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)

There is evidence that the cytokine tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-alpha exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-alpha expression from astrocytes induced by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), and interleukin 1 beta (IL-1 beta). Astrocytes secrete TNF-alpha in response to LPS alone, and can be primed by IFN-gamma to enhance LPS-induced TNF-alpha production. IFN-gamma and IL-1 beta, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-alpha production alone, but act synergistically to stimulate astrocyte TNF-alpha expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-alpha gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-alpha mRNA and protein in response to LPS alone, yet IFN-gamma does not significantly enhance LPS-induced TNF-alpha expression, nor do they express appreciable TNF-alpha in response to the combined stimuli of IFN-gamma/IL-1 beta. In contrast, astrocytes from Lewis rats express low levels of TNF-alpha mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-gamma for subsequent TNF-alpha gene expression. Also, Lewis astrocytes produce TNF-alpha in response to IFN-gamma/IL-1 beta. The differential TNF-alpha production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-alpha expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-gamma, and IL-1 beta in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-gamma priming signals for subsequent TNF-alpha production, suggesting that differential TNF-alpha expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-alpha gene expression in response to LPS and IFN-gamma is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains. 190 Oct 78

To investigate differences among brain-derived microglia and other classes of immune cells, we compared the morphologies and growth properties of mononuclear phagocytes isolated from tissues of the newborn rat. Scanning EM shows that microglia from postnatal rat brain are covered with spines (typically > 20 per cell body) in a distinctive manner which contrasts the smooth surfaces of bone marrow cells and the ruffled surfaces of tissue macrophages from spleen, liver, and peritoneum. The spine-bearing surface of microglia is a specific cell marker, for it does not change with age or after exposure to cytokines or other immunostimulants. Approximately 99% of mononuclear phagocytes cultured from normal adult rat brain are spinous microglia. Five days after injury to rat brain, cells at sites of Wallerian degeneration are essentially all spinous ones while nearly 30% of cells found within areas of infarction or penetrating trauma are invading macrophages. In a similar way, nearly all cells isolated from normal, postmortem adult human brain are spine-bearing microglia (> 99% homogeneity). Brains from patients with amyotrophic lateral sclerosis contain only spinous microglia whereas cells from HIV-1 infected brains include significant numbers of invading ruffled macrophages. Cultured microglia, unlike cultured bone marrow precursors, monocytes, or tissue macrophages, spontaneously develop long, thin processes that extend hundreds of microns in length. Microglia retract these processes after exposure to fetal bovine serum, laminin, or such immunostimulants as recombinant murine interferon gamma (rmIFN gamma) and lipopolysaccharide. Of all types of mononuclear phagocytes tested, only microglia differentiate into quiescent ramified cells when in contact with astrocytes. Thus, microglia represent a unique class of cell maintained, in part, by astroglia as dormant, ramified mononuclear phagocytes in mature CNS. Application of cell surface criteria described here will allow study of distinct populations of mononuclear phagocytes associated with neurologic disorders.
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PMID:Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte. 747 22

An approach for studying neurotoxicity of bacterial products is presented. Pentylenetetrazol, a convulsant drug, was injected into mice, and increased sensitivity to pentylenetetrazol was used as an indicator of neurotoxicity. The preinjection of sonicates of Shigella dysenteriae 60R or Escherichia coli H30 (producing Shiga toxin or Shiga-like toxin I, respectively) enhanced the response of mice to pentylenetetrazol within 6 h. This was indicated by a higher mean convulsion score, increased number of mice responding with convulsions, and induction of seizures in animals pretreated with a subepileptic dose of pentylenetetrazol. Preinjection of purified Shiga toxin significantly changed the response to pentylenetetrazol only when coadministered with bacterial lipopolysaccharide (LPS); mean convulsion scores were 1.6 and 0.9 for the Shiga toxin-LPS group and controls, respectively. LPS alone did not affect sensitivity to pentylenetetrazol. These results suggest that Shiga toxin and LPS together induce neurologic disorders early in the course of infection.
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PMID:An animal model for the study of neurotoxicity of bacterial products and application of the model to demonstrate that Shiga toxin and lipopolysaccharide cooperate in inducing neurologic disorders. 775

To determine the function of monocytes/macrophages in the acute phase of multiple sclerosis (MS), we investigated the production of tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta and IL-6 by peripheral blood monocytes/macrophages (PBM) in patients with MS, other autoimmune neurological disease (OAND), other neurological disease (OND) and normal controls was assessed using enzyme-linked immunosorbent assay (ELISA). When stimulated with lipopolysaccharide or phorbol ester, PBM obtained during acute phase of MS relapse patients produced significantly higher amounts of all these cytokines than did PBM from patients with chronic stable MS or OAND or OND or from normal controls. The results suggest a possible role of activated monocytes/macrophages in the acute exacerbation of MS.
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PMID:Cytokine production by peripheral blood monocytes/macrophages in multiple sclerosis patients. 850 56

Tumor necrosis factor (TNF-alpha) underlies pathological processes and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide alpha-MSH modulates actions and production of proinflammatory cytokines including TNF-alpha, but there is no prior evidence that it alters TNF-alpha induced within the brain. To test for this potential influence of the peptide, TNF-alpha was induced centrally by local injection of bacterial lipopolysaccharide (LPS). alpha-MSH given once i.c.v. with LPS challenge, twice daily intraperitoneally (i.p.) for 5 d between central LPS injections, or both i.p. and centrally, inhibited production of TNF-alpha within brain tissue. Inhibition of TNF-alpha protein formation by alpha-MSH was confirmed by inhibition of TNF-alpha mRNA. Plasma TNF-alpha concentration was elevated markedly after central LPS, indicative of an augmented peripheral host response induced by the CNS signal. The increase was inhibited by alpha-MSH treatments, in relation to inhibition of central TNF-alpha. Presence within normal mouse brain of mRNA for the alpha-MSH receptor MC-1 suggests that the inhibitory effects of alpha-MSH on brain and plasma TNF-alpha might be mediated by this receptor subtype. The inhibitory effect of alpha-MSH on brain TNF-alpha did not depend on circulating factors because the effect also occurred in brain tissue in vitro. This indicates that alpha-MSH can act directly on brain cells to inhibit their production of TNF-alpha. If central TNF-alpha contributes to pathology in CNS disease and injury, and promotes inflammation in the periphery, agents that act on brain alpha-MSH receptors should decrease the pathological TNF-alpha reaction and promote tissue survival.
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PMID:alpha-MSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. 904 42

Campylobacter jejuni (Cj) enteritis is the most frequently recognised infection preceding Guillain-Barre syndrome (GBS) and this combination is commonly associated with anti-GM1 ganglioside (anti-GM1) antibodies. We have examined the hypothesis that the anti-GM1 antibodies represent an immune response against the Cj lipopolysaccharide (LPS). We prepared the LPS fraction from 8 isolates of Cj, 3 from GBS patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 3 from patients with Miller Fisher syndrome (MFS) and 2 from enteritis patients without neurological disease. We looked for IgG antibodies against LPS and GM1 in the serum of 10 GBS and 10 MFS patients, including the patients from whom the Cj had been isolated, and 11 normal control subjects. The highest levels of IgG binding to LPS fractions were found in the GBS patient sera and were with one of the LPS fractions extracted from the C. jejuni isolated from a GBS patient, one from a MFS patient and two Cj isolates from enteritis patients without neurological disease. The level of IgG binding to these LPS fractions was related to the level of IgG anti-GM1 antibody in the serum. Affinity-purified anti-GM1 antibodies showed the same pattern of differential binding to the LPS fractions as the serum from which they were derived. Cholera toxin bound to the same LPS fractions as GBS patients' IgG, the binding of which was blocked by the toxin indicating specific antibody reactivity with a GM1 hapten. The presence of serum anti-GM1 antibodies did not coincide with the presence of the GM1 hapten on the LPS of the infecting strain of Campylobacter indicating that anti-GM1 antibodies do not necessarily arise as part of a simple immune response against the LPS. The IgG antibodies binding to LPS were predominantly of the IgG2 isotype but patients with anti-GM1 IgG had mainly antibodies of IgG1 subclass against both LPS and GM1, implying their production by a T-cell dependent mechanism.
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PMID:Reactivity of serum IgG anti-GM1 ganglioside antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain-Barre syndrome (GBS). 905 56

Apolipoprotein E (apoE) is a 299 amino acid protein with multiple biological functions. Initially described in the context of cholesterol metabolism, apoE also has immunomodulatory properties and recent evidence has implicated a role for apoE in neurological disease. One possibility is that apoE, which is the predominant apolipoprotein produced intra-axially, may modify the CNS response to acute and chronic injury. We prepared mixed neuronal-glial cultures from apoE deficient mouse pups and measured secretion of TNF alpha after stimulation with lipopolysaccharide (LPS) in the presence and absence of human recombinant apoE3 and E4. We demonstrate that preincubation with apoE blocks glial secretion of TNF alpha in a dose-dependent manner. This effect is independent of any direct effect of apoE on cell viability and is greatest when apoE is preincubated with the cell culture for 24 h.
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PMID:Apolipoprotein E suppresses glial cell secretion of TNF alpha. 918 34

To examine the role of human T-lymphotropic virus type 1 (HTLV-1) Tax1 in the development of neurological disease, we studied the effects of extracellular Tax1 on gene expression in NT2-N cells, postmitotic cells that share morphologic, phenotypic, and functional features with mature human primary neurons. Treatment with soluble HTLV-1 Tax1 resulted in the induction of tumor necrosis factor alpha (TNF-alpha) gene expression, as detected by reverse-transcribed PCR and by enzyme-linked immunosorbent assay. TNF-alpha induction was completely blocked by clearance with anti-Tax1 monoclonal antibodies. Furthermore, cells treated with either a mock bacterial extract or with lipopolysaccharide produced no detectable TNF-alpha. Synthesis of TNF-alpha in response to soluble Tax1 occurred in a dose-dependent fashion between 0.25 and 75 nM and peaked within 6 h of treatment. Interestingly, culturing NT2-N cells in the presence of soluble Tax1 for as little as 5 min was sufficient to result in TNF-alpha production, indicating that the induction of TNF-alpha in NT2-N does not require Tax1 to be continually present in the culture medium. Treatment of the undifferentiated parental embryonal carcinoma cell line NT2 with soluble Tax1 did not result in TNF-alpha synthesis, suggesting that differentiation-dependent, neuron-specific factors may be required. These results provide the first experimental evidence that neuronal cells are sensitive to HTLV-1 Tax1 as an extracellular cytokine, with a potential role in the pathology of HTLV-1-associated/tropical spastic paraparesis.
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PMID:Induction of tumor necrosis factor alpha in human neuronal cells by extracellular human T-cell lymphotropic virus type 1 Tax. 926 27

The heat shock response (HSR) provides protection against stress-induced damage, and also prevents initiation of inflammatory gene expression via inhibition of NFkappaB activation. This article describes experiments demonstrating that the HSR prevents induction of nitric oxide synthase type 2 (NOS2) in rat brain. Twenty four hours after intrastriatal injection of lipopolysaccharide (LPS), IL-1beta, and IFN-gamma, NOS2 immunoreactive cells were detected in striatum, corpus callosum, and to a lesser extent in cortex. Induction of a HSR by whole body warming to 41 degrees C for 20 minutes, done 1 day before LPS plus cytokine injection, reduced the number of NOS2-positive staining cells to background levels. Staining for EDI antigen revealed that the HSR also suppressed microglial/brain macrophage activation in the same areas. Striatal injection of LPS and cytokines induced the rapid activation of NFkappaB, and this activation was prevented by prior HS, which also increased brain IkappaB-alpha expression. These results suggest that establishment of a HSR can reduce inflammatory gene expression in brain, mediated by inhibition of NFkappaB activation, and may therefore offer a novel approach to treatment and prevention of neurological disease and trauma.
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PMID:The heat shock response inhibits NF-kappaB activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain. 1082 30

CNS-localized inflammation with microglial activation and macrophage infiltration contributes to the pathogenesis of a broad spectrum of neurologic diseases. A direct injection of lipopolysaccharide (LPS) into the striatum of gerbils induced lectin-positive macrophage parenchymal invasion, minimal local microglial staining but extensive neurodegeneration (cresyl violet and silver staining) when evaluated 4 days later. In mice, LPS activated microglia (increased lectin staining of morphologically identified cells) with substantially less macrophage invasion but no neurodegeneration was seen at 4 days post LPS infusion. To evaluate the role of infiltrating macrophages in the neurodegenerative response in gerbils, peripheral macrophages were depleted by an intravenous injection of liposome-encapsulated clodronate. This preparation depleted spleen and liver macrophages (>95%), decreased blood monocytes by 55% and attenuated striatal macrophage infiltration (32 to 73% in five representative sections). Notably, the liposome-encapsulated clodronate reduced the severity of LPS-induced neurodegeneration, as visualized by cresyl violet staining and quantified in 20 serially stained silver sections (total volume, 1.32+/-0.41 mm(3) in liposome-encapsulated clodronate-treated versus 3.04+/-0.72 mm(3) in saline-treated controls). These results indicate that a local LPS infusion in gerbil brain may be a useful model in which to investigate the role of invading macrophages and other inflammatory responses in neurodegeneration in inflammatory neurological disease.
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PMID:Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils. 1117 45


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