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)

The mechanism of action of recombinant interferon beta 1b (rIFN beta 1b/IFN beta-1b), the approved therapy for multiple sclerosis (MS), is still unclear. Here we present evidence that part of the therapeutic effects of rIFN beta 1b in MS might result from the induction of the secretion of interleukin (IL)-10, a cytokine previously designated cytokine synthesis inhibitory factor (CSIF). We observed that rIFN beta 1b stimulated significant IL-10 secretion by monocytes from MS patients after brief incubation (18 h), whereas rIFN gamma, an inducer of MS exacerbations, was unable to stimulate IL-10 production in similar conditions. To determine the role of IL-10 as CSIF in the disease, we have also investigated its effects on TNF alpha and IL-6 secretion by peripheral blood mononuclear cells from MS patients. Recombinant human IL-10 significantly inhibited tumor necrosis factor alpha and IL-6 secretion induced by rIFN gamma, lipopolysaccharide (LPS), and rIFN gamma + LPS in MS patients and in control subjects. The induction of IL-10 secretion by rIFN beta 1b and the IL-10 inhibitory activity on pro-inflammatory cytokine secretion induced by rIFN gamma in MS make this cytokine a potential candidate to treat the disease.
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PMID:Interferon effects on interleukin-10 secretion. Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients. 756 9

Substance P (SP) is a central and peripheral neurotransmitter which has been found in multiple sclerosis plaques. SP stimulates peripheral immune cells and may play a role in some chronic inflammatory diseases. Human peripheral monocyte/macrophages have been shown to produce the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) in response to SP. Therefore, in this study we examined rat brain microglia for the presence of SP receptors and production of IL-1 and TNF alpha in response to SP. Microglia had 4900 +/- 950 (mean +/- SE) receptors per cell fitting a two-site model. Four percent of these were high-affinity receptors with a Kd of 8.2 x 10(-8) M +/- 3.6 x 10(-8) M (mean +/- SE), and 96% of them were low-affinity receptors with a Kd of 2.1 x 10(-6) M +/- 5.2 x 10(-7) M (mean +/- SE). Competitive studies with CP 96,345 and other SP analogs demonstrate these to be non-classical NK-1 receptors. SP alone did not stimulate IL-1 or TNF alpha production. However, SP in synergy with lipopolysaccharide (LPS) quadrupled IL-1 production compared to LPS alone, but did not affect TNF alpha production. These results have implications for certain inflammatory conditions in the central nervous system.
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PMID:Production of interleukin-1 by microglia in response to substance P: role for a non-classical NK-1 receptor. 767 97

To investigate the function of peripheral blood monocytes in multiple sclerosis (MS), we measured the production of the cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6), and the procoagulant, tissue factor (TF) in 17 patients with chronic progressive MS and 15 normal controls. Monocyte activity was tested under unstimulated, minimal endotoxin conditions and after culture with various stimuli, including Escherichia coli lipopolysaccharide (LPS), crude supernatant from anti-CD3-activated T cells, recombinant interleukin-2 (rIL-2), and recombinant interferon-gamma (rIFN-gamma). A higher number of MS patients than controls had circulating monocytes which spontaneously secreted IL-6 or contained detectable cell-associated IL-1 beta. Monocyte responses to LPS were comparable between the two groups; LPS caused production and secretion of all cytokines and TF in every MS patient and control. In contrast, crude T cell supernatants, rIL-2, and rIFN-gamma induced IL-1 beta release in a higher number of MS monocytes than that in controls, whereas the production and secretion of the other cytokines and TF activity were similar between the groups. We conclude that some MS patients have "primed" circulating monocytes, as shown by excessive spontaneous IL-6 release and intracellular IL-1 beta synthesis. Unstimulated MS monocytes, however, are not different from controls with respect to spontaneous secretion of small amounts of IL-1 beta and TNF alpha and expression of cell surface TF. Excessive IL-1 beta secretion by MS monocytes after stimulation with T-cell-derived lymphokines suggests dysregulation of T cell-monocyte interactions which may be most relevant in the central nervous system plaques where activated T cells are found.
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PMID:T cell lymphokine-induced secretion of cytokines by monocytes from patients with multiple sclerosis. 842 34

Elevated levels of tumor necrosis factor-alpha (TNF alpha) and other cytokines and eicosanoids in the central nervous system (CNS) have been noted in several human neurologic diseases, including multiple sclerosis and AIDS dementia. Recently it was shown that glial cells, especially astrocytes, are a major source of cytokines and eicosanoids. In the present study we have shown that astrocytes derived from fetal rat brain triggered by mycoplasmas produce TNF alpha and prostaglandin E2 (PGE2). Addition of mycoplasma (Mycoplasma capricolum isolated from sheep and M. fermentans KL-4 from human) at a concentration of 1-50 micrograms protein/ml (2 x 10(7)-10(9) colony forming units/ml), as well as lipopolysaccharide (5 micrograms/ml), led to a 200-500-fold increase in TNF alpha and a 2.5-4.5-fold increase in PGE2 production. Preincubation of the cells with the synthetic glucocorticoid, dexamethasone (2 x 10(-5)-2 x 10(-8) M), as well as with the natural hormone, corticosterone, markedly inhibited the secretion of both TNF alpha and PGE2. Thus, mycoplasmas can be added to the wide variety of agents that stimulate glial cells to produce cytokines and eicosanoids, and may contribute to various CNS pathological manifestations. In addition, the ability of glucocorticoids to inhibit particularly the stimulated productions of TNF alpha and PGE2 may explain at least in part the therapeutic benefit of these agents in CNS inflammation and demyelination.
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PMID:Stimulation of tumor necrosis factor-alpha production by mycoplasmas and inhibition by dexamethasone in cultured astrocytes. 849 62

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

Peripheral blood monocytes exposed to bacterial products, phorbol esters, cyclic AMP, and cyclic AMP analogs express cell surface activation protein Mo3, which is the human urokinase plasminogen activator receptor (uPA-R). uPA-R is expressed by circulating monocytes from patients with multiple sclerosis (MS). We examined the role of cytoskeletal elements in the surface expression and subcellular distribution of uPA-R in nonactivated and lipopolysaccharide-activated monocytes and in monocytes from patients with MS. By using immunofluorescence techniques and confocal laser microscopy, we found that in unactivated monocytes, cytoplasmic uPA-R is found to one side of the nucleus, colocalizing with the Golgi. Upon activation with lipopolysaccharide, cytoplasmic Mo3-uPA-R becomes dispersed throughout the cytoplasm and projections concomitant with an increase in the monocyte perimeter (spreading). Cytoplasmic dispersion, as well as cell surface deposition, is dependent on microtubule integrity. Cell surface deposition of uPA-R upon activation is reduced by colchicine, which disrupts microtubules; however, once associated at the cell surface, uPA-R becomes associated with microfilaments via vinculin. Disruption of microfilaments with cytochalasin also alters surface expression of immunologically reactive uPA-R, as well as the distribution pattern. Monocytes from patients with MS display the uPA-R distribution pattern characteristic of an activated monocyte.
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PMID:Role of cytoskeletal elements in expression of monocyte urokinase plasminogen activator receptor, activation-associated antigen Mo3. 855 26

Nitric oxide (NO) is a critical mediator of a variety of biological functions. A range of micro-organisms, including viruses, bacteria, protozoa and helminths, is sensitive to NO produced by macrophages activated with gamma-interferon (IFN-gamma) and lipopolysaccharide. In contrast, NO is involved in a number of important immunopathologies, including diabetes, graft-vs-host reaction, rheumatoid arthritis, systemic lupus erythematosus, experimental autoimmune encephalomyelitis and multiple sclerosis. Thus, it is crucial that the synthesis of NO is under tight regulation. This is achieved, in part, through the opposing cytokines produced by T helper 1 (Th1) and Th2 cells. Th1 cells produce IFN-gamma, which is the most powerful inducer of inducible NO synthase (iNOS). In contrast, interleukin 4 is produced by Th2 cells and inhibits the induction of iNOS at the level of transcription. Furthermore, NO is also produced by Th1 cells, whose proliferation can be inhibited by high concentrations of NO. Thus, apart from being a mediator of Th1/Th2 interaction, NO may also be an important self-regulatory molecule that prevents the over-expansion of Th1 cells which are implicated in a range of severe immunopathologies.
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PMID:Nitric oxide in infectious and autoimmune diseases. 872 41

Production of T helper 1 and T helper 2 cytokines was investigated in peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients by a newly described technique, detection of intracellular cytokines by flow cytometry in conjunction with immunophenotype analysis. T-cell gamma interferon (IFN-gamma) production and interleukin 10 (IL-10) production were examined after PBMC activation with T-cell mitogens at 5 and 24 h, and monocyte spontaneous production of IL-10 and production after PBMC activation with lipopolysaccharide (LPS) for 24 h were also examined. The data indicate that MS patients have decreased percentages of T cells capable of secreting IFN-gama compared with healthy controls, and this change is detectable at 5 and 24 h. the patients displaying decreased T-cell production of IFN-gamma were essentially confined to a group being treated with the newly approved drug Betaseron (berlex Labs, Cedar Knolls, N.J.), a recombinant form of IFN-beta (rIFN-beta 1b). By gating of the entire lymphocyte population, analysis of IFN-gama production in T cells (CD3+ versus that in non-T cells (CD3+) was possible. The percentage of IFN-gamma-producing lymphocytes that was made up of T cells was essentially unchanged between the Betaseron-treated patients, non-Betaseron-treated patients, and controls, indicating that the suppression of IFN-gamma production displayed by betaseron-treated MS patients was a nonspecific suppression of all IFN-gamma-producing lymphocytes as opposed to a suppression of T-cell production only. The data seem to indicate that treatment of MS with Betaseron corresponds to an inhibition of the lymphocyte's ability to produce IFN-gamma. No changes were detected in T-cell production of IL-10 at either time point. We also observed that MS patients in general appear to have small percentages of peripheral blood monocytes spontaneously producing slight but detectable levels of IL-10. No difference was seen regarding monocyte production of IL-10 after PBMC activation with LPS between MS patients and controls. Both populations responded with high percentages of monocytes producing IL-10. The data seem to indicate that treatment of MS with Betaseron, known to decrease the exacerbation rate of relapsing-remitting MS, corresponds to a suppression of peripheral blood lymphocyte production of IFN-gamma. Monocyte production of IL-10 may also play a role in regulating the disease process.
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PMID:Detection of altered T helper 1 and T helper 2 cytokine production by peripheral blood mononuclear cells in patients with multiple sclerosis utilizing intracellular cytokine detection by flow cytometry and surface marker analysis. 880 5

Astrogliosis and microglial activation are associated with many neurodegenerative disorders including multiple sclerosis, its animal model experimental allergic encephalomyelitis, and Alzheimer's disease. To address the hypothesis that chronic astroglial or microglial activation could be contributing factors to neuronal death or injury, the immunostimulant lipopolysaccharide was infused into the hippocampus for 16 days using Alzet mini-osmotic pumps attached to a cannula. Placement of the cannula and infusion of vehicle for 16 days caused a hippocampal lesion with a volume of 0.5 +/- 0.1 mm3. Infusion of lipopolysaccharide at the dose of 2.0 micrograms/day produced a lesion of 4.9 +/- 1.3 mm3 (P < 0.01, Newman-Keuls), whereas, a lower dose of 0.2 microgram/day caused a lesion of 1.3 +/- 0.3 mm3 (P < 0.05). The lesion was defined as a focal necrotic reaction with fibrin deposits outlining an area at an early stage of encapsulation. No apparent neuronal loss was observed by Cresyl Violet staining outside the encapsulated necrotic area. There was a pronounced astrogliosis and an increase in activated macrophages throughout the lipopolysaccharide-infused hippocampus as determined by glial fibrillary acidic protein and ED-1 immunohistochemistry, respectively. Choline acetyltransferase and glutamic acid decarboxylase enzyme activities, used as functional measures of neuronal viability for cholinergic and GABAergic neurons, respectively, were unaffected in the hippocampus following a 16 day infusion of lipopolysaccharide at the doses of 0.2, 0.6 and 2.0 micrograms/day. In addition, unilateral infusion of lipopolysaccharide into the hippocampus did not affect 24 h locomotion when tested on day 13, body temperature or weight gain. Under the experimental conditions employed in the present study, chronic infusion of lipopolysaccharide into the hippocampus resulted in a dose-dependent focal necrotic lesion at the site of infusion. In tissue surrounding the encapsulated lesion, neurons were present among the reactive astrocytes and increased number of macrophages suggesting that astrocytes and macrophages can be activated without causing neuronal loss.
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PMID:Effects of chronic intrahippocampal infusion of lipopolysaccharide in the rat. 884 36

The ability of microglia to migrate through central nervous system (CNS) tissue requires proteolytic degradation of components of the extracellular matrix. Urokinase plasminogen activator (uPA), when bound to its cell surface receptor (uPAR), is an active cell surface protease. uPAR expression has been associated with cell activation. Cultured human microglia express surface uPAR. uPAR expression was found to be associated predominately with spindle- or bipolarshaped microglia. The addition of lipopolysaccharide (LPS) to microglial cultures enhanced the proportion of uPAR expression and shifted cell morphology to the elongated spindle or bipolar shape. When microglia were examined immediately ex vivo, uPAR surface expression could not be detected. Similarly, uPAR transcripts detected by reverse transcription-polymerase chain reaction techniques were found in cultured, but not ex vivo, microglia. Microglia isolated from a patient with multiple sclerosis (MS) displayed a large amount of uPAR+ cells. These cells were predominantly spindle or bipolar in nature. These findings suggest that uPAR surface expression is associated with microglial activation. Surface expression of uPAR and associated cell surface protease activity may provide a mechanism for microglial migration and may be important in the pathophysiology of MS.
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PMID:Expression of the activation marker urokinase plasminogen-activator receptor in cultured human central nervous system microglia. 887 99


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