Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023241 (Legionella)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice were inoculated with Legionella pneumophila via an intratracheal route to establish an experimental model of infection. Lung lavage fluid obtained from infected mice contained a cytolytic factor identified as tumor necrosis factor (TNF). Peak levels of TNF were produced at about 24 h postinfection and rapidly declined thereafter. Treatment of the mice with dextran sulfate before inoculation with the bacteria resulted in lowered amounts of TNF in the lung lavage fluid, suggesting that macrophages were responsible for production of the cytokine. Furthermore, cultures of adherent lung leukocytes and a macrophage cell line, PU 5-1.8, were stimulated to produce TNF by exposure to Legionella antigens. In addition, adherent lung leukocytes from Legionella-infected mice spontaneously released TNF into the culture supernatant. Inoculation of mice with saline or latex particles failed to induce TNF in vivo, indicating that bacterial antigens or products were the stimulating signals. Since there was no detectable TNF activity in sera at any time after intratracheal inoculation, TNF production appeared to be confined to the site of infection. Pretreatment of PU 5-1.8 cultures with gamma interferon, which was detected in the lung lavage fluid before TNF, resulted in augmented TNF production, suggesting cooperativity may exist between the two cytokines, either in the pathogenicity of the bacterium or in a possible immunomodulatory function of TNF and interferon during infection.
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PMID:Induction of tumor necrosis factor by Legionella pneumophila. 243 20

Tumor necrosis factor (TNF) was found in the lung lavage fluids of Legionella pneumophila-infected mice within 24 hr of intratracheal (i.t.) inoculation. Since this cytokine has been reported to activate polymorphonuclear leukocyte (PMN) function, the effect of TNF on the in vitro bactericidal capacity of PMN-enriched cultures was determined. Murine thioglycollate-elicited PMN which were treated with recombinant human TNF demonstrated augmented killing of L. pneumophila bacteria in vitro. Furthermore, treatment of PMN suspensions with cytokine-containing lung lavage fluid was found to enhance the bactericidal activity of PMN. The addition of anti-cachectin/TNF antibodies partially abrogated the stimulatory effects of the lavage fluid, suggesting that in vivo activation of PMN during the course of infection was likely, and that TNF was partially responsible for the enhanced bactericidal activity. In vivo treatment of animals with TNF resulted in significant protection of the animals from mortality. Furthermore, the rate of clearance of bacteria from the lung tissues of infected mice was increased in those animals treated with TNF, and correlated with the ability of this cytokine to protect the animals. These data suggest that the induction of TNF by Legionella bacteria during infection are involved in the non-specific host defense mechanisms, and that PMN activated by the TNF may be instrumental in clearing the organism from infected lung tissues, thereby protecting the animal.
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PMID:Protective effects of tumor necrosis factor in experimental Legionella pneumophila infections of mice via activation of PMN function. 316 17

We have studied the interaction between virulent Legionella pneumophila and human alveolar macrophages, the resident phagocytes at the site of infection in Legionnaires' disease. L. pneumophila multiplied 2.5-5 logs within 3 d, as measured by colony forming units, when incubated with freshly explanted alveolar macrophages in monolayer culture. At the peak of bacterial multiplication, the alveolar macrophage monolayers were destroyed. L. pneumophila multiplied more rapidly in 4-d-old than in freshly explanted alveolar macrophages. Inside alveolar macrophages, L. pneumophila were located within membrane-bound vacuoles whose cytoplasmic sides were studded with ribosomes. Alveolar macrophages that were incubated with concanavalin A (Con A) stimulated human mononuclear cell supernatants (cytokines), inhibited L. pneumophila multiplication, and the degree of inhibition was proportional to the concentration of Con A supernatant added. Anti-L. pneumophila antibody in conjunction with complement promoted phagocytosis of L. pneumophila by alveolar macrophages. By electron microscopy, most (75%) of the phagocytized L. pneumophila were intracellular. However, freshly explanted alveolar macrophages were able to kill only 0-10% of an innoculum of L. pneumophila even in the presence of antibody and complement. At the same time, alveolar macrophages also killed opsonized Escherichia coli poorly. Increasing the ratio of macrophages to bacteria, adhering the macrophages to microcarrier beads, or preincubating the macrophages for 24 or 48 h with Con A supernatants failed to augment alveolar macrophage killing of opsonized E. coli. Corticosteroids appear to increase patient susceptibility to Legionnaires' disease. However, pretreatment of alveolar macrophages and monocytes with hydrocortisone had no influence on intracellular multiplication of L. pneumophila or on the inhibition of that multiplication by activated alveolar macrophages or monocytes. Hydrocortisone did impair cytokine-induced aggregation of alveolar macrophages. These findings demonstrate that L. pneumophila multiplies in human alveolar macrophages and that they do so within a ribosome-lined phagosome; that freshly explanted alveolar macrophages kill few L. pneumophila even in the presence of antibody and complement; that activated alveolar macrophages inhibit L. pneumophila multiplication; and that steroids do not exert a direct suppressive effect on the anti-L. pneumophila activity of activated or nonactivated alveolar macrophages. Our findings indicate that alveolar macrophages may play a central role in both the pathogenesis of Legionnaires' disease and in host defense against it. This paper shows that human resident macrophage can be activated to a higher state of antimicrobial capacity and that the human alveolar macrophage can serve as an effector call in call-mediated immunity.
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PMID:Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. 647 Jan 40

Delta 9-Tetrahydrocannabinol (THC) injection modulates immune cell function, but the significance of this in altering host resistance to infection is not understood. In addition, exposure to THC and other drugs of abuse during infection is associated with an acute mortality syndrome. We examined the effect of THC injection on the survival of mice infected with Legionella pneumophila (Lp). Mice given two injections of THC (8 mg/kg)-one 24 hr before and the second 24 hr after a sublethal Lp infection-experienced acute collapse and death. The drug injection after infection caused death; deaths occurred within 30 min after the injection, and neither one nor two drug injections before infection resulted in death. The THC-induced mortality resembled cytokine-mediated shock in both kinetics and symptoms; therefore, sera from drug-treated animals were measured for the acute-phase cytokines tumor necrosis factor (TNF) and interleukin 6 (IL6). The level of each cytokine was significantly elevated by THC treatment, suggesting a role in the observed mortality. To directly test this role, mice were administered a single injection of either anti-TNF alpha, anti-IL6, or a mixture of anti-IL1 alpha and -IL1 beta antibodies 1 hr before the second THC injection. Results showed that each antibody treatment protected the mice, with anti-IL6 being the most effective. Fluctuations in blood granulocytes levels also supported a role of acute-phase cytokines in THC-induced mortality. These results show that THC injection increases the blood levels of acute-phase cytokines in infected animal and that these elevated levels, at least in part, account for the mortality induced by THC injection.
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PMID:Delta 9-tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. 750 99

The effect of interleukin-1 beta (IL 1 beta) on spatial learning was examined. In one experiment, C57BL/6 mice were given daily injections (100 ng/mouse) of recombinant murine IL1 beta prior to training on the Morris water maze. In another experiment, mice were infected with a sublethal dose of a gram-negative bacterium (Legionella pneumophila; Lp). Mice rendered ill by the infection were given either anti-IL1 beta antibodies (100 micrograms/mouse) or saline and then trained on the water maze. Results indicated that (1) exogenous IL1 beta blocked acquisition of spatial learning, (2) Lp infection attenuated learning on this task, and (3) neutralizing circulating IL1 beta in Lp-infected mice normalized learning despite the continuation of the illness. The data indicate that cognitive impairment may be a component of cytokine-mediated sickness behavior.
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PMID:Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta. 754 35

THC, the major psychoactive component of marijuana, has been shown both in humans and experimental animals to have immunomodulatory properties. For example, marijuana smokers may show impaired immunological functions, including deficiency of blood leukocyte blastogenesis to mitogens. Detailed studies with mice have shown that animals given THC can show marked immunomodulation, including suppression of antibody formation, deficient cytokine production, etc. However, recent studies have also shown that lymphoid cells evince enhanced production or release or IL1, but suppression of IL2 and interferon production. Such lymphoid cells treated in vitro with THC also show suppressed blastogenesis to antigens and mitogens, suppressed NK activity, etc. In contrast, it has recently been shown that THC can enhance production or release of pro-inflammatory cytokines. This includes release of these cytokines from macrophages, including augmented release of IL1, TNF alpha, and IL6 activity. Susceptibility of mice to infection with opportunistic organisms such as L. pneumophila has been found and this increased susceptibility can be modulated by THC. A toxic shock-like death to Legionella has been induced by THC treatment given one day before and one day after infection. Receptors to THC have been detected in the brain as well as in peripheral tissues, including lymphoid cells. Thus, immunomodulation induced by THC may be related to receptor effects as well as unrelated to such receptors. It is clear that THC and other cannabinoids are excellent tools for studying the mechanisms of immune modulation, especially altered susceptibility to microbial infection.
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PMID:Marijuana, receptors and immunomodulation. 766 40

Infecting mice with the opportunistic intracellular pathogen Legionella pneumophila markedly inhibited place learning of infected C57BL/6 mice as determined by the Morris water maze test. Mice infected with L. pneumophila evinced much less ability to learn the position of a hidden platform than did normal noninfected mice, which quickly learned the location of the hidden platform and escaped from the cool water of the pool with increasing efficiency. However, infected mice treated with anti-interleukin-1 (anti-IL-1) neutralizing antibody learned the task with about the same efficiency as the controls. When the animals were tested 1 week after learning, control animals remembered the task well and were able to escape with near maximal efficacy. On the other hand, L. pneumophila-infected mice performed as poorly after the 1 week rest as during the training period, indicating that infection blocked learning and not merely performance. Mice infected with L. pneumophila and given the antibody treatment were found to be indistinguishable from controls in that they remembered the task and escaped with good efficiency. Thus, the results of this study suggest that the pro-inflammatory cytokine, IL-1 beta, is involved, at least partly, in the attenuation of spatial navigational learning in mice infected acutely with a sublethal concentration of L. pneumophila. These results, therefore, suggest that cognitive impairment of L. pneumophila-infected mice may be related to the cytokine IL-1 beta and, furthermore, that cytokines may be related to learning and memory changes experienced by individuals suffering acute bacterial infections.
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PMID:Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta. 767 1

Cytokine production in macrophages infected by bacteria is critical for the course of infection. However, it is not known how infection of macrophages with opportunistic bacteria leads to cytokine production in different populations of cells. Since it is possible that cytokine genes may be differentially regulated by attachment rather than by active infection, the levels of various cytokine mRNAs were measured in alveolar macrophages (AMs), peritoneal resident macrophages (RMs), and peritoneally elicited macrophages (EMs) interacting with Legionella pneumophila by using cytochalasin D-treated macrophages and a newly developed quantitative reverse transcription-PCR procedure with high-performance liquid chromatographic analysis to determine cytokine mRNA formation. Increased levels of interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein 2 mRNAs were quantitated in the macrophages responding to L. pneumophila attachment in vitro. Using this technique, we showed that the three different macrophage populations responded differently to bacterial attachment. We found that the levels of IL-6 and granulocyte-macrophage colony-stimulating factor mRNAs induced by the attachment of L. pneumophila to AMs were significantly lower than the levels in RMs but similar to the levels in EMs. Furthermore, the levels of MIP-2 mRNA in the AMs were found to be higher than those in the RMs, but similar levels were found in EMs. IL-1 beta mRNA levels were higher in both AMs and RMs than in EMs, but tumor necrosis factor alpha levels were not different among the three macrophage populations examined. Thus, the responses of macrophages to bacterial attachment in terms of cytokine mRNA levels were readily quantitated by the reverse transcription-PCR assay. However, the results obtained showed different levels of responsiveness of distinct macrophage populations to L. pneumophila attachment, and this could be related to the characteristic nature of the macrophage type examined.
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PMID:Quantitative reverse transcription-PCR analysis of Legionella pneumophila-induced cytokine mRNA in different macrophage populations by high-performance liquid chromatography. 771 7

The major psychoactive component of marijuana, delta 9-tetrahydrocannabinol (THC), has been shown to suppress the functions of various immune cells. However, the relationship of these findings to THC-induced suppression of host resistance to infection has not been firmly established. In this report, we review the literature concerning THC's effects on cytokine production and resistance to infection with Legionella pneumophila (Lp). Recent reports have linked THC-induced immunomodulation with drug-induced modulation of the cytokine network. Specifically, THC in vivo suppresses interferon (IFN) production while in vitro modulates the production of tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-2 receptor (IL-2R). These results suggested that THC treatment might alter host immunity by disrupting the cytokine network. Immunity and resistance to infection with Lp depends upon the activation of killer cells and the stimulation of the cytokine network. THC injection into rodents was observed to augment acute phase cytokine mobilization in response to a primary Lp infection; on the other hand, the drug suppressed the development of protective immunity and resistance to secondary Lp infection by causing a change in the profile of T helper cell cytokines produced by Th1 and Th2 cells. Thus, it appears that THC injection suppresses resistance to Lp infection by disrupting the cytokine network. Regarding the molecular mechanisms of these effects of THC, data is reviewed concerning the role of cannabinoid receptors (CR) in cells of the immune system. In summary, the literature to date supports the role of THC as an immunomodulator capable of suppressing resistance to infection through mechanisms involving alteration of the cytokine network. The role of CR receptors in these events has yet to be determined.
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PMID:delta 9-Tetrahydrocannabinol, cytokines, and immunity to Legionella pneumophila. 777 82

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


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