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

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

Resistance to infection with Legionella pneumophila is primarily dependent upon cell-mediated immunity rather than humoral immunity. Recent evidence suggests that activation of cell-mediated immunity depends on Th1 cells and activation of humoral immunity depends on Th2 cells. In this report, delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid of marijuana and an immunomodulator, suppressed development of secondary immunity to L. pneumophila, which correlated with a reduction in Th1 activity. BALB/c mice, infected with a primary sublethal dose of L. pneumophila, developed resistance to a larger challenge infection 3 to 4 weeks later. However, intravenous injection of THC (4 mg/kg of body weight) 1 day prior to primary infection resulted in increased mortality after the challenge infection. The level of anti-L. pneumophila antibodies in serum increased in both THC-treated and control mice; however, in the THC group IgG1 antibodies which are stimulated by Th2 cells were elevated while Th1-regulated, IgG2a antibodies were depressed. Furthermore, cultured splenocytes from THC-treated mice had less L. pneumophila-specific lymphoproliferation, indicating a deficiency in cell-mediated immunity. Normal mouse splenocytes treated in vitro with THC and pokeweed mitogen showed suppressed production of gamma interferon, a cytokine associated with Th1 cells, but increased production of interleukin 4, a cytokine produced by Th2 cells. Splenocytes from THC-treated mice, stimulated in vitro with either pokeweed mitogen or anti-CD3 antibodies, also produced less gamma interferon, indicating less Th1 activity in these mice. These results suggest that THC decreases the development of anti-L. pneumophila immunity by causing a change in the balance of Th1 and Th2 activities.
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PMID:Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection. 806 21

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

The inflammatory response and influence of T cell depletion on the pathogenesis of an experimental Legionella infection were studied. A/J mice were infected with 10(6) CFU of Legionella pneumophila intratracheally. With this dose all infected animals survived the infection and bacteria were cleared from lung, spleen, liver, and kidney within 10 to 11 days, leaving no residual changes in the affected organs. Inflammatory cells were recruited into the lung on the second day of infection, reaching a maximum on the third day and filling out predominantly the interstitial areas. During the first 3 days after inoculation, mainly macrophages, B cells, NK cells, and large mononuclear cells of an unknown phenotype were attracted into the lung interstitium, whereas T lymphocytes infiltrated subsequently. During the early phase of infection, serum concentrations of IFN-gamma, TNF-alpha, IL-1beta, IL-4, and IL-6 but not IL-2 increased dramatically. The cytokine secretion decreased on the third day after infection although bacteria were still present in the lung or even disseminated in different organs. Successful clearance of bacteria from the lung was not observed before recruitment of T cells into the lung. In mice depleted of both CD4+ and CD8+ T cells, control of infection was impaired and lethality of infection increased. Depletion of either subset left residual antibacterial mechanisms, which, however, were not sufficient to clear the Legionella as rapidly as in undepleted mice.
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PMID:Legionella pneumophila infection in intratracheally inoculated T cell-depleted or -nondepleted A/J mice. 955 86

Serum samples from 14 patients with Legionella pneumonia were examined for the presence of cytokines. In spite of high levels of serum C-reactive protein in all patients during the acute phase in only four cases (one involving interleukin-1beta [IL-1beta], three involving IL-6, and none involving tumor necrosis factor alpha) was the concentration of cytokines more than 100 pg/ml. Th2 cytokines IL-4 and IL-10 were detected in only one patient each. In contrast, significant increases of serum gamma interferon (IFN-gamma) and IL-12 levels were observed during the acute phase in 6 and 11 cases, respectively. Interestingly, although serum IFN-gamma levels diminished thereafter, in seven cases IL-12 levels remained high or increased further during the convalescent phase. In an additional 22 cases clinically suspected to be but not diagnosed as Legionella pneumonia, increases of serum IL-12 levels were observed in 16 cases, whereas the remaining 6 cases showed no detectable IL-12. Our results demonstrate the relative predominance of Th1 cytokine production in Legionella pneumonia. Although the role and significance of prolonged increases in IL-12 levels in Legionella disease are unknown, our results should prompt further investigation of the host immune response in terms of Th1 and Th2 balance in legionellosis.
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PMID:Serum cytokines in patients with Legionella pneumonia: relative predominance of Th1-type cytokines. 960 98

Legionella pneumophila, the causative agent of legionnaires' disease, is a gram-negative pleomorphic bacillus and fastidious in its growth in artificial medium. These bacteria grow readily intracellularly, including growth in macrophages and other phagocytic cells. Humoral antibodies develop readily to these bacteria not only in infected patients, but also in persons who have had subclinical exposure. High-levels of serum antibodies may also occur in individuals who recover from infection. However, cell-mediated immunity based on lymphocytes reacting with the organisms and cytokines produced by such lymphocytes are important in resistance. Vaccines prepared from killed Legionella or their components readily induce cell-mediated immunity. Immune resistance to disease depends on lymphocyte-based immunity, activating cytokine formation, some of which activate macrophages to resist infection. Resistance to Legionella infection by experimental animals such as mice correlates with activation of macrophages, which can inhibit replication of the bacteria. Much recent experimental work has involved studies using inbred animals, including inbred mice genetically resistant to Legionella versus mice genetically susceptible. Detailed studies show that regulation of macrophage resistance versus susceptibility to infection is mediated by specific genetic mechanisms. Induction of cytokines by Legionella can activate immune cells, especially helper T cells. Th 1 type helper cells that produce type 1 class cytokines, such as interferon gamma and interleukin-2 (IL-2), are known to be important in cellular immunity to Legionella as well as to other opportunistic intracellular bacteria. In contrast, Th 2 type helper cells, which secrete type 2 class cytokines such as IL-4, IL-5, and IL-6, activate B lymphocytes to produce humoral antibodies important in resistance to extracellular bacteria which secrete toxins and extracellular factors as compared to intracellular bacteria such as Legionella. Although Legionella, similar to other ubiquitous opportunistic pathogens, can cause serious infection in immunocompromised individuals, these bacteria have many distinguishing characteristics, such as very rapid replication in macrophages from susceptible individuals. However, activated macrophages restrict the growth of these bacteria. Infection by Legionella, if recognized clinically, can be readily treated with appropriate antibiotics. Currently, many studies are in progress concerning the mechanism of pathogenicity and assessment of the molecular biologic mechanisms of protective immune responses to this bacterium, which causes serious infection in immunocompromised individuals.
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PMID:Immunologic response and pathophysiology of Legionella infection. 964 87

The marijuana cannabinoid, delta 9-tetrahydrocannabinol (THC), suppresses immunity to Legionella pneumophila and development of Th1 activity and cell-mediated immunity. In the current study, THC effects on cytokines regulating the development of Th1 cells were examined. BALB/c mice showed significant increases in serum IL-12 and IFN-gamma within hours of infection; however, the levels of these Th1-promoting cytokines as well as resistance to a challenge infection were suppressed by THC (8 mg/kg) injected 18 h before priming. The Th2-promoting cytokine, IL-4, was increased within hours of a Legionella infection and was further increased by THC treatment. These results suggested that THC injection suppressed the cytokine environment promoting Th1 immunity. In additional experiments, THC pretreatment and infection of IL-4 knockout mice showed that serum IL-12 and IFN-gamma were suppressed equally in both knockout and normal mice. This suggested that the drug-induced increase in IL-4 was not responsible for the decreases in serum IL-12 and IFN-gamma. However, THC treatment was shown to suppress the expression of IL-12 receptor beta 2 mRNA, indicating that, in addition to suppression of IL-12, THC injection suppressed the expression of IL-12 receptors. Finally, the role of cannabinoid receptors in Th1-promoting cytokine suppression was examined, and results with receptor antagonists showed that both cannabinoid receptors 1 and 2 were involved. It is suggested that suppression of Th1 immunity to Legionella is not due to an increase in IL-4 production but to a decrease in IFN-gamma and IL-12. Furthermore, both types of cannabinoid receptors are involved.
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PMID:Delta 9-tetrahydrocannabinol treatment suppresses immunity and early IFN-gamma, IL-12, and IL-12 receptor beta 2 responses to Legionella pneumophila infection. 1084 2

Infection of BALB/c mice with a sublethal concentration of Legionella pneumophila causes an acute disease that is resolved by innate immune responses. The infection also initiates the development of adaptive Th1 responses that protect the mice from challenge infections. To study the early responses, cytokines induced during the first 24 h after infection were examined. In the serum, interleukin-12 (IL-12) was detectable by 3 h and peaked at 10 h, while gamma interferon was discernible by 5 h and peaked at 8 h. Similar patterns were observed in ex vivo cultures of splenocytes. A transient IL-4 response was also detected by 3 h postinfection in ex vivo cultures. BALB/c IL-4-deficient mice were more susceptible to L. pneumophila infection than were wild-type mice. The infection induced higher serum levels of acute-phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-1beta, and IL-6), and reducing TNF-alpha levels with antibodies protected the mice from death. Moreover, the addition of IL-4 to L. pneumophila-infected macrophage cultures suppressed the production of these cytokines. Thus, the lack of IL-4 in the deficient mice resulted in unchecked TNF-alpha production, which appeared to cause the mortality. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is induced by IL-4 during Listeria monocytogenes infection, was detected at between 2 and 30 h after infection. However, MCP-1 did not appear to be induced by IL-4 or to be required for the TNF-alpha regulation by IL-4. The data suggest that the early increase in IL-4 serves to regulate the mobilization of acute phase cytokines and thus controls the potential harmful effects of these cytokines.
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PMID:Induction of interleukin-4 (IL-4) by legionella pneumophila infection in BALB/c mice and regulation of tumor necrosis factor alpha, IL-6, and IL-1beta. 1094 49

We have reported that injection of marijuana cannabinoids, such as Delta(9)-tetrahydrocannabinol (THC), into mice, followed by infection with Legionella pneumophila (Lp), suppresses the development of cell-mediated immunity T helper 1 (Th1) activity. These effects are accompanied by suppression of interleukin (IL)-12 and interferon (IFN) gamma production and enhancement of IL-4 production suggesting THC-induced T helper cell biasing. In the current report, other T helper cell biasing mechanisms were studied. Mice were injected with THC followed 18 h later by a challenge infection with Lp. Two-hour post-infection, spleens were removed and analyzed for mRNA to either IL-12Rbeta2 or GATA3 gene products. The results showed that THC suppressed IL-12Rbeta2 but increased GATA3. Receptor antagonists for CB1 (SR141716A, SR1) and CB2 (SR144528, SR2) were also injected to analyze the involvement of cannabinoid receptors. It was determined that SR1 attenuated the THC suppression of IL-12Rbeta2, while SR2 attenuated the increase in GATA3 mRNA. These results suggest that THC suppresses Th1 biasing activity such as IL-12Rbeta2 by a CB1 mediated mechanism and enhances the Th2 biasing activity, GATA3, by a CB2 mechanism. This dichotomy of receptor involvement might result from differential expression and/or signaling function of CB1 and CB2 on Th1 and Th2 cells.
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PMID:Cannabinoid receptors and T helper cells. 1474 35

Legionella pneumophila infection of mice induces proinflammatory cytokines and Th1 immunity as well as rapid increases in serum levels of IL-12 and IFNgamma and splenic IL-12Rbeta2 expression. Delta-9-tetrahydrocannabinol (THC) treatment prior to infection causes a shift from Th1 to Th2 immunity and here we demonstrate that CB(1) and CB(2) cannabinoid receptors mediate different aspects of the shift. Using cannabinoid receptor antagonists and cannabinoid receptor gene deficient mice (CB(1) (-/-) and CB(2) (-/-)), we showed that both CB(1) and CB(2) receptors were involved in the THC-induced attenuation of serum IL-12 and IFNgamma. IFNgamma production is dependent upon signaling through IL-12Rbeta2 (beta2) and THC treatment suppressed splenic beta2 message; moreover, this effect was CB(1) but not CB(2)-dependent from studies with receptor antagonists and CB1(-/-) and CB2(-/-) mice. Furthermore, observed increases in IL-4 induced by THC, were not involved in the drug effect on beta2 from studies with IL-4 deficient mice. The GATA-3 transcription factor is necessary for IL-4 production and is selectively expressed in Th2 cells. GATA-3 message levels were elevated in spleens of THC-treated and L. pneumophila-infected mice and the effect was shown to be CB(2) but not CB(1)-dependent. Furthermore, GATA-3 regulatory factors were modulated in that Notch ligand Delta4 mRNA was decreased and Jagged1 increased by THC also in a CB2-dependent manner and splenic NFkappaB p65 was increased. Together, these results indicate that CB(1) and CB(2) mediate the THC-induced shift in T helper activity in L. pneumophila-infected mice, with CB(1) involved in suppressing IL-12Rbeta2 and CB(2) involved in enhancing GATA-3.
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PMID:CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection. 1879 85


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