UMLS:C0023241 - FACTA Search

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Query: UMLS:C0023241 (Legionella)
6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of interferon (IFN)-gamma, rat alveolar macrophages, and Legionella pneumophila was studied in vitro to define the effector cell potential of alveolar macrophages against an intracellular pathogen in a model in which the efficacy of IFN-gamma could be tested in vivo. Alveolar macrophages preincubated with IFN-gamma up-regulated Ia antigen and killed 0.5-4 logs of L. pneumophila over 4 days compared with 1-2 logs of bacterial growth in untreated cells. The bactericidal effect was dose dependent, evident over a wide range of bacterial inocula, and not suppressed by hydrocortisone. Preincubation with IFN-gamma was unnecessary and insufficient, as intracellular replication was reversed by exposure to IFN-gamma up to 48 h after infection, and neutralization of IFN-gamma after infection permitted bacterial growth. IFN-gamma thus converts alveolar macrophages from target cells to effector cells in host defense against L. pneumophila and may be of therapeutic benefit in legionellosis.
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PMID:Recombinant murine interferon-gamma reversibly activates rat alveolar macrophages to kill Legionella pneumophila. 143 Dec 53

Similar to guinea pig macrophages and human monocytes, macrophages from the peritoneal cavity of thioglycolate pretreated A/J mice are permissive for growth of Legionella pneumophila. In contrast, macrophages from BDF1 mice are not permissive for L. pneumophila. Lymphocytes from A/J and BDF1 mice proliferated in response to Legionella Ag but guinea pig lymphocytes did not. Also, splenocyte cultures from A/J mice treated with either Con A or Legionella vaccine produced supernatants which induced A/J macrophages to restrict Legionella growth, but guinea pig splenocyte culture supernatants obtained after stimulation with L. pneumophila vaccine did not induce Legionella growth restriction activity by guinea pig macrophages. Murine rIFN-gamma but not rIFN-alpha markedly inhibited growth of Legionella in A/J mouse macrophages and monoclonal anti-IFN-gamma antibody neutralized the anti-Legionella activity of culture supernatants from A/J mouse splenocytes responding to Legionella Ag. From these data, IFN-gamma appears to be an important factor in anti-Legionella activity of Ag-activated mouse splenocyte culture supernatants. Cyclosporin A, when given to either A/J or BDF1 mice, reduced the proliferation responses of splenocytes to T cell mitogens and also decreased the IFN production of A/J spleen cells to Legionella Ag. In addition, drug treatment decreased the resistance of A/J mice to Legionella infection as shown by an increase in the number of viable bacteria in the liver. However, injection of drug treated mice with lymphokine-rich splenocyte culture supernatant reconstituted the resistance of these animals. These results suggest an important role for lymphocyte activation and lymphokine production in the resistance of A/J mice to Legionella infection. The greater resistance of BDF1 mice, however, may result from nonpermissive macrophages and responsive lymphocytes. In the case of guinea pigs, susceptibility to Legionella infections may result from both the permissive nature of the macrophages and the relatively unresponsive nature of the lymphocytes in these animals.
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PMID:Differing macrophage and lymphocyte roles in resistance to Legionella pneumophila infection. 172 75

Formalin-killed Legionella pneumophila bacterial cells, as well as a purified cell wall preparation (designated F-1 antigen) containing lipopolysaccharide (LPS), stimulated production of interferons (IFNs) in mouse spleen cell cultures. L. pneumophila whole-cell vaccine induced an IFN that was pH 2 labile and neutralized by anti-IFN-gamma indicating that IFN-gamma was the dominant form present. F-1 antigen induced a mixture of IFNs, depending upon the age of the culture and cell types present. In freshly prepared whole-spleen cultures and in 2-h adherent cultures, F-1 induced predominantly IFN-alpha/beta. In whole-spleen cultures that were allowed to age for 24 to 48 h before stimulation, F-1 was seen to induce mostly IFN-gamma, with low levels of IFN-alpha/beta present. Since only IFN-alpha/beta was produced in T-cell-depleted populations (at 2 h or at 48 h), it is suggested that T cells are responsible for IFN-gamma production in aged cultures. Additionally, heat-treated F-1, Escherichia coli LPS, and heat-treated E. coli LPS all induced similar levels of IFN-gamma in whole-splenocyte or nonadherent cell cultures which were incubated 48 h before stimulation. This suggests that LPS present in F-1 is responsible for IFN-gamma production and that an activated cell population is required. These results show that L. pneumophila antigens can induce the production of various types of IFN in mouse spleen cell cultures through several mechanisms.
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PMID:Kinetics and characterization of interferon production by murine spleen cells stimulated with Legionella pneumophila antigens. 241 62

Legionella pneumophila has been shown to induce gamma interferon (IFN-gamma) both in vitro and in vivo during experimental infections of mice. With complement-mediated serologic depletion of murine splenocytes, the cellular sources of IFN-gamma following in vitro stimulation with L. pneumophila antigens were Thy-1.2+, Lyt-2-, L3T4-, and asialo-GM1+, which is consistent with the natural killer (NK) cell phenotype. Additionally, Percoll density discontinuous centrifugation demonstrated that maximal production of IFN coincided with high NK activity in fractions which were enriched for large granular lymphocytes. Furthermore, 18- to 24-h incubation of splenocytes with L. pneumophila whole-cell vaccine resulted in augmented NK cytotoxic activity against YAC-1 tumor target cells in a 51Cr release assay. The addition of macrophages to purified large granular lymphocyte populations augmented both IFN-gamma production and NK activity, suggesting that antigen is required for optimal responses. In an experimental infection model using an intratracheal inoculation route, NK activity was enhanced in the spleen, peripheral blood, and lung cells of infected mice, with maximal stimulation in the lung leukocytes at the site of infection. The results of the present study indicate that NK cells respond in vivo and in vitro to stimulation by L. pneumophila by producing IFN-gamma and by increased cytolytic activity.
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PMID:Role of gamma interferon in induction of natural killer activity by Legionella pneumophila in vitro and in an experimental murine infection model. 312 79

Human alveolar macrophages activated by human rIFN-gamma inhibit the intracellular multiplication of Legionella pneumophila, an intracellular bacterial pathogen and the agent of Legionnaires' disease. Activation of alveolar macrophages with IFN-gamma is dose dependent; significant inhibition of L. pneumophila multiplication (mean 1.60 +/- 0.20 logs) is achieved consistently with concentrations of IFN-gamma of greater than or equal to 2 x 10(-2) micrograms/ml (220 U/ml). Activation of alveolar macrophages is also time dependent. In macrophages treated continuously after explantation, macrophages infected at 48 to 96 h after explantation are more inhibitory than macrophages infected at 24 h after explantation. In macrophages not treated continuously after explantation but treated for various lengths of time before infection, the longer their exposure to IFN-gamma before infection, the greater the inhibition of L. pneumophila multiplication (96 greater than 72 greater than 48 greater than 24 h). IFN-gamma-activated alveolar macrophages exhibit morphologic signs of activation, including increased size, spreading, and aggregation. This paper demonstrates that a human resident macrophage can be activated with IFN-gamma such that it exhibits enhanced antimicrobial activity against a relevant pathogen.
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PMID:IFN-gamma-activated human alveolar macrophages inhibit the intracellular multiplication of Legionella pneumophila. 313 22

We examined the ability of two recombinant human cytokines, granulocyte-macrophage colony-stimulating factor (rHu-GM-CSF) and interferon-gamma (rHu-IFN-gamma) to activate antibacterial mechanisms in human pulmonary macrophages (PM) and peripheral blood monocytes (PBM). Growth of Legionella pneumophila (LP) was assessed in PM or PBM which had been exposed to either rHu-IFN-gamma (500-1000 u/ml) or rHu-GM-CSF (1 to 10,000 u/ml). In both PM and PBM exposed to 500 u/ml rHu-IFN-gamma, growth of LP was reduced compared to cells exposed to media alone. By comparison, exposure of these cell types to rHu-GM-CSF had no detectable effect on bacterial replication. In order to investigate potential mechanisms accounting for this observation, the effect of these cytokines on the hydrogen peroxide (H2O2)-releasing capacity of cells was studied. Exposure of PM and PBM to rHu-IFN-gamma (500 to 1000 u/ml) resulted in increased production of H2O2 triggered by phorbol myristate acetate; when subjected to the same experimental conditions, rHu-GM-CSF-exposed cells exhibited no increase in H2O2 production. To further clarify the role of rHu-IFN-gamma-induced augmentation of oxidative metabolism on cellular inhibition of bacterial growth, an amount of catalase capable of completely neutralizing extracellular H2O2 was added to cells before and during infection. This did not abrogate the antibacterial activity of rHu-IFN-gamma. These studies demonstrate that rHu-IFN-gamma but not rHu-GM-CSF is capable of augmenting the capacity of PM and PBM to restrict LP growth. These data suggest that the antibacterial activity of rHu-IFN-gamma in this system may involve oxidative as well as nonoxidative mechanisms.
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PMID:Cytokine activation of antibacterial activity in human pulmonary macrophages: comparison of recombinant interferon-gamma and granulocyte-macrophage colony-stimulating factor. 314 84

In vitro immune responses to Legionella pneumophila were investigated. When human peripheral blood lymphocytes (PBL) from healthy volunteers were stimulated with formalin-killed L. pneumophila for 7 days in vitro, strong proliferative responses were observed. The responding cells were shown to be a CD4 T cell subset. It was also found that the CD4 T cells secreted significant amounts of IFN-gamma into the PBL culture supernatant. The production of IFN-gamma and IL-4 by PBL was measured semiquantitatively by reverse transcriptase-assisted polymerase chain reaction (RT-PCR) methods. Formalin-killed or live L. pneumophila-stimulated PBL expressed the mRNA for IFN-gamma but not the mRNA for IL-4. The results suggest that the whole bacterium, as opposed to the supernatant, predominantly stimulates Th1 type helper T cells. The cloned T cells specific for L. pneumophila expressed the mRNA for IFN-gamma but not for IL-4. In contrast to formalin-killed or live L. pneumophila stimulation, when PBL were stimulated with the bacterial culture supernatant, the proliferating T cells produced the mRNA for IL-4 as well as for IFN-gamma. A significant correlation between the proliferative response to formalin-killed L. pneumophila and IFN-gamma release in culture was observed (r = 0.6932, P < 0.001) in PBL from 30 healthy volunteers. From these in vitro studies, it is suggested that the whole L. pneumophila bacterium and their soluble antigens stimulate T cells in a manner which results in a different pattern of cytokine production.
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PMID:Interferon-gamma (IFN-gamma) production by human T lymphocytes upon Legionella pneumophila stimulation in vitro. 781 13

The differentiation of HL-60, a human leukemic cell line, into monocyte-like cells (D3-HL-60 cells) is induced by 1,25-dihydroxyvitamin D3 (D3). We examined the effects of interferon (IFN) treatment of D3-HL-60 cells on the expression of cell surface antigens, the phagocytic activity for fluorescent beads, production of oxygen radicals, and intracellular growth of Legionella pneumophila. Activation of D3-HL-60 cells with IFN-gamma, Beta, and alpha for 24 h significantly increased expression of CD16, CD36, CD71, and HLA-DR antigens. IFN-gamma markedly enhanced the phagocytic activity of beads in D3-HL-60 cells. There was no significant difference in phagocytic activity between cells exposed to IFN-alpha or beta and untreated D3-HL-60 cells. IFN-alpha, beta, and gamma enhanced production of oxygen radicals, including superoxide, by D3-HL-60 cells. Superoxide production was enhanced to the greatest degree by IFN-gamma, followed by IFN-beta and then IFN-gamma. Intracellular growth of L. pneumophila in D3-HL-60 cells was inhibited by interferons (IFN-gamma > beta > gamma). Similar results were obtained in human mononuclear cells. These data indicate that interferons can act as biologic response modifiers not only in human mononuclear cells but also in differentiated leukemic cells. Our results may have implications for the development of differentiation therapy for treatment of leukemia.
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PMID:Effects of interferon-alpha, beta, and gamma on the function of differentiated leukemic HL-60 cells induced by 1,25-dihydroxyvitamin D3. 872 74

Legionella pneumophila is a facultative intracellular pathogen that parasitizes human alveolar macrophages and blood monocytes recruited to the lungs. The inhibitory cytokines IL-10, TGF-beta, and IL-4 generally deactivate macrophages and permit enhanced microbial growth in some models of intracellular infection, but their effects on human alveolar macrophages are unknown. We hypothesized that inhibitory cytokines could facilitate the infection of human alveolar macrophages and monocytes by virulent intracellular lung pathogens. Therefore, we tested the effects of IL-10, TGF-beta, and IL-4 in an in vitro model of human alveolar macrophage and monocyte infection with L. pneumophila. We found that unstimulated alveolar macrophages supported over 100-fold greater L. pneumophila growth than did unstimulated monocytes. IL-10 treatment significantly enhanced L. pneumophila growth in monocytes, and completely reversed the protective effect of IFN-gamma against intracellular L. pneumophila replication. IL-10 had similar but less potent effects on alveolar macrophages. In contrast, TGF-beta and IL-4 had no significant effects on L. pneumophila growth in resting or IFN-gamma-activated monocytes or alveolar macrophages. IL-10 blocked TNF-alpha production by infected cells, but exogenous TNF-alpha did not reverse the activating defect in cells cocultured with IFN-gamma and IL-10. Finally, L. pneumophila-infected monocytes produced substantially more IL-10 than did infected alveolar macrophages. In summary, IL-10 significantly enhances the growth of L. pneumophila in human monocytes, reverses the protective effect of IFN-gamma, blocks TNF-alpha secretion, and is secreted by infected monocytes and alveolar macrophages. Induction of IL-10 may be a virulence mechanism that promotes intracellular bacterial replication in human legionellosis.
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PMID:IL-10 enhances the growth of Legionella pneumophila in human mononuclear phagocytes and reverses the protective effect of IFN-gamma: differential responses of blood monocytes and alveolar macrophages. 880 54

To facilitate identification of the effector mechanism(s) responsible for gamma interferon (IFN-gamma)-mediated host resistance to Legionella pneumophila, a murine model of legionellosis in BALB/c mice with a targeted disruption in the IFN-gamma gene (gamma knockout [GKO] mice) was developed. Immunocompetent BALB/c mice and GKO mice were inoculated intratracheally with virulent L. pneumophila (10(6) bacteria per mouse), and bacterial clearance and the pulmonary inflammatory response were assessed. L. pneumophila did not replicate in, and was rapidly cleared from, the lungs of immunocompetent BALB/c mice, demonstrating that immunocompetent BALB/c mice are resistant to replicative L. pneumophila pulmonary infections. In contrast, similarly infected GKO mice developed persistent, replicative intrapulmonary L. pneumophila infections with extrapulmonary dissemination of the bacteria to the spleen. Histopathologic and flow cytometric analysis of L. pneumophila-infected lung tissue demonstrated that while immunocompetent BALB/c mice develop multifocal pneumonitis which resolves, similarly infected GKO mice develop diffuse pneumonitis with persistent neutrophil recruitment into the lung. Intratracheal administration of exogenous IFN-gamma to L. pneumophila-infected GKO mice facilitated intrapulmonary clearance of the bacteria, confirming the pivotal role of IFN-gamma in innate host defenses to L. pneumophila lung infection in this murine host. The potential role of endogenous reactive nitrogen intermediates, including nitric oxide (NO), in IFN-gamma-mediated resistance to L. pneumophila pulmonary infections in immunocompetent BALB/c mice was subsequently assessed. Macrophage inducible nitric oxide synthetase (an enzyme responsible for the production of NO) was induced in alveolar cells from L. pneumophila-infected immunocompetent BALB/c mice (with maximal expression at 48 h postinfection) but was not induced in similarly infected GKO mice. However, administration of the NO synthetase inhibitor N-monomethyl-L-arginine did not significantly inhibit clearance of L. pneumophila from the lung of immunocompetent BALB/c mice (compared with that in similarly infected mice not administered N-monomethyl-L-arginine). In contrast, we have previously demonstrated that IFN-gamma-induced host resistance to replicative L. pneumophila lung infections in a susceptible murine host (A/J mice) is mediated, in part, by endogenous NO. Taken together, these studies identify a differing role of endogenous NO in IFN-gamma-mediated resistance to L. pneumophila pulmonary infection in susceptible and resistant murine hosts.
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PMID:Effector mechanisms responsible for gamma interferon-mediated host resistance to Legionella pneumophila lung infection: the role of endogenous nitric oxide differs in susceptible and resistant murine hosts. 894 59

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