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)

Tumor necrosis factor alpha (TNF) is an important mediator in lung injury. The kinetics of TNF uptake by the lung are not completely understood. In this study, we evaluated the role that lipopolysaccharide (LPS) and the two types of TNF receptor (p55 and p75) play in the uptake of circulating murine TNF by the murine lung. TNF radioactively labeled with 125I (I-mTNF) was administered intravenously (2 x 10(6) cpm/mouse) to mice with both receptors (wild-type) or to mice missing one (p55-/- or p75-/-) or both (p55-/- and p75-/-) TNF receptors. Blood to lung non-reversible sequestration (Ki) and reversible uptake (Vi) were measured with multiple-time regression analysis. Uptake by lung of I-mTNF in wild-type mice had reversible and non-reversible components. This uptake was decreased by intratracheal, but not by intravenous, LPS, suggesting modulation by local, rather than systemic, inflammation. The p75-/- deficient mice retained the Ki (saturable, non-reversible) component of TNF uptake, whereas p55-/- deficient mice retained the Vi (saturable, reversible) component of TNF uptake. Both Ki and Vi components of TNF uptake were absent in the lungs of p55-/- p75-/- deficient mice. These studies show that local inflammation inhibits the uptake of circulating I-mTNF by lung and that uptake consists of two distinguishable compartments: reversible uptake mediated by the p75 receptor and non-reversible sequestration mediated by the p55 receptor.
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PMID:Role of LPS and receptor subtypes in the uptake of TNF by the murine lung. 1148 91

Hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessive disorder featured by recurrent febrile attacks. Previous unpublished experience (J. van der Meer and R. Powell) suggested that thalidomide may prevent febrile attacks. Six HIDS patients (5 male and 1 female) who had at least one febrile attack every 6 weeks, entered a randomized, double-blind, placebo-controlled crossover trial to explore the efficacy of a daily 200-mg thalidomide dose in the treatment of recurrent febrile attacks of HIDS. The patients received either thalidomide, 200-mg daily, or placebo for 16 weeks, followed by a 4-week washout period and another 16-week treatment (crossover) with either thalidomide or placebo. Patients completed a weekly diary card noting attacks and side effects. During the study, C-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-1 receptor antagonist, soluble TNF receptor p55 and p75, and lipopolysaccharide-stimulated IL-1 beta and TNF-alpha production were measured at six different points, whereas urine neopterin levels were measured weekly. During the active treatment with thalidomide, there were 10 attacks compared with 13 attacks with placebo. Thalidomide resulted in a nonsignificant decrease of CRP and SAA, but the concentrations of other inflammatory mediators, including urine neopterin, remained unchanged. One patient developed sensory polyneuropathy, but this resolved when thalidomide administration was stopped. The effect of thalidomide in HIDS is limited to a decrease in acute phase protein synthesis without an effect on the attack rate.
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PMID:Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. 1150 24

In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB) signaling transduction pathway. In fetal alveolar type II epithelial cells, PDE blockade at the level of the diverging cAMP/cGMP pathways differentially regulated the phosphorylation and degradation of IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB. Whereas selective inhibition of PDEs 1, 3, and 4, by the action of 8-methoxymethyl-3-isobutyl-1-methylxanthine, amrinone, and rolipram, respectively, exhibited a tendency to augment the translocation of NF-kappaB(1) (p50), RelA (p65), RelB (p68), and c-Rel (p75), selective blockade of PDE 5, 6, and 9, by the action of 4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline and zaprinast, attenuated lipopolysaccharide-endotoxin (LPS)-mediated NF-kappaB translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-kappaB subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-kappaB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-kappaB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-kappaB activation, similar to the effect of 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (pentoxifylline). These results indicate that selective and nonselective interference with the control of the dynamic equilibrium of cyclic nucleotides via PDE isoenzyme regulation represents an immunoregulatory mechanism that requires the differential, biphasic targeting of the IkappaB-alpha/NF-kappaB pathway.
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PMID:Immunopharmacological potential of selective phosphodiesterase inhibition. II. Evidence for the involvement of an inhibitory-kappaB/nuclear factor-kappaB-sensitive pathway in alveolar epithelial cells. 1180 18

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor alpha (TNFalpha) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNFalpha converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNFalpha (proTNFalpha) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNFalpha, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNFalpha and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNFalpha is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNFalpha receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNFalpha. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNFalpha production.
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PMID:Biology of TACE inhibition. 1189 Jun 48

The cholinergic system of the basal forebrain is affected in brains of dementia patients and during neuroinflammation. The aim of this study was to establish a method to cultivate basal forebrain cholinergic neurons in dissociated, pure neuronal cultures and to apply this method to study the effect of acute and chronic experimentally-induced inflammation using lipopolysaccharide. Purity of the cultures, degrees of neuronal dissociation, connectivity and neuronal survival were investigated by immunocytochemistry for microtubule-associated protein-2 (neurons), glial fibrillary acidic protein (astroglia), complement receptor 3 (microglia), choline acetyltransferase and the neurotrophin receptor p75 (cholinergic neurons). Neuronal cultures only contained <7% astrocytes and <1% microglia when using a "sandwich-technique". Acute (1, 10 microg/ml) as well as chronic (0.1, 1 microg/ml) treatment with lipopolysaccharide did neither affect total number of neurons, nor number of p75-positive neurons or enhance expression of major histocompatibility complex I or II. Our results suggest that lipopolysaccharide-induced degeneration of both microtubule-associated protein-2-like immunoreactive as well as specific killing of cholinergic forebrain neurons in vitro are mediated by glial cells.
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PMID:Evidence that toxicity of lipopolysaccharide upon cholinergic basal forebrain neurons requires the presence of glial cells in vitro. 1212 18

The regulation of lipopolysaccharide (LPS)-mediated pro-inflammatory cytokine biosynthesis by reduction-oxidation (redox)-sensitive enzymes involved in maintaining intracellular glutathione homeostasis was investigated in fetal alveolar type II epithelial cells (fATII). Inhibition of glutathione-oxidized disulfide reductase, which recycles GSSG --> 2GSH, by the action of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) augmented LPS-dependent secretion of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. BCNU increased [GSSG] concentration at the expense of [GSH], thereby favoring oxidation equilibrium. Inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of GSH, by the action of L-buthionine-(S,R)-sulfoximine (BSO), potentiated LPS-induced IL-1beta, IL-6 and TNF-alpha production. Similar to BCNU, BSO depleted [GSH] and induced the accumulation of [GSSG]. BCNU and BSO reduced LPS-mediated phosphorylation of inhibitory-kappaB (IkappaB-alpha), allowing its cytosolic accumulation. This effect was associated with the inhibition of the nuclear translocation of selective nuclear factor (NF)-kappaB subunits: NF-kappaB1 (p50), RelA (p65), RelB (p68) and c-Rel (p75), but not NF-kappaB2 (p52). BCNU and BSO reduced LPS-induced NF-kappaB activation as determined by the electrophoretic mobility shift DNA-binding assay. Analytical analysis of the effect of modulating the dynamic redox ratio ([GSH]+[GSSG])/[GSSG] revealed a novel role for GSSG as a disulfhydryl compound which mediates an inhibitory effect on NF-kappaB activation. It is concluded that selective modulation of redox-sensitive enzymes has an immunopharmacological potential in regulating pro-inflammatory cytokines and that the TkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially involved in mediating redox-dependent regulation of cytokine signaling.
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PMID:Inhibition of glutathione-related enzymes augments LPS-mediated cytokine biosynthesis: involvement of an IkappaB/NF-kappaB-sensitive pathway in the alveolar epithelium. 1243 58

Geldanamycin (GA) is an antibiotic produced by Actinomyces, which specifically inhibits the function of the heat shock protein 90 family. Treatment of a murine macrophage cell line (J774) with GA resulted in a reduced response to Escherichia coli lipopolysaccharide (LPS) as visualized by a decrease of NF-kappaB translocation into the nucleus and secretion of tumor necrosis factor alpha (TNF-alpha). To elucidate the mechanism of this effect, the expression of CD14, the formal LPS receptor, was analyzed. Cells treated with GA showed a reduced level of surface CD14 detected by immunostaining, whereas the expression of other surface receptors, such as FC-gamma receptor and tumor necrosis factor receptors (TNF-R1 and TNF-R2), was unaffected. The reduced surface level of CD14 was not due to a reduction in its expression because CD14 steady state mRNA levels or the total cellular pool of CD14 was not altered by GA treatment. Surface CD14 was more rapidly internalized after GA treatment (2-3 h) than after incubation with cycloheximide. Immunostaining of permeabilized cells after GA treatment revealed a higher intracellular content of CD14 colocalizing with calnexin, an endoplasmic reticulum (ER) protein. These results suggest that the decrease in CD14 surface expression after GA treatment is due to rapid internalization without new replacement. These effects may be due to the inhibition of Hsp90 and Grp94 by GA in macrophages.
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PMID:Geldanamycin treatment ameliorates the response to LPS in murine macrophages by decreasing CD14 surface expression. 1258 68

KE-758, an active metabolite of KE-298, is a novel sulfhydryl antirheumatic drug. We analyzed the effect of KE-758 on tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta production by a human monocytes cell line (THP-1 cells), stimulated with interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). We compared the effects with other thiol-modifying antirheumatic drugs such as D-penicillamine, bucillamine and auranofin. THP-1 cells were treated with IFN-gamma for 16 h and were then exposed to LPS for an additional 6 h (for TNF-alpha detection) or 24 h (for IL-1 beta detection). The amounts of TNF-alpha and IL-1 beta in culture supernatants were measured using enzyme-linked immunosorbent assay. KE-758 and auranofin but not D-penicillamine and bucillamine significantly suppressed both TNF-alpha and IL-1 beta. Auranofin suppressed IL-1 beta production by reducing cellular viability. Reverse transcriptase-polymerase chain reaction analysis revealed that the suppressive effect of KE-758 is based on the inhibition of messenger ribonucleic acid expression of TNF-alpha and IL-1 beta. KE-758 had no effect on p75 and p55 soluble TNF receptor production in IFN-gamma and LPS-stimulated THP-1 cells. Thus, KE-758 inhibits both TNF-alpha and IL-1 beta production and its antirheumatic profile is apparently distinct from that of D-penicillamine, bucillamine and auranofin.
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PMID:KE-758, an active metabolite of the new anti-rheumatic drug KE-298, suppresses production of tumor necrosis factor-alpha and interleukin-1 beta in THP-1, a human monocyte cell line. 1263 95

We reported previously that bone marrow granulocytes respond to small amounts of enterobacterial lipopolysaccharide (LPS) via a CD14-independent and TLR4-mediated mechanism by de novo expression of an inducible receptor (CD14) and by down-modulation of a constitutive receptor (L-selectin). In this report we address another effect of LPS: the down-regulation of receptors for tumor necrosis factor-alpha. In mouse bone marrow cells (BMC), this down-regulation is detectable soon (20 min) after exposure of the cells to low levels (0.5 ng/ml) of LPS. This temperature-dependent effect is rather selective for LPS and requires the presence of a conventional lipid A structure in the LPS molecule and a functional TLR4 molecule in the cells. The down-modulation, due to a shedding of the receptors, is blocked by p38 MAPK inhibitors, by a furin inhibitor, and by three metalloproteinase inhibitors (BB-3103, TIMP-2, and TIMP-3). In contrast, inhibitors of MEK, protein kinase C, cAMP-dependent protein kinase, and kinases of the Src family do not block the shedding. Analysis of BMC from mice lacking tumor necrosis factor receptor-1 (CD120a-/-) or tumor necrosis factor receptor-2 (CD120b-/-) indicates that the LPS-induced shedding is specific for CD120b. Thus, exposure of BMC to LPS triggers a rapid shedding of CD120b via a protein kinase C- and Src-independent pathway mediated by p38 MAPK, furin, and metalloproteinase. The additive effects of furin and metalloproteinase inhibitors suggest that these enzymes are involved in parallel shedding pathways.
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PMID:TLR4-dependent lipopolysaccharide-induced shedding of tumor necrosis factor receptors in mouse bone marrow granulocytes. 1266 67

In experimental murine trypanosomiasis, resistance is often scored as the capacity to control peak parasitemia levels, which results in prolonged survival. Infection-induced pathology has not systematically been used as a resistance criterion. Because this parameter could be the most relevant for comparative analysis of natural and experimental infections, as well as for understanding of pathology-associated immune alterations, we analyzed Trypanosoma brucei infections in 4 different established conventional mouse models, as well as in tumor necrosis factor (TNF)-deficient and TNF-receptor-deficient mice. Results indicate the following: (1) there is no correlation between peak parasitemia control or survival and the induction of infection-associated anemia, loss of body weight, liver pathology, reduced locomotor activity, and general morbidity; (2) serum levels of TNF, interferon- gamma, and interleukin-10, which are known to affect survival, do not correlate with induction of pathology; and (3) infection-induced occurrence of lipopolysaccharide hypersensitivity does not correlate with survival. However, one parameter that was found to correlate with the inhibition of trypanosomiasis-associated pathology in all models was the shedding of soluble p75 TNF-receptor during peak parasitemia stages. These results are important for future cytokine and trypanosomiasis pathology studies, because the interplay between TNF and the soluble receptors it sheds has not been considered in either human clinical sleeping sickness studies or in veterinary trypanosomiasis research.
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PMID:P75 tumor necrosis factor-receptor shedding occurs as a protective host response during African trypanosomiasis. 1474 12


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