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PubMed2006

Macrophage colony stimulating factor is a crucial factor for the intrinsic macrophage response in mice heterozygously deficient for the myelin protein P0.

Mouse mutants heterozygously deficient for the myelin protein P0 (P0+/-) resemble certain forms of human hereditary neuropathies. Endoneurial macrophages of intrinsic origin are intimately involved in the pathogenesis of the demyelinating neuropathy in these mutants. We have previously shown that deficiency for macrophage colony stimulating factor (M-CSF) prevents an increase of the number of endoneurial macrophages and alleviates the mutants' demyelinating phenotype. The aim of this study was to investigate which population of endoneurial macrophages - long-term resident macrophages or recently infiltrated macrophages - is affected by M-CSF deficiency. For this purpose, we generated bone marrow chimeric mice by transplanting GFP+ bone marrow into P0 mutants (P0+/-) and P0 mutants that lack M-CSF (P0+/- mcsf-op). This enabled us to discriminate recently infiltrated short-term resident GFP+ macrophages from long-term resident GFP- macrophages. Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice. In contrast, in P0+/- mcsf-op mutants, both GFP- and GFP+ macrophages did not substantially increase. Only small numbers of GFP+ but no GFP- macrophages were activated and phagocytosed myelin in chimeric P0+/- mcsf-op mutants, possibly reflecting recent activation outside the endoneurium before entering the nerve. Our findings demonstrate that M-CSF is crucial for the activation, in situ increase and myelin phagocytosis of both long-term and short-term resident endoneurial macrophages in P0+/- myelin mutants. M-CSF is, therefore, considered as a target candidate for therapeutic strategies to treat human demyelinating neuropathies.

Animals↗
PubMed2006

Francisella tularensis LVS grown in macrophages has reduced ability to stimulate the secretion of inflammatory cytokines by macrophages in vitro.

The virulence of Francisella tularensis LVS is determined in part by its ability to invade and replicate within macrophages and stimulate the production of inflammatory cytokines. The present study determined the effects of growing F. tularensis in macrophages on its ability to stimulate cytokine secretion by macrophages. F. tularensis grown in Mueller-Hinton broth (FtB) stimulated the secretion of large amounts of TNF-alpha, IL-12p40, IL-6 and MCP-1/CCL2 when incubated with macrophages overnight. In contrast, F. tularensis released from infected macrophages (FtMac) stimulated very little secretion of these cytokines by primary cultures of murine peritoneal macrophages, human monocytes or macrophage cell lines. Stimulation of nitric oxide production by FtMac was also less than that elicited by FtB. FtMac killed with gentamicin or paraformaldehyde also stimulated low levels of cytokine secretion. FtMac recovered the ability to stimulate cytokine secretion after overnight culture in broth. Infection of macrophages with FtMac inhibited the cytokine response to subsequent stimulation with LPS from Escherichia coli but did not affect Fcgamma receptor-mediated phagocytosis. FtMac were ingested by macrophages at about half the rate of FtB, however, this did not account for the lower cytokine secretion. FtMac and FtB replicated at similar rates within macrophages. Finally, Mice infected with FtMac had a higher mortality rate than those infected with FtB. These results reveal that growth in macrophages causes a reversible phenotypic change in F. tularensis that is associated with decreased stimulation of cytokine secretion, inhibition of LPS-stimulated secretion of inflammatory cytokines by macrophages and increased lethality in mice.

Animals↗
PubMed1986

Lymphocyte-induced macrophage cytotoxicity. III. Induction of specific macrophage cytotoxicity is independent of lipopolysaccharide.

The induction of specific macrophage cytotoxicity by allo-sensitized T cells in vitro is shown to be independent of the presence of lipopolysaccharide (LPS). This contrasts with the induction of macrophage cytotoxicity by Macrophage Activating Factor (MAF). The specific macrophage cytotoxicity could be induced in LPS-free medium (less than l ng/ml). Addition of LPS to the macrophages did not increase the cytotoxicity. Addition of LPS-binding polymyxin B to the macrophages before and during the induction of cytotoxicity did not reduce the specific macrophage cytotoxicity. Macrophages obtained from the LPS-unresponsive mouse strain C3H/HeJ were rendered cytotoxic by the allo-sensitized lymphocytes to the same extent as the macrophages from LPS-responsive C3HeB/Fe and C57BL mice. This indicates that the induction of macrophage cytotoxicity by MAF is different from the induction of specific macrophage cytotoxicity by Specific Macrophage Arming Factor (SMAF).

Animals↗
PubMed2000

Macrophages deficient in CTP:Phosphocholine cytidylyltransferase-alpha are viable under normal culture conditions but are highly susceptible to free cholesterol-induced death. Molecular genetic evidence that the induction of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response.

Macrophages in atherosclerotic lesions accumulate excess free cholesterol (FC) and phospholipid. Because excess FC is toxic to macrophages, these observations may have relevance to macrophage death and necrosis in atheromata. Previous work by us showed that at early stages of FC loading, when macrophages are still healthy, there is activation of the phosphatidylcholine (PC) biosynthetic enzyme, CTP:phosphocholine cytidylyltransferase (CT), and accumulation of PC mass. We hypothesized that this is an adaptive response, albeit transient, that prevents the FC:PC ratio from reaching a toxic level. To test this hypothesis directly, we created mice with macrophage-targeted disruption of the major CT gene, CTalpha, using the Cre-lox system. Surprisingly, the number of peritoneal macrophages harvested from CTalpha-deficient mice and their overall health under normal culture conditions appeared normal. Moreover, CT activity and PC biosynthesis and in vitro CT activity were decreased by 70-90% but were not absent. As a likely explanation of this residual activity, we showed that CTbeta2, a form of CT that arises from another gene, is induced in CTalpha-deficient macrophages. To test our hypothesis that increased PC biosynthesis is an adaptive response to FC loading, the viability of wild-type versus CTalpha-deficient macrophages under control and FC-loading conditions was compared. After 5 h of FC loading, death increased from 0.7% to only 2.0% in wild-type macrophages but from 0. 9% to 29.5% in CTalpha-deficient macrophages. These data offer the first molecular genetic evidence that activation of CTalpha and induction of PC biosynthesis in FC-loaded macrophages is an adaptive response. Furthermore, the data reveal that CTbeta2 in macrophages is induced in the absence of CTalpha and that a low level of residual CT activity, presumably due to CTbeta2, is enough to keep the cells viable in the peritoneum in vivo and under normal culture conditions.

Animals↗
PubMed1994

Dissection of macrophage differentiation pathways in cutaneous macrophage disorders and in vitro.

Macrophages play important roles in immunity and inflammation, and in allergic, granulomatous and neoplastic diseases. Here, we present the indepth results of an ongoing study of macrophage differentiation pathways in cutaneous macrophage disorders and in vitro. Up to now, a total of 40 cases of cutaneous macrophage disorders (histiocytoses and granulomas) and related diseases were examined using a panel of monoclonal and polyclonal antibodies to macrophage differentiation antigens (mAb MS-1, mAb alpha CD1a, mAb alpha CD34, mAb RM 3/1, mAb alpha CD11c, mAb alpha CD36, mAb MAC 387, mAb 27E10, polyclonal antibodies alpha MRP-8 and -14, mAb alpha CD68, mAb 25F9, mAb DRC1-R4/23, and mAb 1F10). Of these, MS-1 high molecular weight protein, synthesized by non-continuous sinusoidal endothelial cells and highly dendritic perivascular macrophages in normal human organs, is the most specific macrophage differentiation marker. MS-1 high molecular weight protein is selectively expressed by cutaneous non-Langerhans cell histocytoses, and proves to be a valuable diagnostic tool for these diseases. MS-1 high molecular weight protein is not found in Langerhans cell histiocytosis cells, epithelioid cells in sarcoidosis, and palisading histiocytes in granuloma annulare. MS-1+ macrophages may be found intermingled in cellular type dermatofibroma and in foreign body granulomas; they differ from MS-1+ non-Langerhans cell histiocytosis cells by their highly dendritic morphology, and thus rather resemble the MS-1+ macrophages in normal skin. RM 3/1 antigen shows a similar, but broader expression pattern including non-Langerhans cell histiocytoses, xanthelasmata palpebrarum, foreign body granulomas, granuloma annulare, and cellular type dermatofibroma. Moreover, xanthelasmata palpebrarum paradigmatically represent a class of macrophage lesions with strong RM 3/1, but little MS-1 antigen expression. In sarcoidosis, RM 3/1+ macrophages are only found at the very periphery of epithelioid cell granulomas. In contrast, 25F9 antigen is strongly and consistently expressed in epithelioid cells of sarcoidosis, and in foreign body granulomas. In cultured human monocytes/macrophages, RM 3/1 antigen is expressed early on, while MS-1 high molecular weight protein and 25F9 antigen are late and very late macrophage differentiation antigens, respectively. Expression of RM 3/1 antigen and MS-1 high molecular weight protein is inducible by glucocorticoid and interleukin-4, and less so by interleukin-13 and interleukin-10, and combinations thereof, while 25F9 antigen seems to be less influenced by these agents. Interferon-gamma (and less so tumor necrosis factor-alpha) inhibit expression of all three antigens in cultured human monocytes/macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, CD↗
PubMed1985

An in vitro system to study listericidal capacity of macrophages from separate mice: resident macrophages exhibit different activation patterns.

An in vitro system with macrophages from individual mice was established to study their listericidal capacity. Because no antibiotics were used, bacterial killing was really due to macrophages in short-term culture. To restrict the extracellular growth of bacteria, cell culture medium was changed at 1-h intervals. We demonstrated that intracellular growth of listeria in macrophage pools from untreated animals varies considerably. Obviously, preactivated macrophages are constantly present, so that the common procedure of using macrophage pools from several animals is no longer acceptable. In addition, we demonstrated that in vitro mixtures of listeria-immune macrophages of one animal with cells from untreated animals at different ratios exhibit enhanced bacterial killing above a mere additive effect. Consequently, by using macrophages from individual untreated mice, we found that cells of different animals exhibited various activation stages, although unstimulated, inbred specific-pathogen-free mice of the same age, weight, and sex were used. When equal numbers of macrophages from untreated separate animals were mixed in vitro, intracellular growth of listeria was only moderate; that is, the number of preactivated macrophages of the individual animals determined listerial growth in the pooled preparation. Furthermore, we showed that identical doses of phorbol myristate acetate exerted different effects on the listericidal activities of macrophages as a function of their preactivation states. These experiments clearly demonstrate the advantage of using macrophages from individual mice for in vitro studies of macrophage activation.

Animals↗
PubMed1993

Legionella pneumophila growth restriction in permissive macrophages cocultured with nonpermissive lipopolysaccharide-activated macrophages.

Macrophages can be activated by lipopolysaccharides (LPS) from gram-negative bacteria to evince a number of biological activities, including increased resistance to intracellular infection by opportunistic bacteria. In the present study, intraperitoneal injection of LPS into A/J mice activated peritoneal macrophages so that they resisted subsequent in vitro infection with Legionella pneumophila. Coculture of these macrophages with those from nontreated A/J mice converted the entire population of cells from permissive to nonpermissive. This effect did not appear to be mediated by soluble factors released from the LPS-treated macrophages, since the levels of interleukins-1 and -6 and tumor necrosis factor alpha produced by the macrophages were not found to be markedly elevated at the time when the macrophages from the LPS-treated mice were most effective in converting normal macrophages to nonpermissiveness. Furthermore, macrophages from mice injected intraperitoneally with either interferon or tumor necrosis factor alpha did not evince nonpermissiveness and also did not have the ability to convert normal spleen cells to nonpermissiveness. Polymyxin B, a known inactivator of LPS activity, did not inhibit the macrophages from the LPS-treated mice from inducing this resistance. It seemed unlikely that free LPS released from the macrophages mediated this effect. The results of this study thus showed that macrophages activated by LPS in vivo can evince nonpermissiveness for Legionella growth in vitro and also can induce macrophages from normal, permissive mice to become nonpermissive for Legionella growth in vitro.

Animals↗
PubMed2002

A novel phenotype for an activated macrophage: the type 2 activated macrophage.

Activated macrophages were used as antigen presenting cells (APCs) to determine the extent to which these APCs could influence an adaptive immune response. We show that activated macrophages induced a strong polarized Th1-like T cell response that was predominated by IFN-gamma. However, when antigen was targeted to Fcgamma receptors on these macrophages, their phenotype changed, and they now induced a T cell response that was predominated by IL-4. The initial biasing by activated macrophages toward a Th1-like response was a result of activation of the innate immune response, as macrophages from MyD88(-/-) mice failed to produce Th1-inducing cytokines. The reversal of the Th1 biasing was a result of FcgammaR ligation, as macrophages lacking the FcR common gamma chain failed to reverse this biasing. To show that this biasing could occur in vivo, mice were injected with activated macrophages or activated macrophages whose FcgammaR had been ligated with an irrelevant immune complex. Mice injected with FcgammaR-ligated macrophages made more antibody than those receiving conventionally activated macrophages, and the antibody was predominantly of the IgG1 isotype. These studies demonstrate that FcgammaR ligation on activated macrophages can change the phenotype of these APCs to cells that preferentially drive a Th2-like response. We have termed these cells type 2 activated macrophages.

Adaptor Proteins, Signal Transducing↗
PubMed2002

PMA activation of macrophages alters macrophage metabolism of aggregated LDL.

Aggregation of LDL may contribute to its retention in atherosclerotic lesions. Previously, we showed that aggregated LDL induces and enters surface-connected compartments (SCCs) in human monocyte-derived macrophages by a process we have named patocytosis. Aggregated LDL was disaggregated and released from SCCs of macrophages when exposed to human lipoprotein-deficient serum. The serum factor that mediated aggregated LDL release and disaggregation was plasmin generated from plasminogen by macrophage urokinase plasminogen activator. We now show that activation of macrophages with PMA inhibits plasmin-mediated release of aggregated LDL from macrophages. With macrophage activation, plasminogen released about 60% less cholesterol and 63% less TCA-insoluble (125)I-aggregated LDL than when macrophages were not activated. Electron microscopy showed that PMA did not cause SCCs to close, which could have trapped aggregated LDL within the SCCs and limited protease access to aggregated LDL. Rather, PMA decreased macrophage generation of plasmin by 61%, and stimulated lysosomal degradation of aggregated LDL by more than 2-fold. Degradation was mediated by protein kinase C, shown by the finding that degradation was inhibited by the protein kinase C inhibitor Gö6976. PMA-stimulated degradation of aggregated LDL was associated with a 3-fold increase in cholesterol esterification, consistent with hydrolysis and re-esterification of aggregated LDL-derived cholesteryl ester. In conclusion, macrophage activation with PMA causes more of the aggregated LDL that enters macrophage SCCs to be metabolized by lysosomes. This results in more cholesterol to be stored in macrophages and less aggregated LDL to be available for plasmin-mediated release from macrophage SCCs.

Cells, Cultured↗
PubMed1996

Macrophages have cell surface IL-10 that regulates macrophage bactericidal activity.

IL-10, which is secreted by multiple cell types, has regulatory effects on macrophages, including decreasing their ability to kill some microorganisms. The experiments presented here test the hypothesis that endogenous IL-10 inhibits the ability of macrophages to kill the facultative intracellular bacterium, Listeria monocytogenes. We show that the nonbactericidal macrophage hybrid, H36.12j (12j), can kill Listeria after incubation for 3 days with anti-IL-10 mAb. IL-10 was not detected in 12j macrophage supernatants by ELISA. However, flow cytometric analysis revealed high levels of IL-10 on the 12j cell surface. This indicates that macrophages that fail to secrete IL-10 may express IL-10 on the cell surface, and this IL-10 appears to suppress listericidal activity. Surface IL-10 is not unique to the 12j macrophage hybrid and may correlate with the absence of bactericidal activity in other macrophages. For instance, nonlistericidal resident and thioglycolate-elicited peritoneal exudate cells have 24 to 72% IL-10-positive macrophages. In contrast listericidal proteose peptone-elicited peritoneal exudate cells contained < 5% IL-10-positive macrophages. Whether this IL-10 is an integral membrane protein or is bound to IL-10 receptors is not yet known. However, the IL-10 does not elute with acid as other passively bound molecules do, nor does exogenous IL-10 bind to macrophages. In either case, since anti-IL-10 induces nonbactericidal macrophages to become bactericidal, the surface IL-10 is biologically active, and it appears to regulate macrophage bactericidal activity.

Animals↗
PubMed2000

Induction of chemokine secretion and enhancement of contact-dependent macrophage cytotoxicity by engineered expression of granulocyte-macrophage colony-stimulating factor in human colon cancer cells.

We investigated the role of tumor cell-derived GM-CSF in recruitment and tumoricidal activation of tissue macrophages. Transfection of the murine GM-CSF gene into KM12SM human colon cancer cells decreased the tumorigenicity of transfected cells and nontransfected bystander colon cancer cells in nude mice. Sequential tissue sections from sites injected with high GM-CSF-producing tumor cells (but not from nontransfected or low GM-CSF-producing cells) demonstrated a dense infiltration of polymorphonuclear cells (PMN), followed by infiltration of macrophages, which correlated with expression of the macrophage-inflammatory protein-1alpha and the monocyte chemoattractant protein-1 (MCP-1) in mouse PMN and macrophages. GM-CSF-producing KM12SM cells were highly sensitive to lysis by mouse macrophages and also increased macrophage-mediated lysis of bystander nontransfected KM12SM cells. The incubation of macrophages with GM-CSF induced expression of the CD11b surface adhesion molecule, which was associated with increased attachment to tumor cells. All KM12SM cells were sensitive to macrophage-mediated lysis in the presence of rGM-CSF and recombinant MCP-1. Collectively, the results demonstrate that tumor cell-derived GM-CSF stimulates PMN and macrophages to secrete macrophage-inflammatory protein-1alpha and MCP-1, which triggers recruitment of mononuclear cells, induces expression of adhesion molecules on macrophages, and enhances contact-dependent cytolysis of tumor cells.

Animals↗
PubMed1975

The role of macrophages in the generation of T helper cells. III. Influence of macrophage-derived factors in helper cell induction.

Helper cell induction to soluble or particulate antigens in vitro requires the cooperation of T cells and macrophages. A direct contact between macrophages and T cells is not obligatory for this cooperation and factors released from macrophages are as effective in activating T cells as the cells themselves. Two different types of macrophage-derived factors where found. The supernatant obtained from purified macrophages incubated with antigen for several days generates helper cells in absence of macrophages or additional antigen, but only if obtained from macrophages which were identical at the I-A subregion of the H-2 complex as the T cells. This factor was called genetically related macrophages factor (GRF). The other factor(s), which is present in the supernatant obtained from macrophages incubated for several days without antigen, replaces macrophages only if the antigen is particulate. This factor(s), called nonspecific macrophage factor (NMF) is not restricted genetically and is also obtained from allogeneic macrophages. The importance of both these factors in helper cell induction is discussed.

Animals↗
PubMed1986

Correlation of macrophage-mediated tumor-cell lysis with the production of macrophage cytolytic factor (CF). Preliminary characterization of a factor inhibiting CF production.

Macrophage-mediated cytolysis of thymidine-prelabelled murine A9 fibrosarcoma cells was compared to the level of cytolytic factor (CF) present in the cultures by assaying supernatant aliquots on actinomycin (AcD)-treated A9 fibrosarcoma cells. A good correlation between the level of A9 killing and CF titer was observed when different concentrations of lipopolysaccharide (LPS) were added to various macrophage populations: murine peritoneal cells, short-term bone-marrow (BM)-derived macrophages and JBM phi macrophage lines. Optimal A9 killing and CF secretion, equivalent to the killing of about 1000 AcD-pretreated A9 cells by a single macrophage, were obtained following activation of JBM phi by LPS. CF production by BM-derived macrophages was enhanced in serum-free medium when compared to its release in the presence of fetal calf serum. The LPS-activated macrophages could be restimulated by the activating agent to produce CF following one week of propagation in the absence of LPS. On the other hand, CF activity was absent from the supernatants of activated macrophages co-cultured with normal embryonic fibroblasts, which are resistant to macrophage-mediated killing. This effect could be attributed to a factor, secreted by normal fibroblasts but not by A9 cells, which suppressed CF release from the activated macrophages. Our data strongly support earlier observations, suggesting that CF [which appears to resemble the tumor necrosis factor (TNF)] is responsible for LPS-induced macrophage-mediated tumor cell lysis. It is suggested that suppression of the latter process by the fibroblast-derived factor proceeds via inhibition of CF/TNF production from the macrophage.

Animals↗
PubMed1993

Modulation of cytotoxic activity of resident macrophages by postsurgical macrophages.

The purpose of this study was to determine if the secretion of cytotoxic molecules, such as tumor necrosis factor or toxic oxygen molecules, by resident peritoneal macrophages is modulated by postsurgical macrophages elicited by peritoneal trauma. Resident macrophages were collected from nonsurgical rabbits and cultured in vitro with either spent media from cultures of postsurgical macrophages harvested at various times or with varying concentrations of standard cytokines. Superoxide anion (O2-) production of resident macrophages increased with exposure to spent culture media from macrophages obtained after intestinal reanastomosis (3, 6, 12, 24 hr). This increase reached maximal levels by 6 hr after surgery and thereafter decreased to resident levels by 24 hr after surgery. Exposure of resident macrophages to spent media from cells collected after peritoneal sidewall abrasion (1, 3, 5, 7, 10, 14 days) elevated the production of O2- on Postsurgical Days 3 and 5; however, no effect was observed following exposure to spent media of macrophages harvested on Postsurgical Day 14. Interleukin-1 alpha (IL-1 alpha), transforming growth factor beta (TGF-beta), and tumor necrosis factor alpha (TNF alpha) stimulated phorbol ester-induced O2- production by resident macrophages in a concentration-dependent manner. The secretion of TNF activity by resident macrophages increased following exposure to spent media of macrophages harvested 6 to 24 hr after intestinal surgery. IL-1 alpha, TGF-beta, and TNF alpha elevated the secretion of TNF activity by resident macrophages in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Schizophyllan (SPG)-treated macrophages and anti-tumor activities against syngeneic and allogeneic tumor cells. I. Characteristics of SPG-treated macrophages.

We tested anti-tumor activities of macrophages treated with a neutral polysaccharide, schizophyllan (SPG), against syngeneic and allogeneic tumor cell lines. SPG was a macrophage stimulant which was not mitogenic to lymphocytes. That made a sharp contrast with the data that Corynebacterium parvum, BCG, and muramyl dipeptide (MDF) were macrophage stimulants which had lymphocyte-activating properties. Treatment of SPG-treated PEC with Thy12 monoclonal antibody and guinea pig complement did not affect the capabilities of tumor-cell-growth suppression by the treated PEC. Thus, the effector cells were peritoneal adherent cells (macrophages morphologically) and effector-to-target contact seemed to be necessary for effective tumor-cell-growth inhibition, although contradictory data exist for this. Murine peritoneal adherent cells harvested 4 days after a single IP injection of SPG at a dose of 100 mg/kg body weight of mouse showed the most prominent cytostatic and cytotoxic activities against syngeneic and allogeneic tumor cells. The distribution of anti-tumor activity in macrophages of various sizes followed the same pattern as macrophages treated with C. Parvum, i.e., larger macrophages showed more remarkable anti-tumor activity. Crude nonadherent peritoneal cells incubated with SPG at a concentration of 10 micrograms/ml, 100 micrograms/ml, or 1 mg/ml did not secrete lymphokine that rendered macrophages cytotoxic, while ConA-treated nonadherent cells did so. Furthermore, spleen cells treated with SPG in vivo did not secrete macrophage-activating lymphokine in the presence of SPG. On the other hand, addition of 1 mg/ml of SPG-treated peritoneal adherent cells and bone-marrow-derived macrophages in vitro rendered them cytotoxic to a moderate degree. This implies that SPG may activate macrophages directly, allowing them to become cytotoxic in the peritoneal cavity. Lastly, SPG could induce production of II-1-like factor to a moderate degree. SPG, whose molecular structure is well elucidated, will provide us with a strong tool to analyze the mechanism of macrophage activation both in vitro and in vivo.

Animals↗
PubMed1988

Macrophage cell cycling: influence of proliferative state on the antibody-mediated activities of rat resident peritoneal macrophages.

Countercurrent centrifugal elutriation (CCE) was used to isolate fractions of rat resident peritoneal macrophages that were enriched in different phases of the cell cycle. The purpose was to assess the influence of the proliferative status of these cells on their antibody-mediated phagocytic activity. Autoradiographic analysis of the resident peritoneal cell population isolated 1 hr after an intravenous injection of [3H] thymidine showed that about 3% of the macrophages were in S-phase of the cell cycle. CCE yielded fractions of macrophages in which the proportions of S-phase cells ranged from 0% to about 10%. Results of flow cytometric analysis of propidium iodine-stained cells were consistent with the autoradiographic findings. Essentially all of the macrophages in the CCE fractions ingested antibody-coated particles, but there were marked differences in phagocytic capacity and in expression of Fc-receptors among discrete groups of cells. CCE fractions with the smallest cells and no S-phase macrophages ingested approximately six- to eightfold fewer particles than did macrophages from CCE fractions with the largest cells and enriched in S-phase macrophages. Similarly, smaller macrophages bound fewer antibody-coated particles than did larger macrophages. These results, which are identical to those previously reported for murine macrophage cell lines, show that the number of Fc-receptors and the phagocytic capacity of cycling resident peritoneal macrophages increase as the cells progress from G1 to G2. Thus, the proliferative state of macrophages does not determine whether they are phagocytic but rather their phagocytic capacity.

Animals↗
PubMed1983

Macrophages and infertility: oviductal macrophages as potential mediators of infertility.

Human peritoneal macrophages have previously been shown to phagocytize normal sperm. We had hypothesized that if macrophages were present in the distal oviducts, they could interfere with fertilization by phagocytizing sperm in vivo. The present study was designed to determine whether functional macrophages are present in the human oviducts, and to determine the relationship between oviductal and peritoneal macrophages. Forty patients undergoing laparotomy for sterilization or evaluation of infertility or other gynecologic factors were studied. Infertile patients with endometriosis had more peritoneal macrophages than did fertile normal women or infertile women with distal or proximal tubal obstruction. Oviductal macrophages were observed in all patients. The oviductal macrophages were indistinguishable from the peritoneal macrophages, as judged by similar morphologic features, adherence to plastic, phagocytosis of polystyrene spheres and IgG-coated erythrocytes, and presence of peroxidase and alpha-naphthylbutyrate esterase. Patients with endometriosis had the highest numbers of oviductal macrophages, while those patients with distal tubal obstruction had extremely few oviductal macrophages. The results suggest that oviductal macrophages may arise from peritoneal macrophages that migrate into the oviducts.

Adult↗
PubMed1999

Localization of macrophage inflammatory protein: macrophage inflammatory protein-1 expression in rat brain after peripheral administration of lipopolysaccharide and focal cerebral ischemia.

Macrophage inflammatory protein is a member of the C-C subfamily of chemokines, which exhibits, in addition to proinflammatory activities, a potent endogenous pyrogen activity. In this study, we analysed the time-course of expression and cellular source of macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta, in inflammation of the rat brain associated with ischemia and endotoxemia. Using in situ hybridization histochemistry, we observed that intravenously injected bacterial lipopolysaccharide induced a transient expression of macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta messenger RNAs throughout the brain, with maximal expression 8-12 h after lipopolysaccharide treatment. We also revealed an early increase in macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta messenger RNA levels, after permanent and transient middle cerebral artery occlusion, starting as early as 1 h after the occlusion and reaching a peak of expression 8-16 h after middle cerebral artery occlusion. The induction of macrophage inflammatory protein-1 messenger RNA was clearly stronger in the transient than in the permanent middle cerebral artery-occluded rat brains, showing that the reperfusion process influences the extent of the chemokine response after middle cerebral artery occlusion. In situ hybridization combined with immunohistochemistry for glial fibrillary acidic protein, a specific marker for astrocytes, excluded astrocytes as the cellular source of macrophage inflammatory protein-1 messenger RNAs after both middle cerebral artery ischemia and lipopolysaccharide treatment. Using immunohistochemistry, macrophage inflammatory protein-1alpha protein expression was shown to be induced in a time-dependent manner after lipopolysaccharide treatment and middle cerebral artery occlusion. Macrophage inflammatory protein-1alpha immunopositive cells co-localized with cells stained with OX-42 antibody, a microglia/macrophage marker. These results indicate that macrophage inflammatory protein-1 is implicated in the inflammatory reaction of the brain in response to ischemia or infection, and might modulate the host defence febrile response to a pathogenic stimulus.

Animals↗