissue at the edge of the now prominent caseous necrotic center. Both 7-day and 21-day lesions contained many acid phosphatase- and cathepsin-D-positive macrophages, which were numerous in the more peripheral parts of the lesion, where little or no necrosis was present. Enzyme patterns in 42-day lesions resembled those in 21-day lesions. The role of each of these enzymes in the development and regression of the BCG lesion is unknown. Nonetheless, these studies clearly demonstrate that this macrophage population is heterogeneous and that macrophages carry out different functions in different parts of the lesion at different times. Histochemical techniques were developed to stain two enzymes in the same tissue section. The first stain usually contained a naphthol substrate and produced a red color; the second stain contained an indoxyl substrate and produced a blue color. A cell staining with both was colored purple. The peroxidase-antiperoxidase immunocytochemical technique for cathepsin D (producing a red color) was also employed. 1) Red esterase (hydrolyzing naphthol AS-D acetate) and beta-galactosidase, and 2) red esterase and blue esterase (hydrolyzing 5-bromo-4-chloro-indoxyl acetate), probably the same enzyme, were usually present in the same macrophage. In contrast, each of the following enzyme pairs was usually present in a different macrophage: 3) cathepsin D and beta-galactosidase, 4) cathepsin D and blue esterase, 5) acid phosphatase and beta-galactosidase, and 6) acid phosphatase and blue esterase. Roughly 10% of the macrophages stained for one enzyme existed side by side with macrophages stained for a different enzyme. These results suggest that local macrophage activation is under two levels of control. The first, macrolocal control, would determine the overall enzyme distribution in the lesion; whereas the second, microlocal control, would determine enzyme distribution on a cell-by-cell basis, ie, how two neighboring macrophages can each be rich in a different enzyme.

Animals↗
PubMed1995

Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein.

STK, a new member of the hepatocyte growth factor receptor family, is the receptor for macrophage-stimulating protein (MSP), which acts on murine resident peritoneal macrophages. We established polyclonal and monoclonal antibodies against STK and characterized the structure of STK protein and STK expression on cells of the mononuclear phagocyte system. Western blotting showed that the STK transcript is translated into a single-chain precursor and then cleaved into a 165-kD disulfide-linked heterodimer composed of a 35-kD alpha-chain and a 144-kD beta-chain. Western blotting detected STK protein on resident peritoneal macrophages, a target of MSP, and showed that it was autophosphorylated in cells stimulated by MSP. By flow cytometric analysis using a monoclonal anti-STK antibody, we showed that STK protein is expressed on restricted macrophage populations such as resident peritoneal macrophages, but not on exudate peritoneal macrophages or mononuclear phagocytes of the bone marrow, peripheral blood, spleen, or alveoli. Resident peritoneal macrophages were classified into two fractions according to their reactivity with an anti-STK antibody and a marker antibody for macrophages: STKhigh-F4/80high cells and STKnegative-F4/80low cells. Acute exudative macrophages were all STKnegative-F4/80low, but they gradually became predominantly STKhigh-F4/80high several days after entrance into the peritoneal cavity. These results showed that after monocytes migrate into the peritoneal cavity, they undergo terminal differentiation in the peritoneal microenvironment. This is the first evidence of tissue-specific terminal differentiation of peritoneal macrophages, and this terminal differentiation can be characterized by the expression of STK receptor tyrosine kinase.

Animals↗
PubMed1989

Lead inhibits intracellular killing of Leishmania parasites and extracellular cytolysis of target cells by macrophages exposed to macrophage activating factor.

Activation of Leishmania enriettii-infected mouse macrophages in vitro by treatment with macrophage activating factor (MAF)-rich media supplemented with lipopolysaccharide (LPS) leads to rapid killing of the microorganism. When exposed to MAF + LPS in the presence of 30-100 microM lead acetate, however, macrophages failed to destroy the parasites. This effect was not due to lead toxicity for macrophages. Decreased microbicidal activity correlated with depressed respiratory burst as determined by measurements of glucose oxidation through the hexose monophosphate shunt (HMPS). Lead had little effect on intracellular parasite killing induced by exposure of macrophages to the electron carrier methylene blue; HMPS in such cells was similarly little affected, indicating that chemical triggering of this pathway bypassed the lead-imposed blockade. Lead also abolished macrophage activation measured by the lysis of tumor target cells in vitro. The metal failed, however, to interfere with target-cell lysis by macrophages activated in lead-free medium, suggesting that lead inhibited the acquisition of the activated state rather than the functional expression of such state. Lead did not prevent the binding of radiolabelled interferon-gamma to macrophages; it did, however, slow down receptor turnover and degradation of bound interferon. Lead also inhibited the LPS-triggered cytotoxicity in macrophages previously exposed to interferon-gamma in lead-free medium, suggesting that depressed intracellular killing might result from an effect on both the priming (interferon or MAF-dependent) and the triggering (LPS-dependent) steps of activation.

Animals↗
PubMed2000

Differential expression and regulation of macrophage inflammatory protein (MIP)-1alpha and MIP-2 genes by alveolar and peritoneal macrophages in LPS-hyporesponsive C3H/HeJ mice.

A point mutation in Toll-like receptor 4 (Tlr4) gene in C3H/HeJ mice underlies a defect in LPS-induced cytokine production by peritoneal macrophages (PMphi;). Whether the C-C and the C-X-C chemokines are induced differently by LPS between alveolar macrophages (AMphi;) and PMphi; in this mice remains unclear. Thus, we examined the expression and regulation of macrophage inflammatory protein-1alpha (MIP-1alpha) and macrophage inflammatory protein-2 (MIP-2) in C3H/HeJ macrophages. These results showed that the accumulation of MIP-1alpha and MIP-2 mRNA increased dose dependently in response to LPS. PMphi; responded to LPS to produce significantly higher levels of both chemokine mRNA and protein than AMphi;. In addition, both macrophages produced much more MIP-2 than MIP-1alpha by the same doses of LPS stimulation. Moreover, the chemokine production by C3H/HeN macrophages was significantly higher than that of the C3H/HeJ macrophages. IFN-gamma suppressed the LPS-induced MIP-1alpha release but enhanced the LPS-induced MIP-2 secretion in both macrophages. These results show that the chemokine production was induced and regulated differentially in AMphi; and PMphi;.

Animals↗
PubMed1998

Augmentation of human macrophage candidacidal capacity by recombinant human myeloperoxidase and granulocyte-macrophage colony-stimulating factor.

Phagocyte myeloperoxidase (MPO) is believed to be particularly important in defense against candida infection. We reported earlier that monocytes, rich in MPO, killed Candida albicans at a significantly higher rate and extent than did monocyte-derived macrophages, known to lack MPO, and that C. albicans is less resistant to MPO-dependent oxidants than less pathogenic Candida species. We hypothesized, therefore, that the capacity of macrophages to kill C. albicans might be improved in the presence of MPO. In this study, we evaluated the ability of recombinant human MPO (rhMPO) to augment the killing of C. albicans by resident macrophages and macrophages activated by recombinant human granulocyte-macrophage colony-stimulating factor. Addition of rhMPO (concentration range, 0.8 to 6.4 U/ml) to suspensions of resident and activated macrophages and opsonized C. albicans resulted in concentration-dependent and significant increases in candida killing. This enhancement was particularly pronounced with activated macrophages, whether C. albicans was opsonized or unopsonized and ingested through the macrophage mannose receptor. rhMPO did not affect the killing of C. albicans by monocytes, nor did it affect phagocytosis of opsonized or unopsonized C. albicans. These results indicate that exogenous rhMPO can augment the candidacidal capacity of both resident and activated macrophages, with a more profound effect on activated cells. We suggest that rhMPO may be effective in the treatment of invasive candidiasis.

Candida albicans↗
PubMed1996

Glomerular expression of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in patients with various forms of glomerulonephritis.

Macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are major mediators for the differentiation, proliferation, and activation of the macrophage. Recently, M-CSF was documented to play a pivotal role in the development of nephritis via macrophage activation in MRL-lpr mice. The macrophage is also considered to be an important component in the development of human glomerulonephritis. The expression and function of colony-stimulating factors (CSF) in the human kidney have not yet been defined. This study was undertaken to elucidate the various roles of CSF in the development of glomerulonephritis in humans. We examined the glomerular expression of M-CSF and GM-CSF in patients with various forms of glomerulonephritis and in normal subjects using immunohistochemical methods and nonradioisotopic in situ hybridization. The expression of CSF at both the protein and mRNA level in the glomeruli was compared with the degree of mesangial proliferation; the number of macrophages, Ki67-positive cells, and HLA-DR-positive cells; and the degree of alpha-smooth muscle actin-positive area in the glomerulus and clinical data. M-CSF and GM-CSF were expressed mainly on the mesangial cells in the glomerulus. Intraglomerular expressions of CSF at the protein level were increased in cases of IgA nephropathy and lupus nephritis. There was a positive correlation among the M-CSF protein expression and glomerular proliferation, macrophage infiltration, and the degree of proteinuria. M-CSF mRNA expression also was increased in the cases of IgA nephropathy and lupus nephritis. The number of Ki67-positive cells and HLA-DR-positive cells and alpha-smooth muscle actin-positive area in the glomerulus were increased in the cases with enhanced M-CSF expression. These results suggest that the glomerular secretion of M-CSF promotes macrophage infiltration into the glomerulus and activates resident and extraneous macrophages in the mesangial proliferative glomerulonephritis. M-CSF is considered to be a major mediator in the development of mesangial proliferative glomerulonephritis in humans.

Adult↗
PubMed1986

Macrophage activation by trehalose dimycolate requirement for an expression signal in vitro for antitumoral activity; biochemical markers distinguishing primed and fully activated macrophages.

It was possible to define the effects of trehalose dimycolate (TDM), a glycolipid extracted from Mycobacterium tuberculosis, on mouse peritoneal macrophages more precisely using endotoxin-free culture conditions. TDM-elicited macrophages, when assayed in vitro in the absence of endotoxin, were unable to limit tumor growth; however, after a short treatment (4 h) with low doses of lipopolysaccharide (LPS; 1-10 ng/ml), they exhibited a strong cytostatic capacity against P815 mastocytoma cells. Thus, TDM injected in vivo did not activate macrophages fully but it primed them to respond in vitro to low doses of LPS, which provided the final stimulus for activation to antitumor competence. Macrophages elicited by an injection of killed group C Streptococci were also in a primed state; in contrast, thioglycollate-elicited macrophages were in a nonreceptive state. Besides LPS, concanavalin A (5 micrograms/ml), MDP (0.2-1 microgram/ml) and the ionophore A23187 (5 microM) can deliver the activation signal to TDM-primed macrophages. Primed macrophages were found to express several biochemical markers previously described as specific for activated macrophages (low levels of alkaline phosphodiesterase and beta-galactosidase, for example) and, although they were not cytotoxic for tumor cells, they had the capacity to release large amounts of H2O2. However, when pulsed by LPS or MDP, primed macrophages responded by further modifications in their metabolism: the rate of glucose consumption and the labeling of glycoproteins by D-[2-3H]mannose were greatly increased and the secretion of a polypeptide of 22 kDa was enhanced. The activation-associated biochemical markers are thus acquired in two steps. The ability to produce activated oxygen species is expressed earlier than the antitumoral activity.

Animals↗
PubMed1986

Effects of bacterial lipopolysaccharide on protein synthesis in murine peritoneal macrophages: relationship to activation for macrophage tumoricidal function.

Early biochemical events in the response of murine peritoneal macrophages to bacterial lipopolysaccharide (LPS) have been examined (i.e., 0-4 hr after initiation of treatment). At concentrations of 10 ng/ml or less, LPS stimulated the new or enhanced synthesis of a series of at least six polypeptides of 85, 80, 75, 65, 57, and 38 kD. This effect was dependent upon the lipid A moiety of LPS as lipid A itself could induce the changes and the effect of LPS could be blocked by inclusion of polymixin B sulfate in the culture medium. The effect was specific for LPS in that other endotoxin-free agents known to alter macrophage physiology could not produce the same changes. The time course of LPS stimulation of macrophage protein synthesis was remarkable in that the synthesis of all six proteins was transient even in the continued presence of LPS, being first detected approximately 1 hr after exposure and no longer apparent by 8-10 hr after treatment was initiated. Furthermore, both pulse-chase and cumulative radiolabeling studies indicated that at least two of the proteins (85 and 38 kD) were short-lived and did not accumulate in LPS-treated cells, suggesting the possibility that they participate in a regulatory rather than a functional role. Macrophage tumoricidal activation involves cooperation in response to two independent signals; interferon gamma and LPS. Pretreatment of macrophages with interferon gamma increased the sensitivity of macrophages to LPS-stimulated protein synthesis by one to two orders of magnitude documenting such cooperativity in molecular terms. The LPS-induced stimulation of specific protein synthesis could be reproduced by treatment of macrophages with heat killed Listeria monocytogenes, a gram-positive, endotoxin-negative bacterial stain which has been shown to substitute effectively for LPS in macrophage tumoricidal activation. Furthermore, reversible inhibition (i.e., treatment with cycloheximide) of protein synthesis during LPS treatment abrogated the acquisition of tumoricidal function. These results identify an early biochemical response to LPS which may be a necessary component of the intracellular transduction of signals which regulate macrophage functional development.

Animals↗