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PubMed1997

Beta-chemokines that inhibit HIV-1 infection of human macrophages stimulate uptake and promote destruction of Trypanosoma cruzi by human macrophages.

Recently beta-chemokines have been shown to inhibit HIV-1 infection of human macrophages. Here, we show that the beta-chemokines RANTES, MIP-1alpha and MIP-1beta enhance the uptake and cause intracellular destruction of Trypanosoma cruzi trypomastigotes by human macrophages obtained from healthy individuals. The trypanosome enhancing uptake and the trypanocidal effect induced by these beta-chemokines in human macrophages are abrogated by neutralizing antibodies to RANTES, MIP-1alpha and MIP-beta, whereas irrelevant antibodies of the same class do not affect these parameters. These results indicate that the effects seen are beta-chemokine specific. Pretreatment of human macrophages with RANTES, MIP-1alpha and MIP-1beta induced strong tyrosine phosphorylation of several proteins, suggesting that signal transduction events are involved in enhanced trypanosome uptake and parasite killing. Taken together these results suggest that the beta-chemokines RANTES, MIP-1alpha and MIP-1beta, might play a beneficial role in parasite clearance and destruction in individuals infected with T. cruzi. Alternatively, these three beta-chemokines may play a beneficial role in individuals concurrently infected with T. cruzi and HIV-1.

Animals↗
PubMed1995

Differential regulation of fyn-associated protein tyrosine kinase activity by macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

The proliferation and differentiation of macrophages are regulated by, among others, GM-CSF and M-CSF. Treatment of bone marrow nonadherent (NA) cells with M-CSF induced a greater percentage of NA cells into adherent cells, recognized as monocyte/macrophages, than did GM-CSF. The effect of GM-CSF and M-CSF on the activation of fyn kinase, a 59-kDa src family-related protein tyrosine kinase (PTK), was studied. Control cultures of bone marrow NA cells expressed only minimal levels of fyn kinase activity. Treatment of bone marrow NA cells with M-CSF, but not GM-CSF, for 12 to 24 h greatly enhanced the levels of fyn kinase activity. The effect of M-CSF on the activation of fyn kinase was further investigated using bipotential adherent bone marrow-derived macrophages (BMDMs) that coexpress receptors for both GM-CSF and M-CSF. BMDMs can be induced by either growth factor to undergo extensive proliferation in vitro. Compared to bone marrow NA cells, BMDMs displayed higher levels of basal fyn kinase activity, which were similarly elevated by M-CSF but not GM-CSF treatment. The role of fyn kinase in regulating cell adhesion was investigated by growing BMDMs in both tissue culture and Teflon flasks. The growth of BMDMs was anchorage independent; the majority of them continued to proliferate as cell suspension in Teflon flasks. Whereas the levels of fyn kinase activity in adherent BMDMs grown in tissue culture flasks increased steadily, those in BMDMs grown in Teflon flasks diminished. To study the role of fyn kinase in growth regulation, BMDMs were treated with c-fyn sense and antisense s-oligos. In the presence of c-fyn antisense s-oligos, the proliferative response of BMDMs to M-CSF but not GM-CSF was inhibited. In contrast, the proliferation of BMDM in response to either GM-CSF or M-CSF was not influenced by c-fyn sense s-oligos. Collectively, our data suggest that the activation of fyn kinase is closely associated with the acquisition of adherent capacity in maturing macrophages.

Animals↗
PubMed1992

Up-regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors in murine peritoneal exudate macrophages by both GM-CSF and IL-3.

Murine peritoneal exudate macrophages (PEM) display multiple CSF receptors. In this study, the expression of granulocyte-macrophage (GM)-CSF receptors in PEM was studied. PEM displayed over 5000 single type, high affinity GM-CSF receptors/cell with a Kd = 38 to 42 pM and an apparent molecular mass of 86,000 Da. Treatment of PEM with low, but not high, concentrations of recombinant murine (rMu) GM-CSF continuously for 24 h resulted in a marked up-regulation of GM-CSF receptors in PEM. A similar up-regulation of GM-CSF receptors also was detected in PEM cultures treated with rMuIL-3 (1-100 ng/ml) for 24 h or longer, regardless the doses of rMuIL-3 added in this case. Scatchard analysis of equilibrium binding showed that the enhanced binding activities in both cases were due to an increase in total number of GM-CSF receptors rather than changes in receptor affinity. Contrariwise, treatment with recombinant human macrophage-CSF (greater than 100-1000 ng/ml) partially inhibited the expression of GM-CSF receptors in PEM. Removal of rMuGM-CSF from culture medium 24 h after treatment led to a further up-regulation of GM-CSF receptors over a 4 to 24-h period, depending on the doses of initial treatment. On the other hand, removal of rMuIL-3 from culture medium after prolonged treatment did not result in further increase in GM-CSF receptors. The protein synthesis inhibitor cycloheximide abrogated GM-CSF receptor up-regulation induced by both rMuIL-3 and rMuGM-CSF, whereas actinomycin D inhibited only the second (8-24 h) phase of GM-CSF receptor up-regulation induced by exposure to high concentrations rMuGM-CSF (10 ng/ml). These findings suggest that rMuGM-CSF and rMuIL-3 up-regulate GM-CSF receptors in PEM in part through similar or identical metabolic pathways and provide further evidence of a close linkage between IL-3 and GM-CSF receptors.

Animals↗
PubMed1979

Investigation of the human macrophage. II. The in vitro cytotoxicity of macrophages.

Macrophage-mediated cytotoxicity in vitro was studied by a tritiated thymidine incorporation inhibition assay as well as by microscopic examination and optical transmitance determination. It was found that macrophages from patients with malignant diseases showed cytotoxic effects on two malignant human cell lines. The cytotoxic activity was more marked in patients who were clinically tumor-free. Some patients with benign diseases and normal subjects also exhibited cytotoxic macrophages. Macrophage-mediated cytotoxicity (MMC) was thus nonspecific in nature. Cell-free exudate from cancer patients did not influence MMC appreciably. The experimental methods and the possible significance of MMC are discussed.

Animals↗
PubMed1988

Increased bactericidal macrophage activity induced by immunological stimuli is dependent on interferon (IFN)-gamma. Interference of anti-IFN-gamma but not anti-IFN-alpha/beta with modulation of macrophage activity caused by lymphocytic choriomeningitis virus infection or systemic graft-vs.-host reactions.

During generalized immune responses such as the acute phase of graft-vs.-host reaction (GvHR) or many systemic viral infections the macrophage-monocyte system of mice is activated as demonstrated by their increased bactericidal capacity against Listeria monocytogenes. To study the effect of interferon (IFN)-gamma in maintainance of macrophage activity, lymphocytic choriomeningitis virus (LCMV) primed C57BL/6 mice or (C57BL/10 x B10.BR) F1 mice undergoing a GvHR were treated with polyclonal specific sheep anti-IFN-gamma antiserum. In both cases injection of anti-IFN-gamma resulted in inhibition of the stimulatory effects on macrophages as detected by reduced bactericidal activity when compared to mice treated with normal serum. Treatment with a polyclonal sheep anti-IFN-alpha,beta antiserum on the other hand did not interfere with the activation status of the macrophages. The findings suggest that IFN-gamma is produced both early in a GvHR and during the acute phase of an systemic infection with LCMV, and that it is involved in in vivo modulation of the increased activity of mononuclear phagocytes in immunologically stimulated mice.

Animals↗
PubMed1994

Macrophage-T cell interaction in experimental mycobacterial infection. Selective regulation of co-stimulatory molecules on Mycobacterium-infected macrophages and its implication in the suppression of cell-mediated immune response.

The most important immunopathological consequence of experimental mycobacterial infection is the suppression of T cell-mediated immune response to both mitogens and mycobacterial antigens. We registered that there was decreased concanavalin A-induced spleen cell proliferation in infected susceptible BALB/c mice as compared to normal mice. In resistant (C3H/HeJ) mice, infection with the bacteria did not induce any suppression in the mitogen-induced lymphoproliferation. Likewise, delayed-type hypersensitivity (DTH) responses, to keyhole limpet hemocyanin and mycobacterial crude soluble antigen were suppressed in infected BALB/c mice but not in C3H/HeJ mice. This depressed T helper cell function may either be due to defective T cell-receptor occupancy by antigen-Ia complex or altered co-stimulatory signals provided by antigen-presenting cells. In the present study, we have investigated the status of certain co-stimulatory molecules on the infected macrophages from both susceptible and resistant mice. Our results demonstrate that upon mycobacterial infection, the macrophages are rendered incapable of delivering the co-stimulatory signals to T helper cells, possibly due to the involvement of prostaglandin, as inhibition of its biosynthesis by indomethacin reversed the defect. Furthermore, the selective regulation was bacteria-induced as killing of the bacteria by rifampicin abrogated the derangements in the expression of co-stimulatory molecules on the Mycobacterium-infected macrophages. Our observations revealed that upon infection with Mycobacterium tuberculosis, B7 was down-regulated while ICAM-1 was increased only in BALB/c but not in C3H/HeJ mice. Expression of VCAM-1 did not change during the infection in either strain of mice. We found that these changes in ICAM-1 and B7 expression on the surface of infected macrophages resulted in inhibition of DTH-mediating functions of T helper cells from BALB/c mice. The results obtained in this study describe not only a novel immune evasion strategy adopted by Mycobacterium, but also open up the possibility of immunotherapy of mycobacterial infection by selective manipulation of co-stimulatory molecules.

Animals↗
PubMed1987

Modulation of macrophage I-A expression: lack of effect of prostaglandins and glucocorticoids on macrophages that continuously express I-A.

The ability of prostaglandins, glucocorticoids and lipopolysaccharide to modulate I-A expression on macrophages that continuously or transiently express I-A was compared. We found that neither prostaglandins nor glucocorticoids affected I-A expression by macrophages that continuously expressed I-A. In contrast, prostaglandin E2 (PGE2) inhibited the lymphokine-induced maintenance of I-A on macrophages that transiently expressed I-A while glucocorticoids inhibited both the induction and expression of I-A. Lipopolysaccharide caused a loss in the expression of Class II molecules on macrophages that continuously expressed I-A by a prostaglandin-independent mechanism. The lack of effect of PGE2 and glucocorticoids may be related to our observation that continuous expression of I-A does not require its continued synthesis.

Animals↗
PubMed1998

Profile of human macrophage transcripts: insights into macrophage biology and identification of novel chemokines.

High throughput partial sequencing of randomly selected cDNA clones has proven to be a powerful tool for examining the relative abundance of mRNAs and for the identification of novel gene products. Because of the important role played by macrophages in immune and inflammatory responses, we sequenced over 3000 randomly selected cDNA clones from a human macrophage library. These sequences represent a molecular inventory of mRNAs from macrophages and provide a catalog of highly expressed transcripts. Two of the most abundant clones encode recently identified CC chemokines. Macrophage-derived chemokine (MDC) plays a complex role in immunoregulation and is a potent chemoattractant for dendritic cells, T cells, and natural killer cells. The chemokine receptor CCR4 binds MDC with high affinity and also responds by calcium flux and chemotaxis. CCR4 has been shown to be expressed by Th2 type T cells. Recent studies also implicate MDC as a major component of the host defense against human immunodeficiency virus.

Base Sequence↗
PubMed1991

Alpha-1 antichymotrypsin is increased in human alveolar macrophages by phorbol myristate acetate or lipopolysaccharide and released from these activated macrophages by glucocorticoid.

Alveolar macrophages were obtained from 23 patients and the effects of phorbol myristate acetate (PMA), lipopolysaccharide (LPS), and dexamethasone (DEX) on the proportion of cells with intracellular alpha-1 antichymotrypsin (ACT), and concentrations of ACT in the culture medium were studied in vitro. The alveolar macrophages were obtained by bronchoalveolar lavage at autopsy or from resected lungs at operation and were cultured in suspension for 3 days in medium containing PMA, LPS, DEX, PMA+DEX, or LPS+DEX. Both PMA and LPS significantly increased the percentage of macrophages with intracellular ACT. Dexamethasone did not increase the number of ACT-positive cells and significantly suppressed the increase induced by PMA or LPS, releasing ACT into the culture medium. The release of ACT from macrophages may contribute to the anti-inflammatory effects of corticoids.

Adult↗
PubMed1995

Oxidation of mesangial matrix using a mixed function oxidase system augments adhesion of macrophages: possible role of macrophage scavenger receptors.

Oxygen radicals are believed to play a role in the pathogenesis of aging and glomerular injury. Changes in cellular function may result from modification of the extracellular matrix with which they interact. We produced oxidized mesangial matrix protein using a mixed function oxidase system. Carbonyl content of the oxidized matrix was significantly increased. Adhesion of macrophages to the oxidized mesangial matrix was significantly enhanced, an effect which was significantly abrogated by scavenger receptor blockade with polyinosinic acid or dextran sulfate. Neither polyinosinic acid nor dextran sulfate diminished macrophage adhesion to unmodified matrix. These data demonstrate for the first time that mesangial matrix can undergo oxidation and that such oxidation may promote accumulation of macrophages in the mesangium via interaction of macrophage scavenger receptors with oxidized matrix proteins.

Analysis of Variance↗
PubMed1997

Characterization of a new human macrophage cell line 2MAC. 1. Expression of functional macrophage CD16 (Fc gammaRIIIA/gamma) and tissue factor induction on ligation of HLA-DR.

A human macrophage-like line, designated 2MAC, has been established from peripheral blood. 2MAC expresses a number of lineage-specific markers as well as a broad array of intercellular adhesion molecules. In particular, 2MAC expresses CD16/Fc gammaRIII, the low-affinity Fc receptor for IgG, as well as high levels of HLA class I and class II. Consistent with this macrophage assignment, we present evidence that 2MAC expresses the macrophage form of CD16, namely, Fc gammaRIIIA/gamma. By several criteria also applicable to signal transducing NK CD16 and T cell CD3/TCR complexes, including modulation from the cell surface and Ca2+ mobilization in response to ligation by specific monoclonal antibody, CD16 expressed by 2MAC is functional. Ligation of 2MAC HLA class II, but not HLA class I, by specific mAb induces an increase in free cytoplasmic Ca2+ concentration ([Ca2+]i). This Ca2+ flux appears to be physiologically relevant, as ligation of HLA-DR, but not HLA class I, by mAb results in the efficient, Ca2+ mobilization-dependent induction of tissue factor by 2MAC. 2MAC, therefore, should prove useful for studying signal transduction through macrophage CD16 and HLA class II.

Antibodies, Monoclonal↗
PubMed1988

Correlation between the synergistic effect of liposomes and endotoxins on the activation of macrophage tumoricidal activity and the effect of liposomes on the rough endoplasmic reticulum of macrophages.

Treatment of resident peritoneal macrophages of rats with small unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC SUV) potentiated their activation for tumor cell lysis by endotoxins. The fluorescence polarization of diphenylhexatriene (DPH) embedded in rough endoplasmic reticulum membranes isolated from DPPC SUV-treated macrophages was enhanced. The average fluorescence lifetime of DPH and the rotational correlation time deduced from anisotropy decay were unchanged, whereas the residual anisotropy and hence the order parameter were increased. The measurement of the fluorescence anisotropy of DPH as a function of the temperature showed a phase transition. No phase transition was observed in the rough endoplasmic reticulum membranes of macrophages either treated or not treated with cholesterol/DPPC SUV (1/1; mol/mol). The synergistic effect of DPPC SUV on the tumoricidal activity of macrophages induced by endotoxins appears to be correlated with the changes in the properties of the rough endoplasmic reticulum membranes. Both effects were transient; they had the same kinetics of induction and reversion, and they were both inhibited by cholesterol.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2007

Monocyte macrophage differentiation in vitro: Fibronectin-dependent upregulation of certain macrophage-specific activities.

Transendothelial migration of monocytes followed by their differentiation into macrophages involves interaction of monocytes with subendothelial matrix. The influence of extracellular matrix on monocyte-macrophage differentiation was studied using an in vitro model system with human PBMC maintained on different matrix protein substrata. Upregulation of macrophage specific marker activities such as endocytosis of modified proteins, changes in expression of cell surface antigen, and production of matrix metalloproteinases was studied. Cells maintained on Fibronectin (Fn) showed significantly higher rate of endocytosis and production of MMP2 and MMP9 when compared to other matrix protein substrata. Immunoblot analysis, ELISA, and zymography showed that Fn-dependent upregulation of MMPs was blocked by antibodies to alpha(5)beta(1) integrin indicating that the Fn effect was mediated by integrins. The Fn effect on mo-mPhi was blocked by genistein and herbimycin. As monocytes differentiate to macrophages there was an increase in the rate of production of Fn. These results indicate the influence of the microenvironment of the cell, particularly Fn, on mo-mPhi differentiation and integrin-mediated downstream signaling through focal adhesion kinase and Src type tyrosine kinase is involved in this.

Acetylation↗
PubMed1984

The ontogeny of thymic macrophages: thymic macrophages express Ia from 15 days gestation onwards in the mouse.

This study reports the isolation and enrichment of murine foetal thymic macrophages. The majority of enriched adherent cells of thymus from 15 days gestation onwards were classical macrophages as judged by phagocytosis as well as expression of F4.80 and Fc receptors. In addition, a proportion of foetal thymic macrophages was shown to be Ia+ by double labelling with latex particles and indirect immunofluorescence for surface Ia antigens, and using monoclonal antibodies, it was shown that the Ia+ cells expressed both I-A- and I-E-region-coded determinants. The function of Ia+ macrophages in the developing thymus is discussed.

Animals↗
PubMed1988

Interaction between thymocytes and thymus-derived macrophages. II. Engulfment of thymocytes by macrophages.

A high percentage (80-90%) of immature thymocytes were engulfed by syngeneic thymus-derived macrophages (TDM phi) following cocultivation for 3 days. Elimination occurred via internalization of thymocytes by the macrophages. We unequivocally demonstrated the presence of many live thymocytes inside the TDM phi by means of specific staining. Mature PNA- thymocytes were phagocytized to a lower degree than immature thymocytes, and T splenocytes were not eliminated at all. Bone marrow-derived macrophages internalized immature thymocytes to a degree similar to TDM phi. Since thymocyte survival was not at all affected by M phi culture supernatants alone, we conclude that cell to cell contact is necessary for thymocyte elimination. To identify the surface molecules which participate in internalization of thymocytes by the macrophages, both cell types were pretreated with a variety of agents. Treatment of thymocytes with tunicamycin (N-glycosylation inhibitor) and anti-Lyt-2 mAb decreased their elimination by M phi. Similarly, treatment of M phi with neuraminidase, trypsin, and anti-Ia mAb markedly suppressed their capacity to engulf thymocytes. On the other hand, thymocyte elimination was unaffected by (1) cell cultivation in syngeneic serum rather than heterologous serum; (2) use of allogeneic rather than syngeneic thymocytes; and (3) use of X-irradiated M phi and LPS-activated M phi rather than nontreated M phi.

Animals↗
PubMed1979

Alveolar macrophages. I. A simple technique for the preparation of high numbers of viable alveolar macrophages from small laboratory animals.

A simple technique is described for the collection of substantial numbers of alveolar macrophages by repeated in situ endobronchial lavage. Macrophage recoveries are maximized by the inclusion of the local anaesthetic lignocaine in the lavage fluids. The technique is suitable for mice, rats and guinea pigs, and yields up to 2.4, 6.7 and 25.3 X 10(6) viable macrophages per animal from these 3 species respectively. A one-step adherence procedure yields alveolar macrophages in excess of 95% purity.

Animals↗
PubMed1996

PAF and haematopoiesis XII: macrophage colony-stimulating factor (M-CSF) decreases platelet-activating factor (PAF) acetylhydrolase production in macrophagic J774 cells.

Platelet-activating factor (PAF) is a phospholipid mediator with major immunoregulatory activities. Macrophages produce PAF acetylhydrolase activity, which regulates blood PAF concentrations. Macrophage colony-stimulating factor (M-CSF) is involved in the differentiation and functions of cells from the monocytic/macrophagic lineage. We found that murine macrophagic J774 cells metabolized PAF with lyso PAF as the major metabolite product. As in mouse plasma, the metabolism of PAF by J774 cells was not inhibited by PMSF, p-BPB, DTNB and quinacrine, M-CSF (100-5000 U/ml) significantly decreased PAF acetylhydrolase activity of the J774 cell without exhibiting a significant effect on cell growth. Elevated concentrations of M-CSF are found in blood and tissues during inflammatory states. It could be suggested that a decreased PAF catabolism by tissue macrophages in response to M-CSF may induce local elevated PAF concentrations, thus amplifying the inflammatory response.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Macrophage-stimulating protein differently affects human alveolar macrophages from smoker and non-smoker patients: evaluation of respiratory burst, cytokine release and NF-kappaB pathway.

Macrophage activation is a key feature of inflammatory reactions occurring during bacterial infections, immune responses and tissue injury. We previously demonstrated that human macrophages of different origin express the tyrosine kinase receptor recepteur d'origine nantaise, the human receptor for MSP (RON) and produce superoxide anion (O(2)(-)) when challenged with macrophage-stimulating protein (MSP), the endogenous ligand for RON. This study was aimed to evaluate the role of MSP in alveolar macrophages (AM) isolated from healthy volunteers and patients with interstitial lung diseases (sarcoidosis, idiopathic pulmonary fibrosis), either smokers or non-smokers, by evaluating the respiratory burst, cytokine release and nuclear factor-kappa B (NF-kappaB) activation. MSP effects were compared with those induced by known AM stimuli, for example, phorbol myristate acetate, N-formyl-methionyl-leucyl-phenylalanine, lipopolysaccharide.MSP evokes O(2)(-) production, cytokine release and NF-kappaB activation in a concentration-dependent manner. By evaluating the respiratory burst, we demonstrate a significantly increased O(2)(-) production in AM from healthy smokers or smokers with pulmonary fibrosis, as compared to non-smokers, thus suggesting MSP as an enhancer of cigarette smoke toxicity. Besides inducing interleukin-1 beta (IL-1beta) and interleukin-10 (IL-10) production, MSP triggers an enhanced tumor necrosis factor-alpha release, especially in healthy and pulmonary fibrosis smokers. On the contrary, MSP-induced IL-10 release is higher in AM from healthy non-smokers. MSP activates the transcription factor NF-kappaB; this effect is more potent in healthy and fibrosis smokers (2.5-fold increase in p50 subunit translocation). This effect is receptor-mediated, as it is prevented by a monoclonal anti-human MSP antibody. The higher effectiveness of MSP in AM from healthy smokers and patients with pulmonary fibrosis is suggestive of its role in these clinical conditions.

Aged↗