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PubMed1975

Macrophage heterogeneity in receptor activity: the activation of macrophage Fc receptor function in vivo and in vitro.

The Fc receptor activity of single macrophages and of distinct macrophage populations was examined in terms of cellular avidity for IgG antibody by using a rosette assay which permits characterization of receptor activity at the cellular level and quantitation of any changes in such receptor activity. Marked heterogeneity was shown to exist within normal populations of macrophages. Both normal peritoneal and alveolar macrophage populations exhibit a normal or logistic distribution of cellular avidities for IgG antibody. The mean avidity of the peritoneal population, however, was found to be approximately 3 times greater than that of the alveolar population. Moreover, alveolar macrophages possess a range of cellular avidities 3 times greater than that of peritoneal macrophages. Comparison of normal unstimulated peritoneal macrophages and induced inflammatory exudate macrophages revealed a 6-fold increase in the proportion of high avidity cells in the latter population. Normal peritoneal and normal alveolar macrophages were shown to undergo a striking increase in Fc receptor activity in vitro. Under certain conditions of culture these cells acquire the antibody-binding capacity characteristic of high avidity cells in the inflammatory exudate population. Fresh guinea pig serum was shown to prevent this activation of Fc receptor function in vitro. Aged guinea pig serum was somewhat less effective. The serum factor(s) responsible appears to be consumed or exhausted in some way by macrophages. It is heat stable and has a molecular weight of less than 100,000 daltons. Serum IgF was found not to be involved in the effects of fresh serum on receptor activation in vitro. The activation of Fc receptor function described here may facilitate both the presentation of antigen to specific T lymphocytes and the antibody dependent killing of tumor cells by macrophages. Changes in receptor activity of the kind described may thus play an important regulatory role in the induction of an immune response and in the effector mechanisms of immunologic surveillance.

Animals↗
PubMed1990

Macrophage control of normal and leukemic erythropoiesis: identification of the macrophage-derived erythroid suppressing activity as interleukin-1 and the mediator of its in vivo action as tumor necrosis factor.

Macrophages have been shown to directly influence the growth and development of mature erythroid progenitors (CFU-E) in normal and erythroleukemic mice. We examined the mechanism by which macrophages mediate their effect on in vivo erythropoiesis. As reported for whole macrophages, serum-free supernatants (SN) from normal resident peritoneal macrophages suppressed in vivo normal and conventional Friend virus (CFV)-infected CFU-E and caused clinical regression of CFV-induced leukemia in mice. Macrophage SN had no effect on the erythropoietin (EPO)-independent CFU-E characteristic of infection with the polycythemia-inducing strain of Friend virus (FVP), or progression of FVP leukemia. Using biochemical, immunologic, and functional assays, the erythrosuppressive factor in macrophage SN was identified as interleukin-1 alpha (IL-1 alpha). The in vivo erythroid suppressive effects of macrophages, macrophage SN, and IL-1 alpha were reversed by simultaneous treatment with EPO. IL-1 alpha itself had no effect on CFU-E colony formation in vitro. Pretreatment of animals with antibodies to murine tumor necrosis factor-alpha (TNF-alpha) completely abrogated the suppression of CFU-E by macrophages, macrophage SN, or human recombinant IL-1 alpha. These results suggest that macrophages regulate erythropoiesis by production of IL-1 alpha, which in turn mediates its in vivo suppressive effects on CFU-E through TNF.

Animals↗
PubMed1985

Macrophages in glomerular injury. I. The kinetics of macrophages in accelerated Masugi nephritis in the rat.

To evaluate the role of macrophages in glomerulonephritis, the relationship between the existence of macrophages and proteinuria in the long course of glomerulonephritis was studied in accelerated Masugi nephritis in the rat. Non-specific esterase staining was used as a marker of macrophages and the kinetics of glomerular macrophages was analysed by an image processor. Macrophages became detectable 48 hours after nephrotoxic serum injection and their accumulation reached a maximum level at 5 days. At 1 month, they had clearly decreased. At 3 months, however, many macrophages were found within the capsular drop-like lesions and crescents. Urinary protein excretion took roughly the same time course as the number of macrophages for 2 weeks. However, at 1 month, whereas macrophages had decreased, the proteinuria kept a persistently high level. At 3 months it showed a tendency to decrease. The correlation between the rate of appearance of macrophages and the urinary protein excretion assessed in 20 cases exhibited no significance. In addition, discrepancy in their time course was evident at 1 month. Although macrophages may happen to contribute to the tissue injury resulting in proteinuria in the early phase of nephrotoxic serum nephritis, factors other than macrophages should be considered in the subsequent duration of proteinuria in this model.

Animals↗
PubMed1994

LPS induces selective translocation of protein kinase C-beta in LPS-responsive mouse macrophages, but not in LPS-nonresponsive mouse macrophages.

Translocation of protein kinase C (PKC) after PMA or LPS stimulation has been studied in thioglycolate (TGC)-elicited murine peritoneal macrophages. Among the PKC subtypes we examined (alpha, beta, gamma, delta, and epsilon) by indirect immunostaining and immunoblot analysis, conventional PKC-beta, as well as novel PKC-delta and PKC-epsilon were found to exist in TGC-elicited C3H/HeN mouse macrophages. Translocation of PKC-beta to the Triton-stable cytoskeleton could be seen in macrophages after stimulation by both PMA and LPS. On the other hand, novel PKCs redistributed only after PMA stimulation. Macrophages obtained from LPS-nonresponsive C3H/HeJ mice also exhibited PKC-beta, and the m.w., cellular distribution, and cellular content of this enzyme could not be distinguished from those of C3H/HeN macrophages. These macrophages exhibited PKC-delta and PKC-epsilon, as did the C3H/HeN macrophages. In these macrophages, however, LPS did not induce any remarkable change in the intracellular distribution of PKC-delta and PKC-epsilon or PKC-beta, whereas PMA was able to induce the translocation of PKC-beta to the cytoskeleton. These results suggest that LPS stimulation induces selective redistribution of PKC-beta in LPS-responsive macrophages, whereas a defect related to LPS unresponsiveness exists in C3H/HeJ mouse macrophages before the PKC activation. Translocation of PKC-beta can be understood to be an important event in LPS signaling in macrophages.

Animals↗
PubMed1997

In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation.

Communication between resident glomerular cells and infiltrating macrophages plays a crucial role in the pathogenesis of glomerular disease. Using matrix metalloproteinase-9 (MMP-9) as an indicator molecule, we examined the interaction between mesangial cells and macrophages. Mesangial cells cocultured with activated macrophages or exposed to macrophage-conditioned media produced abundant MMP-9. We identified the stimulator secreted by macrophages as IL-1 because mesangial cells overexpressing IL-1 receptor antagonist protein showed a blunted expression of MMP-9 in response to the macrophage-conditioned medium. In contrast, culture supernatants of mesangial cells inhibited MMP-9 production by macrophages in a dose-dependent fashion. This inhibitor was identified to be TGF-beta1, since neutralization of TGF-beta1 abrogated the inhibitory effect of the mesangial cell-conditioned medium. To investigate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta1 modulates the induction, stimulated reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1 glomerulonephritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induction was substantially repressed in the regenerating glomeruli that produced active TGF-beta1. These results point to potential mechanisms involved in glomerular control of MMP-9. Based upon the in vitro evidence, TGF-beta1 was identified as an endogenous "defender" that attenuates certain actions of infiltrating macrophages in the glomerulus.

Animals↗
PubMed1995

Macrophage colony stimulatory factor-activated bone marrow macrophages suppress lymphocytic responses through phagocytosis: a tentative in vitro model of Rosai-Dorfman disease.

NBXFO hybridoma cells produced macrophage colony-stimulating factor (M-CSF), which stimulated the growth of murine bone marrow-derived macrophages with potent suppressor activity. These macrophages suppressed lymphocyte responses to mitogens and antigens in a dose-dependent manner. Using a transwell chamber, we demonstrated that macrophages needed physical contact with the lymphocytes to suppress lymphocyte proliferation on day 1 in the concanavalin A mitogen reaction. In addition, no soluble suppressor factor was detected at that time. The number of lymphocytes disappeared with time when they were cocultured with the macrophages. Electron microscopy revealed that the macrophage phagocytosized the lymphocytes after 7 1/2 h. Dextran sulfate, heparan, and fucoidan prevented the macrophages from suppressing the lymphocytes. This phenomenon resembles the human disease sinus histiocytosis, also called Rosai-Dorfman disease, in which macrophages (histiocytes) phagocytosize autologous lymphocytes; occasionally, this disease is associated with immunological abnormalities. Thus we believed that macrophage-activating cytokines, such as M-CSF, may stimulate macrophages to phagocytose lymphocytes in vivo.

Animals↗
PubMed1998

Induction of murine macrophage growth by oxidized low density lipoprotein is mediated by granulocyte macrophage colony-stimulating factor.

We have examined whether certain secreted factor(s) is involved in oxidized low density lipoprotein (Ox-LDL)-induced murine macrophage growth. An antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) effectively inhibited Ox-LDL-induced macrophage growth by >80%. Ox-LDL as well as phospholipase A2-treated acetylated LDL enhanced mRNA levels and protein release of GM-CSF from macrophages, while neither acetylated LDL nor lysophosphatidylcholine (lyso-PC) showed such effects. The maximal induction of GM-CSF by Ox-LDL was noted at 4 h, followed by a time-dependent decrease to a basal level within 24 h. Ox-LDL-induced macrophage growth was inhibited by 75% by replacement of the culture medium at 24 h by a fresh medium containing the same concentration of Ox-LDL, when GM-CSF had already returned to the basal level. Thus, a cytokine(s) other than GM-CSF is also expected to participate in Ox-LDL-induced macrophage growth in a later phase. The Ox-LDL-induced GM-CSF release was inhibited by calphostin C, a protein kinase C inhibitor, and was significantly reduced in macrophages from the knockout mice lacking class A, type I and type II macrophage scavenger receptors (MSR-AI/AII). These results taken together indicate that effective endocytosis of lyso-PC of Ox-LDL by macrophages through MSR-AI/AII and subsequent protein kinase C activation have led to GM-CSF release into the medium which may play a priming role in conjunction with other cytokines in Ox-LDL-induced macrophage growth.

Animals↗
PubMed1994

Macrophage colony-stimulating factor induction of enhanced macrophage anticryptococcal activity: synergy with fluconazole for killing.

Enhancement of anticryptococcal activity in macrophages by macrophage colony-stimulating factor (M-CSF) and possible synergy between macrophages and fluconazole for killing of Cryptococcus neoformans were tested. M-CSF (48 h)-treated macrophages underwent dramatic morphologic changes and inhibited cryptococcal multiplication by 96% +/- 4%, which was greater (P < .001) than that of macrophages cultured in medium alone. M-CSF (5000 units/mL) induced optimal anticryptococcal activity but did not increase percentage of phagocytosis. NG-mono-methyl-L-arginine did not affect enhanced fungistatic activity. For a very fluconazole-sensitive isolate, fungistatic macrophages synergized with fungistatic doses of fluconazole for killing; for a less sensitive isolate, synergy was significant only when macrophages were activated with M-CSF or interferon-gamma plus lipopolysaccharide; for a fluconazole-resistant isolate, macrophages collaborated with fluconazole for additive fungistasis but not killing, and M-CSF-treated macrophages were significantly more fungistatic with fluconazole than were nonactivated macrophages.

Animals↗
PubMed1996

Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor.

NBXFO hybridoma cells produced both the membrane and secreted isoforms of macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+ macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor cells. In cytotoxicity studies, M-CSF activated macrophages and freshly isolated macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the possibility that contaminating lipopolysaccharide (LPS) was responsible for the delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the secreted isoform of M-CSF, transferred the ability of macrophages to kill these transfected T9 cells in a mM-CSF dose-dependent manner. Macrophage-mediated killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide inhibitor, N-omega-nitro-arginine methyl ester (NAME), did not effect macrophage cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when cultured in the presence of an equal number of the mM-CSF transfectant cells were not killed, indicating specific target cell cytotoxicity by the macrophages. Electron microscopy showed that macrophages were capable of phagocytosizing mM-CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible mechanism of this cytotoxicity. This study indicates that mM-CSF provides the necessary binding and triggering molecules through which macrophages can initiate direct tumor cell cytotoxicity.

Animals↗
PubMed1995

Partial characterization of the RNA from LPS-stimulated macrophages that induces the release of chemotactic cytokines by resident macrophages.

It is well established that exogenous RNA is incorporated into eukaryotic cells and is able to exert various biological responses. Little, however, is known about the effects of such RNA on macrophages. In this study, we demonstrate that RNA extracted from macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, in contrast to RNA from non-stimulated macrophages (N-RNA), induces the release of a macrophage-derived neutrophil chemotactic factor (MNCF) and interleukin-8 (IL-8) from macrophage monolayers. The effect of L-RNA was dependent of the integrity of the polynucleotide chain and was not due to LPS contamination since its ability to induce MNCF and IL-8 release was strongly reduced by RNase but was not affected by DNase or polymyxin B. The poly A(+)L-RNA and poly A(-)L-RNA fractions were able to induce the release of MNCF and IL-8, indicating that the L-RNA could be acting at transcriptional and translational levels. The demonstration that actinomycin-D and cycloheximide inhibited the release of MNCF and IL-8 by L-RNA-stimulated macrophages confirms this assumption. Fractionation of the total L-RNA by centrifugation on a 5-20% sucrose gradient showed that the L-RNA which sediments in the 4-5S region of the gradient is the only fraction capable of inducing the release of MNCF from naive macrophages. We have previously shown that macrophage monolayers stimulated with interleukin-1 beta or LPS release a low molecular RNA which also sediments in the same 4-5S region. Taken together, these results support our proposal that resident macrophages, when activated by injurious stimuli, in addition to secreting cytokines, also release a low molecular weight (4-5S) RNA which may act on the surrounding macrophages to further stimulate the release of cytokines. This process would amplify the inflammatory response and would increase the mechanisms involved in the defense response or tissue injury.

Animals↗
PubMed1986

The relationship between iron release, ferritin synthesis and intracellular iron distribution in mouse peritoneal macrophages. Evidence for a reduced level of metabolically available iron in elicited macrophages.

The rate of iron release from thioglycollate-elicited mouse peritoneal macrophages pulsed with 59Fe-labelled transferrin-antitransferrin immune complexes was lower than that from resident or Corynebacterium parvum-activated macrophages. Anaerobic conditions increased the rate of iron release by thioglycollate-elicited macrophages but had no effect on resident or C. parvum-activated macrophages. Thioglycollate-elicited macrophages also contained less ferritin and were deficient in their ability to synthesis ferritin. Incubation of these cells in medium containing 100 microM iron caused some increase in ferritin synthesis, but the response to iron was much less pronounced than that by resident or C. parvum-activated macrophages. In the thioglycollate-elicited macrophages, relatively less iron was incorporated into ferritin, and more into other soluble macromolecules and insoluble haemosiderin-like compounds than in the other types of macrophages. It is proposed that thioglycollate-elicited macrophages tend to divert iron to a relatively inert intracellular pool, and that this could account for their reduced ability to release iron. Such a mechanism might help to explain the reduced release of iron by liver and spleen macrophages occurring during inflammation.

Anaerobiosis↗
PubMed2004

The use of a model of in vivo macrophage depletion to study the role of macrophages during infection with Bacillus anthracis spores.

The pathogenesis of infection by Bacillus anthracis has been the subject of many investigations, but remains incompletely understood. It has been shown that B. anthracis spores germinate in macrophages and perhaps require this intracellular niche to germinate in vivo before outgrowth of the vegetative organism. However, it has also been reported that macrophages are sporicidal in vitro. In our in vivo model, macrophages were depleted from mice by either silica treatment or treatment with liposome-encapsulated dichloromethylene disphosphonate (Cl(2)MDP), and the animals were infected parenterally with virulent ungerminated B. anthracis (Ames strain) spores. The mice in which macrophages had been depleted were killed more rapidly than untreated mice. In addition, augmenting peritoneal populations of macrophages with cultured RAW264.7 cells partially protected mice from disease, increasing the survival rate in a dose dependent relationship. Alveolar macrophages were depleted by intranasal instillation of liposome-encapsulated Cl(2)MDP. The animals with normal alveolar macrophage numbers had significantly greater survival rates after inhaling B. anthracis spores than the macrophage-depleted mice. These findings do not preclude the observations that macrophages provide a site permissive for spore germination, however, these data suggest that macrophages do play an important role in limiting and/or clearing a B. anthracis infection.

Animals↗
PubMed1998

Inhibition of macrophage migration inhibitory factor secretion from macrophages by vitamin E.

Macrophage migration inhibitory factor (MIF) was identified in rat peritoneal macrophages by Western blot analysis and its secretion into culture medium by enzyme-linked immunosorbent assay. We investigated the effect of vitamin E on MIF production in macrophages in response to phorbol 12-myristate-13-acetate (PMA), calcium ionophore A23187, and lipopolysaccharide (LPS). Intraperitoneal injections of vitamin E (5 mg per rat) for 6 successive days resulted in a significant increase of alpha-tocopherol content in peritoneal macrophages (478.3+/-90.7 ng/106 cells) compared with the control (1.5+/-0.5 ng/10(6) cells). For the control macrophages, MIF content of the medium (2.5x10(6) cells/18 ml) without stimulation was 2.27+/-0.20 ng/ml after 14 h culture, whereas stimulation with calcium ionophore A23187 (400 nM) and LPS (5.0 microg/ml) induced the elevation of MIF content to 3. 66+/-0.41 and 4.12+/-0.58 ng/ml, respectively. On the other hand, vitamin E-enriched macrophages without stimulation showed less MIF content (0.77+/-0.23 ng/ml) than the control. Similarly, the increase of MIF of vitamin E-treated macrophages was significantly suppressed after stimulation with calcium ionophore A23187 or LPS, compared with the control macrophages. From analysis of intracellular MIF content by Western blot, we found no alteration of intracellular MIF content of vitamin E-macrophages, in contrast to the decreased content of control stimulated-macrophages. Taken together, these results indicate that vitamin E may contribute to the regulation of immune responses through regulation of MIF secretion.

Animals↗
PubMed1983

Apoprotein E is synthesized and secreted by resident and thioglycollate-elicited macrophages but not by pyran copolymer- or bacillus Calmette-Guerin-activated macrophages.

Macrophages are active secretory cells that display functionally distinct phenotypes that are regulated by inflammation. We have found that apoprotein E (ApoE), a component of plasma lipoproteins, was synthesized and secreted by resident and nonspecifically stimulated macrophages elicited with thioglycollate broth, but not by activated macrophages obtained from mice treated with bacillus Calmette-Guerin, pyran copolymer, whole Corynebacterium parvum, or bacterial endotoxin. ApoE represented approximately 1% of the newly synthesized protein and approximately 10% of secreted protein of resident and thioglycollate-elicited macrophages. ApoE from thioglycollate-elicited macrophages was indistinguishable from ApoE in mouse plasma lipoproteins, as determined by immunoreactivity, peptide mapping, and molecular weight. When specific antibodies were used to localize cell-associated ApoE, strong immunofluorescence was seen in the Golgi region of resident and thioglycollate-elicited macrophages immediately after removal from the peritoneal cavity, as well as after culture for up to 7 d. In contrast, activated macrophages did not synthesize or secrete ApoE to an appreciable extent and had no immunocytochemically detectable intracellular ApoE. When activated macrophages were cultured in medium containing serum, their activated state, as judged by production of H2O2, declined within 48-72 h in parallel with the induction of synthesis and secretion of ApoE and detection of intracellular ApoE by immunofluorescence. During prolonged culture the rate of synthesis and secretion of ApoE increased in both resident and activated macrophages. Therefore, the synthesis and secretion of ApoE may serve as markers for the functional state of macrophages.

Animals↗
PubMed1998

Local regulation of macrophage subsets in the adult rat testis: examination of the roles of the seminiferous tubules, testosterone, and macrophage-migration inhibitory factor.

In the adult rat testis, macrophages belong to one of two subsets differentiated by expression or lack of expression of the resident macrophage surface antigen recognized by monoclonal antibody ED2. Local regulation of the testicular macrophage subsets was investigated in normal and 4-wk experimentally cryptorchid adult rats with and without s.c. testosterone implants (T-implants). Macrophage subsets ED2(+) (resident-type) and ED2(-) (monocyte-like) were identified immunohistochemically and counted in perfusion-fixed frozen testis sections. Depletion of the spermatogenic cells by cryptorchidism had no effect on testicular macrophage numbers. Inhibition of Leydig cell and seminiferous tubule function by low-dose (3 cm) T-implants caused a 40% reduction in ED2(+) resident macrophages in both scrotal and abdominal testes. High-dose (24 cm) T-implants, which inhibit Leydig cell function while maintaining normal seminiferous tubule function, also reduced the number of resident macrophages by approximately 40%, although this reduction was at least partially prevented in the abdominal testes. In the scrotal testis only, the ED2(-) monocyte/macrophage subset was significantly reduced in number by low-dose, but not high-dose, T-implants. The concentration of the Leydig cell-secreted cytokine macrophage-migration inhibitory factor (MIF) in testicular fluid was reduced by cryptorchidism, but not by the T-implants. When data from all experimental groups were combined, ED2(+) resident macrophage numbers showed a significant positive correlation with parameters of Leydig cell function (serum LH and testicular testosterone levels) but a negative correlation with MIF levels. This study indicates that Leydig cells regulate testicular macrophage numbers directly, rather than via an effect upon the seminiferous epithelium, in the adult rat testis. The data also suggest that testosterone and MIF play only a minor role, if any, in this regulation.

Animals↗
PubMed1988

Enhancement of host resistance against Listeria infection by Lactobacillus casei: activation of liver macrophages and peritoneal macrophages by Lactobacillus casei.

The functions of liver macrophages and peritoneal macrophages obtained after injection of Lactobacillus casei were examined. Listericidal activity in vivo was enhanced in liver macrophages 13 days after L. casei injection but was somewhat suppressed in the macrophages 2 days after the injection. The listericidal activity in vitro was enhanced in peritoneal macrophages obtained 13 days after L. casei injection but was suppressed in cells obtained 2 days later. The PMA-triggered respiratory burst in the liver macrophages elicited by L. casei was higher than that of resident macrophages. Alkaline phosphodiesterase activity in the liver macrophages was decreased by L. casei injection, as was also the case with peritoneal macrophages. These observations indicate that L. casei augmented cellular functions of both liver and peritoneal macrophages.

Acid Phosphatase↗
PubMed1989

Effects of Histoplasma capsulatum on murine macrophage functions: inhibition of macrophage priming, oxidative burst, and antifungal activities.

Histoplasma capsulatum yeast cells fail to trigger an oxidative burst response in normal murine macrophages. The results of this study, in which an in vitro assay of macrophage antifungal effects was used, extend these findings. During 18 h of incubation, unprimed elicited murine macrophages inhibited H. capsulatum growth only when macrophages were present in great excess. Gamma interferon (IFN-gamma)-primed macrophages showed enhanced fungal growth inhibition but a similar requirement for an excess of phagocytes. Macrophages containing heat-killed H. capsulatum exhibited diminished antifungal effects toward viable H. capsulatum and Saccharomyces cerevisiae cells. Parallel experiments showed no comparable effect of ingested latex particles on macrophage antifungal activity. Using chemiluminescence as a measure of the oxidative burst, we found that macrophages primed in vitro with IFN-gamma alone failed to exhibit a significant response to triggering by H. capsulatum yeast cells unless a second priming agent (tumor necrosis factor alpha or bacterial lipopolysaccharide) was added to IFN-gamma. Furthermore, macrophage priming with single agents was blocked by the prior ingestion of heat-killed H. capsulatum. These studies provide evidence that ingestion of H. capsulatum yeast cells can induce a prompt and enduring deactivation of murine macrophages.

Animals↗
PubMed2004

Effects of Clostridium perfringens alpha-toxin (PLC) and perfringolysin O (PFO) on cytotoxicity to macrophages, on escape from the phagosomes of macrophages, and on persistence of C. perfringens in host tissues.

Clostridium perfringens is the most common cause of clostridial myonecrosis (gas gangrene). Polymorphonuclear cells (PMNs) appear to play only a minor role in preventing the onset of myonecrosis in a mouse animal model of the disease (unpublished results). However, the importance of macrophages in the host defense against C. perfringens infections is still unknown. Two membrane-active toxins produced by the anaerobic C. perfringens, alpha-toxin (PLC) and perfringolysin O (PFO), are thought to be important in the pathogenesis of gas gangrene and the lack of phagocytic cells at the site of infection. Therefore, C. perfringens mutants lacking PFO and PLC were examined for their relative cytotoxic effects on macrophages, their ability to escape the phagosome of macrophages, and their persistence in mouse tissues. C. perfringens survival in the presence of mouse peritoneal macrophages was dependent on both PFO and PLC. PFO was shown to be the primary mediator of C. perfringens-dependent cytotoxicity to macrophages. Escape of C. perfringens cells from phagosomes of macrophage-like J774-33 cells and mouse peritoneal macrophages was mediated by either PFO or PLC, although PFO seemed to play a more important role in escape from the phagosome in peritoneal macrophages. At lethal doses (10(9)) of bacteria only PLC was necessary for the onset of myonecrosis, while at sublethal doses (10(6)) both PFO and PLC were necessary for survival of C. perfringens in mouse muscle tissue. These results suggest PFO-mediated cytotoxicity toward macrophages and the ability to escape macrophage phagosomes may be important factors in the ability of C. perfringens to survive in host tissues when bacterial numbers are low relative to those of phagocytic cells, e.g., early in an infection.

Animals↗