Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharides derived from cell walls of Gram-negative bacteria have proven a useful tool to simulate bacterial infection of the central nervous system. Rapid activation of microglia within the brain parenchyma as well as in vitro has thereby been shown to be an early event upon bacterial or lipopolysaccharide challenges. Less is known about microglial responses to a contact with Gram-positive bacteria, such as Streptococcus pneumoniae, a lethal pathogen causing meningitis with a 30% mortality rate. In the present study, we compared lipopolysaccharide-induced microglial activation in vitro with that induced by preparations of pneumococcal cell walls. As a readout of microglial activation, we studied by patch-clamp recording the expression of outward rectifying potassium currents (IK+OR), which are known to be induced by lipopolysaccharide. We found that pneumococcal cell walls and lipopolysaccharide induced a similar type of IK+OR. Stimulation of IK+OR by pneumococcal cell walls and lipopolysaccharide involved protein synthesis since it was not induced in the presence of cycloheximide. Pharmacological characterization of the pneumococcal cell wall- and lipopolysaccharide-induced currents with specific ion channel blockers indicated for both cases expression of the charybdotoxin/margatoxin-sensitive Kv1.3 subtype of the Shaker family of voltage-dependent potassium channels. Activation of the outward currents by pneumococcal cell walls depended on the developmental stage: while lipopolysaccharide triggered IK+OR in both embryonal and postnatal microglial cells, pneumococcal cell walls had only a marginal effect on embryonal cells. This, however, does not imply that embryonic microglial cells are unresponsive to pneumococcal cell walls. In both embryonic and postnatal cells, (i) the amplitude of the constitutively expressed inward rectifying potassium current was significantly reduced, (ii) tumor necrosis factor-a was released and (iii) the cells changed their morphology, similarly as it was induced by lipopolysaccharide treatment. Thus, embryonic microglial cells are sensitive to pneumococcal cell wall challenges, but respond with a distinctly different pattern of physiological reactions. The expression of IK+OR could thus be a suitable tool to study signalling cascades selectively involved in the activation of microglia by Gram-negative and -positive cell wall components and to functionally distinguish between populations of microglial cells.
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PMID:Induction of potassium channels in mouse brain microglia: cells acquire responsiveness to pneumococcal cell wall components during late development. 1036 22

Streptococcus suis capsular type 2 is an important etiological agent of swine meningitis, and it is also a zoonotic agent. Since mononuclear phagocytes have been suggested to play a central role in the pathogenesis of meningitis, the objective of the present study was to evaluate the capacity of whole killed S. suis type 2 organisms to induce the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) by murine macrophages. Induction of cytokines was evaluated in the presence or absence of phorbol ester (phorbol 12-myristate 13-acetate [PMA]) costimulation. Results showed that S. suis type 2 stimulated the production of both cytokines in a concentration- and time-dependent fashion. Although large doses of bacteria were required for maximal cytokine release, titers were similar to those obtained with the lipopolysaccharide (LPS) positive control. An increase in cytokine release was observed with both S. suis and LPS with PMA costimulation. Experiments with cytochalasin-treated macrophages showed that the stimulation of cytokine production was phagocytosis independent. When macrophages were stimulated with an unencapsulated mutant, an increase in TNF production was observed, but the absence of the capsule had no effect on IL-6 production. In fact, whereas purified capsular polysaccharide of S. suis failed to induce cytokine release, purified S. suis cell wall induced both TNF and, to a lesser extent, IL-6. IL-6 secretion probably requires some distinct stimuli which differ from those of TNF. Finally, the S. suis putative virulence factors suilysin and extracellular protein EF showed no cytokine-stimulating activity. The ability of S. suis to trigger macrophages to produce proinflammatory cytokines may have an important role in the initiation and development of meningitis caused by this microorganism.
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PMID:Heat-killed Streptococcus suis capsular type 2 strains stimulate tumor necrosis factor alpha and interleukin-6 production by murine macrophages. 1045 11

The diagnosis of human neurobrucellosis usually relies on the detection of antibodies to Brucella lipopolysaccharide (LPS) in cerebrospinal fluid (CSF) by agglutination tests or enzyme-linked immunosorbent assay (ELISA). Here we describe the detection of immunoglobulin G (IgG) to cytoplasmic proteins (CP) of Brucella spp. by ELISA and Western blotting in seven CSF samples from five patients with neurobrucellosis. While IgG to CP (titers of 200 to 12, 800) and IgG to LPS (800 to 6,400) were found in the CSF of these patients, these antibodies were not detected in CSF samples from two patients who had systemic brucellosis without neurological involvement. The latter, however, had serum IgG and IgM to both LPS and CP. No reactivity to these antigens was found in CSF samples from 14 and 20 patients suffering from nonbrucellar meningitis and noninfectious diseases, respectively. These findings suggest that, in addition to its usefulness in the serological diagnosis of human systemic brucellosis, the ELISA with CP antigen can be used for the specific diagnosis of human neurobrucellosis.
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PMID:Detection of antibodies to Brucella cytoplasmic proteins in the cerebrospinal fluid of patients with neurobrucellosis. 1047 31

Gram-positive Streptococcus pneumoniae is the major pathogen causing lethal meningitis in adults. We used pneumococcal cell walls (PCW) to investigate microglial consequences of a bacterial challenge and to determine the role of serum in the activation process. PCW caused the characteristic induction of an outwardly rectifying K+ channel (IK+(OR)), together with a concomitant suppression of the constitutively expressed inward rectifier K+ current, and evoked the release of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), IL-12, KC, macrophage inflammatory protein (MIP) 1alpha and MIP-2. Serum presence strongly facilitated the PCW effects, similarly as observed for lipopolysaccharide (LPS) from gram-negative Escherichia coli. The inflammatory cytokine, interferon-gamma (IFNgamma) induced the same electrophysiological changes, but independent of serum. Recombinant LPS binding protein (LBP) could partially replace serum activity in LPS stimulations. In contrast, neither LBP nor an antibody-mediated blockade of the LPS receptor, CD14 had significant influences on PCW-inducible changes. Cell surface interactions and cofactor involvement in microglial activation by gram-positive bacteria are thus distinct from the mechanisms employed by LPS. Moreover, tyrphostin AG126, a protein kinase inhibitor that prevents activation of the mitogen-activated protein kinase, p42MAPK (ERK2), potently blocked the PCW-stimulated cytokine release while having only a limited effect on LPS-inducible cytokines. In contrast, AG126 did not influence IK+(OR) inductions. This indicates that PCW recruits more than 1 intracellular signaling pathway to trigger the various responses and that different bacterial agents signal through both common and individual routes during microglial activation.
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PMID:Microglial activation by components of gram-positive and -negative bacteria: distinct and common routes to the induction of ion channels and cytokines. 1051 31

Bacterial meningitis is a disease worsened by neutrophil-induced damage in the subarachnoid space. In this study, the A2A adenosine receptors on human neutrophils were characterized, and the role of A2A receptors on the trafficking of leukocytes to the cerebrospinal fluid and on blood-brain barrier permeability (BBBP) was assessed in a rat meningitis model. Neutrophils bind the A2A selective antagonist, 125I-ZM241385 (Bmax=843 receptors/neutrophil; KD=0.125 nM). A selective A2A receptor agonist, WRC-0470 (2-cyclohexylmethylidene-hydrazinoadenosine; 0.03-1 microM), alone and synergistically with the type IV phosphodiesterase inhibitor, rolipram, increased neutrophil [cAMP]i and reduced cytokine-enhanced neutrophil adherence, superoxide release, and degranulation. These effects of WRC-0470 were reversed by ZM241385 (100 nM). In a lipopolysaccharide-induced rat meningitis model, WRC-0470 (0-0.9 microgram/kg/h), with or without rolipram (0-0.01 microgram/kg/h), inhibited pleocytosis and reduced the lipopolysaccharide-induced increase in BBBP, indicative of decreased neutrophil-induced damage.
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PMID:Neutrophil A2A adenosine receptor inhibits inflammation in a rat model of meningitis: synergy with the type IV phosphodiesterase inhibitor, rolipram. 1051 15

To detect endogenous nitric oxide (NO) produced in a rat bacterial meningitis model, the authors applied an electron paramagnetic resonance (EPR) NO-trapping technique. Iron complex with N,N-diethyldithiocarbamate were used as a trapping agent. Experimental meningitis was induced by a mixture of lipopolysaccharide and interferon-gamma. Sequential changes of NO formation under meningitis were observed in rat brain tissue by using X-band (9 GHz) EPR spectroscopy, and endogenous NO was detected in the head of a living rat with a 700-MHz EPR system. Inducible NO synthase mRNA expression in the brain tissues also was proven by using a reverse transcriptase-polymerase chain reaction technique.
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PMID:Direct evidence of in vivo nitric oxide production and inducible nitric oxide synthase mRNA expression in the brain of living rat during experimental meningitis. 1056 63

The CD14 antigen, an important cell surface molecule of monocytic cells, is involved in cellular activation: it binds lipopolysaccharide and other cellular lipid structures. Brain macrophages play a pivotal role during inflammatory reactions of the CNS parenchyma, ventricles and meninges. A soluble form of CD14 (sCD14) was measured in paired cerebrospinal fluid (CSF) and serum samples from 91 patients with different neurological diseases. Mean levels of circulating sCD14 in CSF in a control group of 22 patients with neurologic complaints but no neurological deficit on clinical examination were 0.19 +/- 0.06 (mean +/- SD) mg/l. The CSF/blood ratios of sCD14 was 49 +/- 16 x 10(-3), while those of albumin were 4.4 +/- 1.4 x 10(-3). These extremely high CSF/blood ratios of the sCD14 molecule compared to albumin indicate a local cerebral production. No significant changes in CSF sCD14 levels were found in patients with non-inflammatory neurological diseases (NID). In contrast, CSF sCD14 levels were markedly elevated during acute meningitis, but there was no direct correlation between sCD14 and monocyte count in the CSF. Thus, sCD14 could not originate in the CSF compartment from monocytes alone. The highest values for sCD14 were found in CSF during infections with various pathogens such as Staphylococcus aureus or Listeria monocytogenes. While sCD14 serum levels dramatically increased during acute bacterial meningitis, sCD14 ratios did not correlate with albumin ratios during the course of disease. Therefore, increased CSF sCD14 may originate from cerebral production by activated or infiltrated macrophages rather than passive diffusion from the blood, while elevated sCD14 serum levels resulted from enhanced local production. Increased CSF and serum sCD14 values were also observed in meningitis caused by viral infection. As in bacterial meningitis, sCD14 in CSF specimens did not correlate with the function of the blood/CSF barrier. Repeated lumbar punctures revealed a normalization of CSF sCD14 levels during clinical recovery. These results provide the first evidence for local production of sCD14 within the CNS. Our findings further indicate that sCD14 in CSF is a reliable marker for activation of macrophages within the CNS during inflammatory processes.
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PMID:Cerebrospinal fluid levels of soluble CD14 in inflammatory and non-inflammatory diseases of the CNS: upregulation during bacterial infections and viral meningitis. 1058 Jul 99

Haemophilus influenzae is a small, nonmotile, non-spore-forming bacterium, and a strict parasite of humans found principally in the upper respiratory tract. The production of capsule is of major significance to clinicians since it is an important virulence factor. We described six antigenically distinct capsular types, designated a-f. Spread from one individual to another occurs by airborne droplets or by direct contagion with secretions. Haemophilus influenzae produces at least two factors that inhibit the ciliary activity of human epithelial cells in vitro. One of this has been shown to be lipopolysaccharide and the other factor is of low molecular weight, most likely a heat-stable glycopeptide. Type b strains are distinguished by the production of capsular polysaccharide composed of repeating units of ribosyl-ribitol phosphate, account for greater than 95 percent of systemic infections in children. Two contrasting patterns of Haemophilus influenzae disease can be identified. The first and the most serious in its consequences is invasive infection such as meningitis, septic arthritis, epiglottitis, and cellulitis in which bacteremia is a prominent feature; these infections are usually caused by type b strains and occur in young children. The second category includes less serious but numerically more common infections, that occur as a result of contiguous spread of Haemophilus influenzae within the respiratory tract; e.g. otitis media, sinusitis. These latter infections are usually, but not invariably, caused by unencapsulated strains. A provisional diagnosis of meningitis, epiglottitis, facial cellulitis, or septic arthritis will usually be prompted by the history and clinical findings. Confirmation requires microbiologic studies. Cultures of blood, CSF and other normally sterile fluids are diagnostic and therefore under the appropriate circumstances mandatory. Whenever feasible, specimens obtained for culture should also the gram-strained. Detection of capsular antigen in serum, CSF or concentrated urine using immunoelectrophoresis, latex agglutination or enzyme linked immunosorbent assay may be diagnosed and can be found in up to 90 percent of culture proved cases of meningitis. Without treatment, infection due to Haemophilus influenzae can be rapidly fatal, particularly by meningitis and epiglottitis. There is currently a trend to use certain parenteral third generation cephalosporins as initial therapy when lifethreatening Haemophilus influenzae infection is known or suspected in children beyond the neonatal period, commonly used agents included cefotaxime or ceftriaxone. Antibiotic therapy is only one facet of the management of the child with Haemophilus influenzae infection, and critical attention must also be given to supportive therapy. In the ambulatory setting, ampicillin or amoxicillin for 10 days is often satisfactory for the less severe Haemophilus influenzae infections. Cephalosporins are often chosen for treatment of adults, with pneumonia when Haemophilus influenzae is documented.
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PMID:[Clinical manifestations, diagnosis and treatment of Haemophilus influenzae infection]. 1089 74

Thalidomide, a psychoactive drug that readily crosses the blood-brain barrier, has been shown to possess immunomodulatory attributes, including the inhibition of cytokine production by monocytes and microglia. In this study, we investigated the effect of thalidomide on chemokine production by human microglial cells. Microglial cells were stimulated with lipopolysaccharide, a key cell-wall component of gram-negative bacteria responsible for meningitis, and production of chemokines (regulated upon activation normally T cell expressed and secreted [RANTES], monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, and interleukin [IL]-8) was examined by ELISA. Thalidomide treatment was found to cause potent and selective inhibition of IL-8 production in a dose-responsive manner. This inhibition was associated with decreased intracellular IL-8 staining as well as reduced transcription of IL-8 mRNA. In addition, thalidomide treatment of lipopolysaccharide-stimulated microglia inhibited the activation of protein NF-kappaB, a transcription factor known to be important for IL-8 production. These results suggest thalidomide could have a therapeutic role in acute bacterial meningitis through inhibition of IL-8-mediated neutrophil chemotaxis.
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PMID:Effect of thalidomide on chemokine production by human microglia. 1095 Aug 3

Interleukin-8 (IL-8) is elevated in the cerebrospinal fluid (CSF) of patients with meningitis and is proposed to participate in subarachnoid-space pleocytosis. However, intracisternal injection of IL-8 into rabbits failed to induce indices typical of meningitis (leukocyte, tumor necrosis factor, or protein accumulation in the CSF or histopathological changes), indicating that merely increasing the CSF level of this chemokine is insufficient to induce inflammation in this anatomical site. IL-8 treatment did not affect inflammatory responses to subsequently intracisternally administered lipopolysaccharide (LPS). IL-8 was chemotactic for rabbit neutrophils in vitro, and subcutaneous injection of IL-8 (diluted in buffer or CSF) proved the in vivo activity of this peptide and suggested the absence of an IL-8 inhibitor in normal rabbit CSF. LPS-dependent pleocytosis was only slightly diminished by intracisternally administered murine anti-rabbit IL-8 monoclonal antibody (MAb) WS-4 but was dramatically reduced by intravenously administered MAb. Therefore, elevated CSF IL-8 levels may contribute to, but cannot solely account for, neutrophil influx into the subarachnoid space during meningitis. However, inhibition of IL-8 activity of the bloodstream side of the blood-brain barrier effectively reduces pleocytosis, indicating a central role of IL-8 in neutrophil influx into CSF during bacterial meningitis. Thus, inhibition of IL-8 is a possible therapeutic target for adjunct treatment of meningitis.
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PMID:Systemic neutralization of interleukin-8 markedly reduces neutrophilic pleocytosis during experimental lipopolysaccharide-induced meningitis in rabbits. 1099 82


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