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PubMed1999

Macrophage-mediated lysis of a beta-cell line, tumour necrosis factor-alpha release from bacillus Calmette-Guérin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism.

Macrophages and monocytes are cells with a large capacity for cytokine production. Cytokines produced by these cells are not preformed and released upon stimulation, but must be transcribed and translated. Although much is known concerning the regulation of the latter processes at the molecular level, the role of exogenous amino acids in the secretory process has not been actively investigated. Glutamine is utilized by macrophages at a much faster rate than any other amino acid. The role for high rates of glutamine utilization in macrophages or monocytes is not fully understood. We demonstrate here that the rates of lipopolysaccharide-stimulated tumour necrosis factor-alpha secretion from bacillus Calmette-Guérin (BCG)-activated murine peritoneal macrophages and lipopolysaccharide-stimulated interleukin-8 production from human monocytes are dependent upon extracellular glutamine concentration. We also demonstrate that potent inhibition of cytokine production can be achieved by incubating macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo-5-oxo-norleucine. On co-culture of BCG-activated macrophages and the clonal pancreatic beta-cell line BRIN-BD11, macrophage-specific beta-cell death was significantly reduced on prior exposure of macrophages to 6-diazo-5-oxo-norleucine. Thus glutamine metabolism may be essential for generation of cytotoxic products from macrophages, including tumour necrosis factor-alpha.

Animals↗
PubMed2001

Binding and uptake of differently oxidized low density lipoprotein in mouse peritoneal macrophages and THP-1 macrophages: involvement of negative charges as well as oxidation-specific epitopes.

Oxidatively modified low-density lipoprotein (LDL) has been found in vivo, and oxidized LDL (oxLDL) could bind to scavenger receptors, leading to foam cell formation. Macrophages bear a number of different scavenger receptors for oxLDL, and macrophages of different origins may have a different scavenger receptor repertoire. In addition, LDL oxidized to different degrees may differ in the ability to bind macrophage scavenger receptors. In this study, we characterized the patterns of the binding and uptake of differently oxidized LDL in mouse peritoneal macrophages (MPM) and human THP-1 macrophages, and the influence of negative charge and oxidation-specific epitopes in oxLDL on these processes. Thresholds of increased binding and uptake in MPM were found when LDL was oxidized to the degrees with a relative electrophoretic mobility (REM) of 2.6 (minor threshold) and 3.0 (major threshold), corresponding to 49 and 57%, respectively, of the loss of free amino groups in these oxLDL. There was no threshold for the binding of oxLDL to THP-1 macrophages, while for uptake, a major threshold with REM of 3.0 (57% free amino groups lost) was found. The presence of the F(ab')(2) fragments of the monoclonal antibody OB/04, which was raised against copper-oxidized LDL, led to the reduction of the binding and uptake, respectively, of Eu(3+)-oxLDL (REM:3.6) in MPM by 31 and 29%, and by 19 and 22% in THP-1 macrophages. It is concluded that LDL oxidized to different degrees binds differently to macrophages, and the patterns of binding and uptake are different for MPM and human THP-1 macrophages. Both, the negative charge and the oxidation-specific epitopes of oxLDL are involved in these processes.

Animals↗
PubMed1986

Macrophage antigens and the effect of a macrophage activating factor, interferon-gamma.

Molecules characteristic of mononuclear phagocytes have been identified using monoclonal antibodies (MAb). MAb 3.9 reacts with a 150/95 000 dalton heterodimer which is found exclusively on monocytes and macrophages and appears to be the third member of the lymphocyte function-associated (LFA) family of molecules. In contrast, the reactivity of MAb 24, which bonds to a 175 000 dalton protein, is most highly expressed on the macrophages in lymphoid tissue. Both 3.9 and 24 detect the interdigitating cells in the T cell areas of these tissues, which strongly suggests that this cell type belongs to the macrophage family. A third MAb, 10.1, reacts selectively with a set of macrophages outside lymphoid tissue, particularly on Kupffer cells, alveolar macrophages and microglia. Thus subsets of tissue macrophages are proving easy to identify whereas it appears that circulating monocytes are not easily subdivided. None of the MAbs detected either Langerhans' cells, dendritic reticulum cells of B cell areas, or osteoclasts, indicating that these cells are not mononuclear phagocytes. As a first step towards identifying macrophage molecules which have a biological function, we have investigated the effect of macrophage-activating factor, interferon-gamma, on the expression of macrophage membrane molecules. There was greatly increased expression of only two out of ten molecules detected with anti-myeloid antibodies.

Antibodies, Monoclonal↗
PubMed1992

Macrophage development: II. Early ontogeny of macrophage populations in brain, liver, and lungs of rat embryos as revealed by a lectin marker.

Earliest origins of macrophage populations in the central nervous system, the liver, and the lungs were studied in rat embryos aged between 10.5-11 days and 14 days of gestation, based on light and electron microscopic identification of macrophages using peroxidase-coupled isolectin B4 of Griffonia simplicifolia (GSA I-B4), which recognizes alpha-D-galactose groups on the cell membrane. During embryonic life macrophages and their precursors are GSA I-B4-positive and generally bereft of peroxidase-positive granules. At 10.5 days the yolk sac and embryonic circulations have just become joined, the brain has five vesicles but nerve cells are little differentiated, the liver exists as a diverticulum of the gut with fingerlike extensions of hepatocytes, and the lungs as a laryngotracheal groove. Macrophages and/or their precursors occurred in small numbers in embryonic mesenchyme and blood vessels but showed no special affinity for either liver or lung rudiments. The developing brain was the first organ to be colonized, beginning on prenatal day 12. The liver followed between days 12 and 13 and was succeeded by the lungs, beginning between days 13 and 14. Dividing macrophages were present in these organs at the outset of colonization and throughout the duration of the embryo series, indicating that from the beginning, replication of resident cells contributes to growth of the local population. Granulocyte precursors were first apparent in the liver around day 13; they are also GSA-positive but are distinguished from macrophages by their content of peroxidase-positive granules. Organ cultures of 13-day liver and lungs, and 14-day brain tissue, indicate that whereas isolated liver fragments support the formation of both granulocytes and macrophages, only the latter develop in brain or lung cultures. A resident population of macrophages evidently is set up very early in these organs, well before white cells colonize the spleen, bone marrow, and other future blood forming regions. The events outlined are seen as stages in an embryo-wide process that leads to establishment of macrophage populations in various organs.

Animals↗
PubMed2003

Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages.

The human immunodeficiency virus (HIV) is an enveloped virus whose surface glycoprotein gp120 binds CD4 on target cell membranes to initiate infection. About half of the carbohydrates on gp120 are terminally mannosylated, a pattern common to many pathogens. We have examined the ability of macrophage mannose receptor (MMR) on primary monocyte-derived macrophages to bind HIV and facilitate its transmission to T cells. We adapted the tyramide signal amplification system for fluorescence detection of HIV bound to macrophages. Our data show that approximately 60% of the initial association of HIV with macrophages that lack expression of DC-SIGN (a dendritic cell-specific ICAM-3 receptor/HIV-1-binding protein) is MMR mediated, as evidenced by inhibition with mannan, D-mannose, EDTA, and soluble mannose-binding lectin, but not by D-galactose. This inhibition is not seen in cells that lack MMR. Macrophages are able to mediate transmission of bound HIV to co-cultured T cells, and this transmission is blocked up to 80% by inhibitors of MMR binding. Unlike virus bound to DC-SIGN, macrophage-bound HIV has a slightly lower half-life compared to free virus, with no transmission in co-culture observed beyond 24 h after virus binding to macrophages. Results obtained with endocytosis inhibitors indicate that this decrease in viral longevity is due to rapid internalization of macrophage-bound HIV. Together, these results suggest a substantial role for MMR in the binding and transmission of HIV-1 by macrophages.

Cell Adhesion Molecules↗
PubMed1989

Macrophages in bronchoalveolar lavage fluid are not representative of macrophages in granulomas of the lungs of BCG-infected mice.

To find out whether macrophages obtained by bronchoalveolar lavage (BAL) represent the macrophage population in alveoli, we performed a quantitative study to compare the expression of cell-surface antigens by macrophages in the lavage fluid as well as in the alveolar spaces of sectioned lung tissue from normal and BCG-infected mice. The amount of antigen on cells, determined with a quantitative immunocytochemical method, was expressed as the mean specific absorbance per 0.25 micron2 cell-surface area. In normal mice, BAL and intra-alveolar macrophages are identical. Macrophages in BAL fluid and intra-alveolar macrophages, both from BCG-infected mice, expressed antigen F4/80 and Fc receptor II to about the same extent, but the former showed a significantly higher level of antigen expression as defined by antibodies M1/70, M5/114, 30.G.12, and M3/38. In granulomatous lesions, expression of antigens by macrophages, assessed semi-quantitatively, was considerably less than that by BAL macrophages. Lymphocytes in the BAL fluid resembled those in the granulomas. These findings led to the conclusion that in BCG-infected mice, the macrophages found in BAL fluid do not resemble those occurring in either the alveoli or the granulomatous lesions of the lungs. On these grounds, the relevance of findings in BAL fluid to lung interstitial lung diseases should be reconsidered.

Animals↗
PubMed1988

Inhibition of the accumulation of macrophages and the generation of macrophage chemotactic activity by dexamethasone in concanavalin A-induced peritonitis of mice.

A delayed-type inflammatory response was evoked in mice using concanavalin A (Con A) as a stimulus, and the effect of various anti-inflammatory agents on the inflammation was examined. The intraperitoneal injection of Con A in the mouse resulted in the marked accumulation of leukocytes, especially macrophages, in the peritoneal cavity between 16 and 48 hr after the injection. Prior to the accumulation of macrophages, the chemotactic activity for macrophages appeared in the peritoneal fluid, and was associated with protein(s) in the molecular weight range from 10,000 to 100,000 daltons. When the effect of various agents on Con A-induced peritonitis was examined, neither anticomplementary agents (FUT-175 and K-76 COONa), bromophenacyl bromide, nordihydroguaiaretic acid nor indomethacin affected the generation of chemotactic activity and the accumulation of macrophages, suggesting that C5a, prostaglandins and leukotriene B4 are hardly involved in the Con A-induced macrophage accumulation. On the other hand, dexamethasone suppressed both the generation of chemotactic activity and the accumulation of macrophages. Taking into consideration the observation that the synthesis of macrophage chemotactic factors by mitogen-stimulated lymphocytes is inhibited by glucocorticoids, these results suggest that the macrophage chemotactic lymphokines might be involved in the accumulation of macrophages in Con A-induced peritonitis.

Animals↗
PubMed1983

Phorbol diester-induced H2O2 production by peritoneal macrophages. Different H2O2 production by macrophages from normal and BCG-infected mice despite comparable phorbol diester receptors.

Mouse peritoneal macrophages respond to environmental stimuli in different ways depending on their state of differentiation. Macrophages from mice with bacillus Calmette--Guerin (BCG) infection produced large amounts of H2O2 in response to phorbol diesters (PDEs), while those from noninfected mice produced little or no H2O2. The effects of PDEs on cells are mediated by specific cellular receptors for these ligands. The purpose of this study was to determine if the varying responses of macrophages from different groups of mice were caused by differences in their receptors for the PDE ligands. By all parameters studied, the binding of [20-3H]phorbol 12,13-dibutyrate ( [3H]PDBu) was similar in all macrophages irrespective of their ability to produce H2O2 in response to PDEs. Binding of [3H]PDBu was rapid at 23 degrees C reaching a maximum at 10-20 min with a subsequent decline to 50-60% of maximum by 30-60 min. Binding was slower at 0 degrees C reaching a maximum at 90-120 min. The binding was reversible, with dissociation kinetics paralleling association kinetics. The binding was saturable; the Kd's (45 to 91 nM) and number of binding sites (about 7-14 X 10(5)/cell or 11-12 pmol/mg protein) were essentially the same for the different classes of macrophages. The binding was specific, and analogs of PDBu inhibited [3H]PDBu binding to macrophages with potencies comparable to their potencies in causing in vivo tumor promotion and elicitation of other cellular responses in vitro. The ligands [3H]PDBu and [3H]PMA were degraded to comparable degrees by macrophages from normal or BCG-infected mice. Macrophages from C3H/HeJ and C3H/HeN mice, although known to differ in their abilities to respond to stimuli such as lymphokines and LPS, did not differ in their ability to produce H2O2 in response to PDEs or in their receptors for PDEs. Results of this study suggest that in vivo "activation" of macrophages in mice infected with BCG is not associated with a change in the cells' receptors for PDEs, but may be associated with "postreceptor" changes such as linkage of the PDE receptor with NAD(P)H oxidase, a change in NAD(P)H oxidase, or induction of synthesis of NAD(P)H oxidase.

Animals↗
PubMed1990

Identification of subpopulations of human macrophages through the generation of human macrophage hybridomas.

We have generated a series of human macrophage hybridomas by fusing an HGPRT-deficient promonocytic cell line, U937, with macrophages obtained by allowing monocytes to mature into macrophages in teflon bags. The fusions were documented as true hybrids by the acquisition of donor class I molecules, as well as donor derived macrophage surface antigens. The hybridomas represent clonal expansion of individual macrophages, retaining the surface antigen expression and functional capacity of the normal donor cells including cytokine production and stimulation in a mixed lymphocyte reaction. These cell lines differentially express Vmax antigens found on normal macrophages, potentially identifying subpopulations of macrophages. These lines may be useful not only to study normal macrophage function but may be relevant to a variety of disease states where expansion of subpopulations of macrophages identified by Vmax antigens may be important in disease pathogenesis.

Antibodies, Monoclonal↗
PubMed1992

Swine leukocyte antigen and macrophage marker expression on both African swine fever virus-infected and non-infected primary porcine macrophage cultures.

Swine leukocyte antigens (SLA) and a macrophage specific marker were monitored on porcine macrophages cultured with or without macrophage colony stimulatory factor (M-CSF) and on cells infected with African swine fever virus (ASFV). SLA expression was maximal either in the total cell extract or on the cell surface at 3-4 days of culture; after 4 days these values began to decrease. Fluorescence analyses of immunostained macrophages cultured with or without M-CSF indicated a major upward shift in the number of SLA Class I molecules on individual macrophages whereas for SLA Class II both a novel expression of Class II and an upward shift in the number of molecules per cell were evident. Infection of 3-day-old macrophage cultures with three different isolates of ASFV resulted in minor changes in surface expression of SLA Class I, SLA Class II, and macrophage markers. No differences in infection with ASFV was observed whether macrophages were SLA Class II positive or negative, nor was there blocking by anti-SLA Class I or Class II monoclonal antibodies of ASFV infection of cultured macrophages.

African Swine Fever↗
PubMed2001

TGF-beta reduced binding of high-density lipoproteins in murine macrophages and macrophage-derived foam cells.

The expression of macrophage scavenger receptors is regulated by intracellular cholesterol levels, as well as by cytokines affecting macrophage effector functions. CD36, a member of the type B scavenger receptor family, will bind a variety of nonlipoprotein and lipoprotein ligands including high-density lipoprotein (HDL). Transforming growth factor-beta (TGF-beta) has been demonstrated to modulate macrophage effector functions and is present within atherosclerotic lesions. In the present study, the effect of TGF-beta on HDL binding by both macrophages and macrophage-derived foam cells was evaluated. TGF-beta, in a dose-dependent manner, reduced the binding of flurochrome-labeled HDL to both macrophages and foam cells. These effects were observed in macrophages derived from nonatherosclerotic (BALB/c) as well as from macrophages obtained from both apolipoprotein E and low-density lipoprotein receptor knockout mice. The decrease in HDL binding was consistent with a significant reduction in CD36 message levels. The effect of TGF-beta on type B scavenger receptor expression was not limited to CD36 as SR-BI message was also downregulated, although the effect was more modest. A similar reduction in HDL binding and CD36 message was also observed with the immunosuppressive glucocorticoid dexamethasone. These results suggest that within the microenvironment of an atherosclerotic lesion, TGF-beta and other agents that inhibit macrophage inflammatory responses may impact lesion progression through mechanisms that include the modulation of HDL-foam cell interactions.

Animals↗
PubMed2000

Macrophage subpopulations and macrophage-derived cytokines in sputum of atopic and nonatopic asthmatic subjects and atopic and normal control subjects.

BACKGROUND: Previous studies have shown a prominent macrophage signal in the bronchial mucosa from nonatopic (intrinsic) compared with atopic (extrinsic) asthmatic subjects. This observation might have represented an expansion of a proinflammatory macrophage population or a homeostatic mechanism to decrease T(H)2-type inflammation. OBJECTIVE: The aim of the study was to investigate the numbers of macrophages and macrophage subpopulations and the expression of IL-10 and IL-12 in sputum from asthmatic and control subjects. METHODS: Eight atopic asthmatic (AA) subjects, 10 nonatopic asthmatic (NAA) subjects, 6 atopic control (AC) subjects, and 7 normal control (NC) subjects underwent sputum induction. Macrophages were enumerated by using Romanowsky stain and immunocytochemistry (CD68). RFD1 (interdigitating cell marker) and RFD7 (mature phagocyte marker) mAbs were used for immunocytochemical phenotyping, whereas IL-10 and IL-12 messenger (m)RNA was examined with in situ hybridization by using (35)S-labeled riboprobes. The phenotype of cells expressing IL-10 or IL-12 mRNA was examined by simultaneous in situ hybridization and immunostaining. RESULTS: No differences in the numbers of CD68(+) macrophages and RFD1(+), RFD7(+), and RFD1(+)/RFD7(+) subpopulations were found between AA, NAA, AC, and NC subjects. However, the numbers of IL-10 and IL-12 mRNA(+) cells were increased in AA subjects compared with NAA, AC, and NC subjects (P <.05). No other differences were found among the groups. Most of the IL-10 and IL-12 mRNA(+) cells in sputum from asthmatic subjects were macrophages (>80%), with less than 10% of mRNA colocalizing to epithelial cells. CONCLUSIONS: Sputum macrophage numbers, unlike tissue macrophages, as previously reported, were not elevated in NAA subjects. Increased IL-10 and IL-12 expression in atopic asthma may indicate the existence of a homeostatic mechanism to decrease lung inflammation. The lack of such cytokines in intrinsic asthma may predispose to bronchial inflammation in these subjects.

Asthma↗
PubMed1999

Macrophage depletion by albumin microencapsulated clodronate: attenuation of cytokine release in macrophage-dependent glomerulonephritis.

A macrophage plays an important role in mediating the inflammatory response. Cytokines released by activated macrophages contribute to inflammation in glomerulonephritis (GN). Clodronate, a biphosphonate, causes macrophage depletion when administered in an encapsulated form in liposomes. We used albumin as the polymer matrix to microencapsulate clodronate to the microspheres (MS) in the 1-micron size range. The purpose of this study was to (a) determine macrophage depletion by clodronate MS, (b) determine the effect of clodronate MS on endotoxin-induced cytokine release in vitro, and (c) assess the effect of clodronate MS on macrophage infiltration in experimental antiglomerular basement membrane nephritis. Macrophage depletion by clodronate MS was assessed by staining for the EDI marker. The results indicate greater than 95% depletion of macrophages from the spleen, liver, kidney, and blood. In the whole blood model, clodronate MS attenuated endotoxin-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) release, and the attenuation by the microencapsulated form of clodronate was also more effective than the free (solution) form of clodronate. Macrophage infiltration into the glomerulus in experimental GN was also blocked very effectively by pretreatment with clodronate MS. In conclusion, macrophage depletion by clodronate MS may be beneficial in reducing cytokine release and renal damage in GN.

Albumins↗
PubMed1978

Studies on the mechanisms of macrophage activation. I. Destruction of intracellular Leishmania enriettii in macrophages activated by cocultivation with stimulated lymphocytes.

When cultures of normal mouse peritoneal macrophages were infected with the intracellular protozoan parasite Leishmania enrietti, the micro-organism was found to survive intracellularly for several days, apparently without multiplication. However, exposure of infected macrophages to certain stimuli led to rapid parasite killing and digestion, providing a sensitive assay with which the mechanisms of macrophage activation can be studied. Microbicidal activity was induced by incubation of macrophages with syngeneic spleen lymphocytes, which were stimulated either by allogeneic cells in mixed lymphocyte culture (MLC) or by the plant lectin concanavalin A (Con A). Cocultivation with MLCs led to parasite killing within 48-72 h, whereas exposure of infected cells to Con A-stimulated lymphocytes resulted in substantial destruction of the micro-organism within less than 24 h, an effect which was dependent on the presence of thymus-derived lymphocytes and was inhibited by alpha methyl-mannoside. Incubation with Con A-stimulated lymphocytes also led to lysis of part of the macrophage monolayer. However, parasite killing did not result from decreased macrophage survival, as destruction of the micro-organism was highest under culture conditions which were the least detrimental to the phagocytes. Conversely, excess numbers of Con A-stimulated lymphocytes were less efficient at inducing macrophage activation and displayed marked toxicity to the macrophage monolayer. When spleen cells were stimulated by Con A at concentrations above 10 mug/ml, a decrease was noted in the capacity of macrophages to destroy the parasite, probably reflecting a toxicity of the lectin for lymphocytes resulting in impaired activating capacity.

Animals↗
PubMed1980

Macrophage oxygen-dependent antimicrobial activity. III. Enhanced oxidative metabolism as an expression of macrophage activation.

The capacity of 15 separate populations of mouse peritoneal macrophages to generate and release H2O2 (an index of oxidative metabolism) was compared with their ability to inhibit the intracellular replication of virulent Toxoplasma gondii. Resident macrophages and those elicited by inflammatory agents readily supported toxoplasma multiplication and released 4-20X less H2O2 than macrophages activated in vivo by systemic infection with Bacille Calmette-Guérin or T. gondii, or by immunization with Corynebacterium parvum. Immunologically activated cells consistently displayed both enhanced H2O2 production and antitoxoplasma activity. Exposure to lymphokines generated from cultures of spleen cells from T. gondii immune mice and toxoplasma antigen preserved both the antitoxoplasma activity and the heightened H2O2 release of toxoplasma immune and immune-boosted macrophages, which otherwise were lost after 48-72 h of cultivation. In vitro activation of resident and chemically-elicited cells by 72 h of exposure to mitogen- and antigen-prepared lymphokines, conditions that induce trypanocidal (5) and leishmanicidal activity (14), stimulated O2- and H2O2 release, and enhanced nitroblue tetrazolium reduction in response to toxoplasma ingestion. Such treatment, however, failed to confer any antitoxoplasma activity, indicating that intracellular pathogens may vary in their susceptibility to macrophage microbicidal mechanisms, including specific oxygen intermediates. In contrast, cocultivating normal macrophages with lymphokine plus heart infusion broth for 18H rendered these cells toxoplasmastatic. This in vitro-acquired activity was inhibited by scavengers of O2-, H2O2, OH., and 1O2, demonstrating a role for oxidative metabolites in lymphokine-induced enhancement of macrophage antimicrobial activity. These findings indicate that augmented oxidative metabolism is an consistent marker of macrophage activation, and that oxygen intermediates participate in the resistance of both in vivo- and vitro-activated macrophages toward the intracellular parasite, T. gondii.

Animals↗
PubMed1998

Ovarian follicle macrophages: is follicular atresia in the immature rat a macrophage-mediated event?

Macrophages have recently been found to play roles in most ovarian events through cytokine release and/or cell-cell communication. We studied the presence of macrophages in the ovaries of neonatal (0-7 days of age), juvenile (10-20 days of age), and prepubertal (25-30 days of age) rats, as well as adult cycling rats, in relation to follicular development and atresia. Macrophages were extremely scarce in the ovarian stroma up to 30 days of age. However, at 10 days of age, about 13% of small growing healthy follicles contained macrophages among granulosa cells. The percentage of macrophage-containing follicles at 15 days of age was about 60%, and the vast majority of these follicles also had pyknotic granulosa cells, which increased in number from 15 to 20 days of age. This type of atresia showed distinctive morphological and functional features in comparison with the atretic process observed in adult cycling rats. At 25 and 30 days of age, atretic follicles in advanced stages of atresia, together with atretic follicles similar to those present in adult rats, were observed. In adult rats, only a small proportion of healthy growing follicles contained macrophages. These cells were absent from early atretic follicles, and invasion by macrophages occurred at advanced stages of atresia. These data indicate that a different type of atresia occurred during early postnatal development, probably related to the special endocrine environment in immature rats. The close association between the presence of macrophages inside the follicles and of apoptotic granulosa cells strongly supports the hypothesis that macrophages mediate follicular atresia in immature rats.

Aging↗
PubMed1979

Analysis of the effects of lipopolysaccharide on macrophages: differential phagocytic responses of C3H/HeN and C3H/HeJ macrophages in vitro.

The phenomenon of lipopolysaccharide (LPS)-induced in vitro macrophage cytotoxicity has been reported by a number of investigators but has often been difficult to reproduce and to quantitate. In this report, we have examined the effect of LPS on the ability of macrophages to ingest 51Cr-labeled, opsonized sheep erythrocytes as a method for examining the direct toxic effects of LPS on macrophages in vitro. By using this assy, we can clearly discriminate between LPS responder C3H/HeN macrophages and LPS nonresponder C3H/HeJ macrophages and demonstrate that LPS induces a profound inhibition of Fc-mediated phagocytosis in LPS responsive macrophages. Furthermore, low concentrations of LPS stimulate phagocytosis in macrophages derived for C3H/HeJ mice. The lipid A moiety of the LPS is responsible for the observed enhancement or inhibition of Fc-mediated phagocytosis. This assay was more sensitive than LPS-induced cytotoxicity, since inhibition of phagocytosis was detectable in cultures of LPS-sensitive macrophages even when cytotoxicity, assessed by trypan blue exclusion, was not. Thus, this assay represents an extremely sensitive method for analyzing the direct effects of LPS on macrophages.

Animals↗
PubMed1985

Gamma interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria.

Recombinant human gamma interferon (rIFN-gamma) was examined for its ability to activate human peripheral blood monocyte-derived macrophages to kill tumor cells and to affect the replication of two phylogenetically distinct intracellular pathogens, Mycobacterium tuberculosis and Leishmania donovani. Macrophages preincubated overnight with doses of rIFN-gamma from 5 to 500 U/ml killed [3H]thymidine-labeled mouse L929 tumor targets, as measured by the release of [3H]thymidine into the supernatant after 48 h. Counts of macrophages initially infected with leishmania promastigotes showed that rIFN-gamma-pretreated macrophages could both inhibit the replication of and kill the resulting intramacrophage amastigotes over a 7-day period. However, rIFN-gamma pretreatment of macrophages actually enhanced mycobacterial replication over a 5- to 7-day period, as assessed by (i) counting acid-fast bacilli or (ii) lysing macrophages to release bacteria and determining the numbers of viable units. Mycobacterial growth was not affected by rIFN-gamma in the absence of macrophages. rIFN-gamma pretreatment had opposite effects on the uptake of mycobacteria and leishmania. As many as 80% fewer activated macrophages ingested mycobacteria compared with controls, whereas 50% more activated macrophages were infected with leishmania. These results suggest that rIFN-gamma may interfere with the immune destruction of intracellular tubercle bacilli and that the mechanisms of immunity against mycobacteria and leishmania may differ.

Cytotoxicity, Immunologic↗