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)

Bacterial heat shock proteins (hsp) have been shown to be important immunogens stimulating both T cells and B cells. However, little is known concerning the direct interactions between hsp and macrophages. In this study, we demonstrated that treatment of macrophage cultures with purified bacterial hsp, including Legionella pneumophila hsp60, Escherichia coli GroEL, Mycobacterium tuberculosis hsp70, Mycobacterium leprae hsp65, and Mycobacterium bovis BCG hsp65, increased the steady-state levels of cytokine mRNA for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor as well as supernatant IL-1 secretion. This effect was shown not to be due to contamination of the hsp preparations with bacterial lipopolysaccharide. However, not all hsp induced cytokines; M. tuberculosis hsp10 showed minimal activity in our study. These results suggest that bacterial hsp might modulate immunity by rapidly and directly increasing cytokine production in macrophages.
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PMID:Bacterial heat shock proteins directly induce cytokine mRNA and interleukin-1 secretion in macrophage cultures. 796 Jan 55

Infection of macrophages with Legionella pneumophila induces formation of interleukin 1 beta (IL-1 beta), but the molecular basis of this is not understood. Binding of bacteria to macrophage surfaces is the first step in an infection process. Therefore, we examined whether this step was sufficient to increase the cellular level of mRNAs for IL-1 beta and other cytokines. To assess the effect of binding of L. pneumophila on the steady-state levels of cytokine mRNAs, cultures of thioglycolate-elicited macrophages from L. pneumophila-susceptible A/J mice were treated with cytochalasin D and infected with L. pneumophila and the total RNA was extracted for analysis by reverse transcription-PCR with primers for IL-1 alpha, IL-1 beta, IL-6, tumor necrosis factor alpha, granulocyte macrophage colony-stimulating factor, and beta interferon (IFN-beta). L. pneumophila treatment increased the cellular steady-state mRNA levels of all cytokines except IFN-beta. To determine the specificity of this effect, macrophage cultures were treated with cytochalasin D and either bacterial lipopolysaccharide, bovine serum albumin-sensitized latex, Salmonella typhimurium, or Escherichia coli. Lipopolysaccharide treatment increased all mRNAs, bovine serum albumin-sensitized latex had no significant effect, and treatment with S. typhimurium or E. coli increased all mRNAs except that of IFN-beta. These results suggested that the binding of gram-negative bacteria to the macrophage surface was sufficient to induce a unique pattern of cytokine mRNAs. Additional studies that examined the characteristics of the bacterial ligands involved indicated involvement of both heat-labile and heat-stable surface ligands.
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PMID:Binding of Legionella pneumophila to macrophages increases cellular cytokine mRNA. 806 12

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

The attachment of bacteria to macrophages is mediated by different ligands and receptors and induces various intracellular molecular responses. In the present study, induction of cytokines and chemokines, especially granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein 2 (MIP-2), was examined, following bacterial attachment, with regard to the ligand-receptor systems involved. Attachment of Legionella pneumophila or Salmonella typhimurium to cultured mouse peritoneal macrophages increased the steady-state levels of cellular mRNAs for the cytokines interleukin 1beta (IL-1beta), IL-6, and GM-CSF as well as the chemokines MIP-1beta, MIP-2, and KC. However, when macrophages were treated with alpha-methyl-D-mannoside (alphaMM), a competitor of glycopeptide ligands, induction of cytokine mRNAs was inhibited, but the levels of chemokine mRNAs were not. Pretreatment of the bacteria with fresh mouse serum enhanced the level of GM-CSF mRNA but not the level of MIP-2 mRNA. In addition, serum treatment reduced the inhibitory effect of alphaMM on GM-CSF mRNA. These results indicate that bacterial attachment increases the steady-state levels of the cytokine and chemokine mRNAs tested by at least two distinct receptor-ligand systems, namely, one linked to cytokine induction and involving mannose or other sugar residues and the other linked to chemokine induction and relatively alphaMM insensitive. Furthermore, opsonization with serum engages other pathways in the cytokine response which are relatively independent of the alphaMM-sensitive system. Regarding bacterial surface ligands involved in cytokine mRNA induction, evidence is presented that the flagellum may be important in stimulating cytokine GM-CSF message but not chemokine MIP-2 message. Analysis of cytokine GM-CSF and chemokine MIP-2 signaling pathways with protein kinase inhibitors revealed the involvement of calmodulin and myosin light-chain kinase in GM-CSF but not MIP-2 mRNA induction, adding further evidence that several distinct receptor systems are engaged during the process of bacterial attachment and induction of cytokines and chemokines, such as GM-CSF and MIP-2, respectively.
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PMID:Induction of cytokine granulocyte-macrophage colony-stimulating factor and chemokine macrophage inflammatory protein 2 mRNAs in macrophages by Legionella pneumophila or Salmonella typhimurium attachment requires different ligand-receptor systems. 875 34

Nitric oxide (NO) is an intercellular messenger molecule produced by a variety of cells, including macrophages. However, the role of NO in infection, especially its immunological role, is poorly understood. In the present study, the role of NO in Legionella pneumophila-infected macrophages was examined. Whereas infection of mouse macrophages in vitro with L. pneumophila did not induce detectable NO, when the macrophages were primed with interferon-gamma (IFN-gamma), the treated macrophages markedly inhibited bacterial replication and produced a large amount of NO. Treatment with NO inhibitors, such as NG-monomethyl-L-arginine (L-MMA) or aminoguanidine, as well as culture in arginine-free medium, significantly inhibited NO production; however, the anti-L. pneumophila activity induced by IFN-gamma was not diminished. Examination of cytokine levels in L. pneumophila-infected macrophages primed with IFN-gamma revealed a moderate increase of interleukin-6 (IL-6) production; however, inhibition of NO by L-MMA markedly increased IL-6 production. Reconstitution of NO in the L. pneumophila-infected macrophages primed with IFN-gamma and treated with L-MMA to inhibit endogenous NO production following addition of sodium nitroprusside reduced IL-6 production to normal levels. The levels of IL-6 mRNA in L-MMA-treated macrophages were the same as in nontreated macrophages, as demonstrated by quantitative RT-PCR. Thus, these results indicate that NO may regulate IL-6 production independently of its role in antimicrobial function in L. pneumophila-infected macrophages and their immunoregulation on IL-6 production may be due to a post-transcriptional mechanism.
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PMID:Immunoregulatory role of nitric oxide in Legionella pneumophila-infected macrophages. 880 92

Heat-shock proteins (hsp) are chaperon molecules important in protein folding and assembly. Furthermore, they may have functions in immunoregulatory processes, like T-cell stimulation and antigen presentation, which are not yet fully understood. It has been shown that several hsp of various species and family derivations modulate functions in macrophage immunity by directly increasing cytokine production. In the present study we showed that the 60,000 MW hsp of Legionella pneumophila (Lp-hsp 60) increased cellular steady-state levels of interleukin-1 beta (IL-1 beta) mRNA measured by quantitative reverse transcription-polymerase chain reaction and Northern blotting as well as IL-1 secretion, when added to cultures of thioglycollate-elicited mouse peritoneal macrophages in vitro. The level of mRNA increased in a dose-dependent manner with a minimum effective concentration of 0.5 microgram/ml and peaked 3 hr after stimulation. Lp-hsp 60-coated latex beads also increased IL-1 beta mRNA levels in the presence of cytochalasin D, which inhibits bead uptake but permits binding, indicating that binding to the macrophage surface was sufficient for induction. Accumulation of IL-1 beta mRNA was completely blocked by pretreatment with the protein kinase C (PKC) inhibitor, H7, but not decreased by prior treatment with cycloheximide. The cell lysates of macrophages stimulated with Lp-hsp 60 showed an increased PKC activity measured by phosphorylation of PKC pseudosubstrate. The IL-1 bioactivity in culture supernatants after 24 hr of stimulation with Lp-hsp 60 was increased in a dose-dependent manner but at hsp concentrations in excess of those needed to increase mRNA. Thus, the present study demonstrates that Lp-hsp 60 rapidly increases the steady-state level of IL-1 beta mRNA, possibly through a cell surface receptor system involving a PKC-dependent signalling pathway.
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PMID:Legionella pneumophila heat-shock protein-induced increase of interleukin-1 beta mRNA involves protein kinase C signalling in macrophages. 894 27

Marijuana contains both psychoactive and nonpsychoactive cannabinoids which have varying effects on the immune response system. Previous studies with delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, showed that this substance augmented the susceptibility of mice to infection with the opportunistic pathogen Legionella pneumophila. The present study compared the enhancement of Legionella-induced mortality in mice due to two other major of marijuana components, cannabinol and cannabidiol, as well as the synthetic psychoactive cannabinoid CP 55,940. Inbred BALB/c mice, relatively resistant to infection with Legionella, were given the marijuana component 1 day before and 1 day after a sublethal intravenous infection with Legionella. Unlike the effect of THC, an 8 mg/kg dose of either cannabinol or cannabidiol did not affect mortality of the mice sublethally infected with Legionella. Mice given a 16 mg/kg dose of these components of marijuana, however, showed a slight to moderately increased mortality following the sublethal infection with Legionella. In contrast, a dose of 6 mg/kg of the synthetic psychoactive cannabinoid CP 55,940 given 1 day before and 1 day after infection with Legionella resulted in about 50% of the animals dying, the same level of augmentation of lethality induced by THC. Liver, spleen, and lung tissues were removed from the surviving mice 24 hr after the second THC injection and tested for the presence of viable Legionella using a standard CFU assay. The mice injected with THC before and after infection showed significantly higher levels of bacteria in their lung than mice that were not given any cannabinoid but were infected sublethally with the Legionella. Mice injected with the other cannabinoids, including the synthetic cannabinoid, showed a much smaller increase in the number of Legionella in their lung when infected with Legionella and treated with the drug. The number of bacteria recovered from the kidney and liver of the mice regardless of treatment with a cannabinoid, including with THC, did not show significant changes. RNA isolated from the spleen of the THC- and Legionella-treated animals was examined to determine at the molecular level whether acute phase pro-inflammatory cytokines (i.e., IL-1, IL-6 and TNF-alpha) were altered following drug treatment and infection, since previous studies had shown there were increased serum levels of these cytokines in the mice. It was found that the mRNA levels for IL-1 remained generally constant regardless of whether the infected animals were treated with a cannabinoid. However, the mRNA level for IL-6 was markedly increased following treatment of the infected animals with THC, suggesting the possible involvement of this pro-inflammatory cytokine in increased mortality. The mRNA level for TNF-alpha was generally low and not significantly altered in the drug treated animals. Mice given other cannabinoids, including cannabinol and cannabidiol, as well as the synthetic CP 55,940, showed no significant change in the level of mRNA for any of the cytokines tested.
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PMID:Psychoactive cannabinoids increase mortality and alter acute phase cytokine responses in mice sublethally infected with Legionella pneumophila. 901 63

On the assumption that specific host defences are lower in newborn and infant animals, the susceptibility of CD1 suckling mice to Legionella pneumophila was studied with the hypothesis that this model could detect consistent differences in virulence among Legionella isolates from various clinical and environmental sources. Mice 3-14 days old were indeed markedly susceptible to intraperitoneal challenge with fresh clinical isolates, but not to serially subcultured or type collection strains of L. pneumophila. For example, intraperitoneal inoculation of 10(7) cells of a fresh clinical isolate of L. pneumophila (strain Monza 3) caused 60% mortality of suckling mice in 1 day whereas the same number of cells of a culture-attenuated derivative (strain Monza 3p50) caused <10% mortality in >15 days. Lethal infection by the 'virulent' Monza 3 strain was strictly dependent on mouse age (no death was observed in mice >26 days old), required the inoculation of viable cells and was not related to endotoxin production. The 'virulent' L. pneumophila strain was cleared from mouse lungs less rapidly, while adhering to, and being internalised into the peritoneal exudate cells (PEC) of suckling mice to a greater extent, than the avirulent derivative, as shown by immunofluorescence and confocal microscopy. The Monza 3 strain also induced the production by PEC in vivo of 5-to-10 times more tumour necrosis factor-alpha (TNF-alpha) mRNA than the Monza 3p50 strain. Overall, suckling CD1 mice appear to provide a promising, easily handled, highly reproducible and relatively inexpensive animal model for studies of the virulence of L. pneumophila, and possibly, of the role of pro-inflammatory cytokine production in this phenomenon.
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PMID:Suckling CD1 mice as an animal model for studies of Legionella pneumophila virulence. 951 12

The ability of Legionella species to multiply within human mononuclear phagocytes is usually regarded as being associated with their pathogenicity. Activation of host cells results in inhibition of intracellular Legionella multiplication. The most effective substance to induce macrophage activation, both in vivo and in vitro, is interferon-gamma. In addition, some evidence exists that macrophage-derived cytokines may contribute to the host defense against L. pneumophila, but the production of pro- and antiinflammatory cytokines by monocytes after infection with different Legionella species has not been reported with regard to their ability to multiply within the host cells. We therefore examined the production of TNF-alpha, IL-1, IL-6, IL-8, IL-10 and TGF-beta by Mono Mac 6 cells after infection with Legionella species of different human prevalence that differ in their ability to replicate within this macrophage-like cell line. After infection, Mono Mac 6 cells showed a cytokine response with time kinetics characteristic for the cytokine. Maximum cytokine levels produced differed with Legionella species, but were not related to intracellular multiplication rates. Moreover, LPS-tolerant Mono Mac 6 cells, which failed to produce cytokines, showed intracellular increase or decrease of bacterial numbers identical to that of untreated Mono Mac 6 cells. By FACS analysis, an up-regulation of CD14 (LPS receptor) and CD54 (ICAM-1) could be demonstrated. We conclude that, in the Mono Mac 6 cell line, induction of macrophage-derived cytokines after infection with members of the genus Legionella mimics an inflammatory reaction without association with intracellular multiplication rate.
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PMID:Induction of cytokines and expression of surface receptors in Mono Mac 6 cells after infection with different Legionella species. 953 66

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


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