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)

Dexamethasone inhibits lipopolysaccharide-induced synthesis of the cytokine, interleukin-1 beta, in cerebrospinal fluid of patients with bacterial meningitis. Along with monocytes, astrocytes are capable of producing lipopolysaccharide-induced interleukin-1 beta in the central nervous system. The objective of this study was to investigate the induction of interleukin-1 beta mRNA by lipopolysaccharide, and the inhibition of this process by dexamethasone, in human astrocytes using the astrocytoma cell line U-373MG as a model system. Dexamethasone-mediated inhibition of induction of interleukin-1 beta mRNA by lipopolysaccharide required a functional glucocorticoid receptor. In contrast to monocytes, lipopolysaccharide induction of interleukin-1 beta mRNA in U-373MG cells required de novo protein synthesis. Dexamethasone also had no effect on lipopolysaccharide-induced interleukin-1 beta transcriptional initiation in U-373MG cells. U-373MG cells were similar to monocytes, however, with respect to the ability of dexamethasone to decrease interleukin-1 beta mRNA half-life. These findings demonstrate that the mode of lipopolysaccharide induction of interleukin-1 beta mRNA, and inhibition of this process by dexamethasone, can vary in different cell types.
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PMID:Protein synthesis-dependent induction of interleukin-1 beta by lipopolysaccharide is inhibited by dexamethasone via mRNA destabilization in human astroglial cells. 759 67

The objective of adjunct anti-inflammatory therapy of bacterial meningitis is the containment of heightened inflammation caused by lysis of bacteria by antibiotics. This can be modelled by giving two consecutive intra-cisternal injections of lipopolysaccharide (LPS) to rabbits, the first at 0 h to induce inflammation to mimic that occurring during the proliferation of bacteria in the cerebrospinal fluid (CSF), and the second at 6 h to mimic inflammation subsequent to antibiotic-induced bacterial lysis. Injection of 2.5 ng of LPS induced pleocytosis at 4 h which was preceded by a peak of tumour necrosis factor (TNF) activity at 2 h. A subsequent injection of 25 ng of LPS at 6 h induced second peaks of pleocytosis and CSF TNF. Dexamethasone (1.5 mg/kg, i.v.) administered 15 min or 1 h before the second injection of LPS tended only to reduce CSF TNF, but effectively prohibited further pleocytosis. Brain TNF alpha mRNA levels were unchanged at 6 and 7 h after LPS injection, and were unaffected by dexamethasone. These results indicate that the subarachnoid space is distinct from the general circulation in that the TNF-producing cells present do not display a hypo-responsive state towards LPS as occurs when LPS is injected systemically. Furthermore, dexamethasone is able to attenuate the secondary inflammatory response resulting from a second LPS injection without eliminating a second peak of TNF activity.
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PMID:Dexamethasone treatment of lipopolysaccharide-induced meningitis in rabbits that mimics magnification of inflammation following antibiotic therapy. 760 53

Mannan-binding protein (MBP), a calcium-dependent plasma lectin, may play a role in the innate defence against microorganisms. After binding to carbohydrate structures at the bacterial surface, MBP activates the classical pathway of the complement system. To investigate the binding capacity of MBP to various bacteria associated with meningitis, an assay was developed to study the binding of MBP to bacteria grown in a semisynthetic fluid culture medium. Salmonella montevideo (containing a mannose-rich lipopolysaccharide (LPS)), used as a positive control strain, showed binding of radiolabelled MBP at a level of 80% compared with binding of MBP to zymosan. Binding of labelled MBP to Salm. montevideo was time-dependent, temperature-dependent and saturable. The binding was inhibited by unlabelled MBP, by mannose and by N-acetyl-D-glucosamine. Among bacterial pathogens often found to cause meningitis, a wide range of MBP binding capacities could be determined. The encapsulated Neisseria meningitidis (representatives from 11 serogroups other than group A were included: n = 22), N. mucosa (n = 1), Haemophilus influenzae type b (n = 10) and Streptococcus agalactiae (n = 5) had a low MBP binding capacity of 21.7% (95% confidence interval (CI) 3.3-40.1%). Escherichia coli K1 (n = 11), Strep. suis (n = 5), Strep. pneumoniae (n = 10) and N. meningitidis serogroup A (n = 2) showed intermediate MBP binding capacity of 58.4% (95% CI 40.0-76.8%). A third group consisting of non-encapsulated Listeria monocytogenes (n = 11), non-encapsulated H. influenzae (n = 2), non-encapsulated N. meningitidis (n = 2), N. cinera (n = 1) and N. subflava (n = 1) strains had a high MBP binding capacity of 87.5% (95% CI 62.5-112.5%). The majority of encapsulated pathogens causing bacterial meningitis seem to have a rather low MBP binding capacity.
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PMID:Binding of mannan-binding protein to various bacterial pathogens of meningitis. 808 95

The E. coli endotoxin 0111 B4, a lipopolysaccharide (LPS), in a dose of 200 ng/kg body weight/50 microl artificial cerebrospinal fluid (CSF) was given intracisternally to 14-day-old rats. Four hours later CSF, blood and urine were sampled, and consecutive brain sections from the hypothalamic area of the brain were prepared for in situ hybridization. The LPS treatment resulted in a significant (p<0.001) pleocytosis and an elevation of the protein content of the CSF. There were no changes observed in the chemical parameters of the CSF, plasma, blood or urine, i.e. vasopressin (VP) levels, osmolality, Na+ and K+ concentrations, glucose level, pH, bicarbonate or PaCO2, PaO2 values. LPS injection, however, resulted in a significantly (p<0.01) increased VP mRNA level (121% of the control value) in the supraoptic nuclei (SON), but not in the paraventricular nuclei (PVN), as compared to controls. Our findings suggest an early effect of LPS on VP gene expression selectively in the SON of 14-days-old rats. This animal model might be suitable for studying the regulation of VP gene expression and the role of this peptide in the pathogenesis of bacterial meningitis in pediatric patients.
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PMID:Differential regulation of vasopressin gene expression in the hypothalamus of endotoxin-treated 14-day-old rat. 1042 32

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

A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-alpha and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.
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PMID:Immunoglobulin A1 protease, an exoenzyme of pathogenic Neisseriae, is a potent inducer of proinflammatory cytokines. 1052 3

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

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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