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)

Rat peritoneal macrophages incubated with the two stable analogues of cAMP, dibutyryl-cAMP and 8-bromo-cAMP, as well as with cholera toxin, released nitrite in a dose-dependent manner. Cholera toxin and dibutyryl-cAMP enhanced nitrite release induced by bacterial lipopolysaccharide. The stimulatory effects of all these substances were inhibited by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine, dexamethasone and the protein synthesis inhibitor, cycloheximide. Our data indicate that the activation of cAMP-dependent pathway(s) can induce nitric oxide synthesis in rat peritoneal macrophages even in the absence of immunological stimuli, such as exogenous cytokines or lipopolysaccharide, although the exact mechanism of this phenomenon remains to be established.
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PMID:cAMP analogues and cholera toxin stimulate the accumulation of nitrite in rat peritoneal macrophage cultures. 815 66

Recent reports have shown that dibutyryl cAMP (DbcAMP) blocks endotoxin-induced lung injury. To determine whether DbcAMP suppresses the production of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in human monocytes, we measured the levels of TNF and IL-1 in response to E. Coli lipopolysaccharide (40 micrograms.ml-1) in vitro. We now show that DbcAMP suppressed dose-dependently the production of TNF in human monocytes, and DbcAMP totally suppressed it at the dose above 5 x 10(-4) M. However, DbcAMP did not suppress the production of IL-1 even at the dose of 5 x 10(-3) M in human monocytes. These data suggest that the productive mechanism of IL-1 may be different from that of TNF. Further, suppression of TNF by DbcAMP may contribute to the beneficial effects in animal models of septic shock or lung injury and this may have clinical implications.
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PMID:[Effects of DbcAMP on tumor necrosis factor and interleukin-1 production in human monocytes]. 823 Jul 18

The goal of our study was to assess whether the human immunodeficiency virus (HIV) coat protein gp120 induces functional alterations in astrocytes and microglia, known for their reactivity and involvement in most types of brain pathology. We hypothesized that gp120-induced anomalies in glial functions, if present, might be mediated by changes in the levels of intracellular messengers important for signal transduction, such as cAMP. Acute (10 min) exposure of cultured rat cortical astrocytes or microglia to 100 pM gp120 caused only a modest (50-60%), though statistically significant, elevation in cAMP levels, which was antagonized by the beta-adrenergic receptor antagonist propranolol. More importantly, the protein substantially depressed [by 30% (astrocytes) and 50% (microglia)] the large increase in cAMP induced by the beta-adrenergic agonist isoproterenol (10 nM), without affecting that induced by direct adenylate cyclase stimulation by forskolin. Qualitatively similar results were obtained using a glial fibrillary acidic protein (GFAP)-positive human glioma cell line. The depression of the beta-adrenergic response had functional consequences in both astrocytes and microglia. In astrocytes we studied the phosphorylation of the two major cytoskeletal proteins, vimentin and GFAP, which is normally stimulated by isoproterenol, and found that gp120 partially (40-50%) prevented such stimulation. In microglial cells, which are the major producers of inflammatory cytokines within the brain, gp120 partially antagonized the negative beta-adrenergic modulation of lipopolysaccharide (10 ng/ml)-induced production of tumor necrosis factor alpha. Our results suggest that, by interfering with the beta-adrenergic regulation of astrocytes and microglia, gp120 may alter astroglial "reactivity" and upset the delicate cytokine network responsible for the defense against viral and opportunistic infections.
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PMID:Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions. 838 71

Several in vitro and in vivo studies have demonstrated suppression of tumour necrosis factor-alpha (TNF-alpha) synthesis by pentoxifylline. In the present study we compared the effect of pentoxifylline with that of five other xanthine derivatives. We addressed two questions. First, what is the relative potency of those chemically related compounds in suppressing the lipopolysaccharide (LPS)-induced production of TNF-alpha in human mononuclear cells? Second, does suppression of TNF-alpha production by these xanthine derivatives correlate with their capacity to inhibit 3',5'-cAMP phosphodiesterase (PDE) activity? The experimental drug A 80 2715 [1-(5-hydroxy-5-methylhexyl)-3-methyl-7-propylxanthine] was identified as the most potent agent with an IC50 (concentration exerting 50% suppression of LPS-induced TNF-alpha production) of 41 microM (mean of 13 individuals). The IC50 values of the other substances ranged between 106 microM for HWA 138 and 419 microM for theophylline. The LPS-induced interleukin-1 beta (IL-1 beta) production was not influenced by all substances tested at comparable concentrations. Inhibition of PDE activity was determined in a cell-free system using PDE isolated from bovine heart. All xanthine derivatives dose-dependently inhibited PDE activity. Furthermore, with the exception of theophylline, there was a high degree of correlation between the potency to suppress TNF-alpha production in the cell culture system and the potency to inhibit PDE activity in the cell-free enzymatic assay. This argues for a crucial role of PDE inhibition in the suppression of TNF-alpha synthesis by xanthine derivatives.
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PMID:Xanthine derivatives: comparison between suppression of tumour necrosis factor-alpha production and inhibition of cAMP phosphodiesterase activity. 838 63

Phosphodiesterase inhibitors were used as a tool to manipulate cellular nucleotide levels in vitro and in vivo. The lipopolysaccharide (LPS)-induced release of tumor necrosis factor alpha (TNF-alpha) from mouse peritoneal macrophages was inhibited by prostaglandin E2 with an IC50 of 0.05 microM and by dibutyryl-cAMP with an IC50 of 180 microM. In the presence of the phosphodiesterase inhibitors zardaverine or rolipram the intracellular cAMP concentration of LPS-stimulated macrophages was significantly increased. In these cells, LPS-inducible TNF release was inhibited by zardaverine (IC50 = 1.5 microM) or by rolipram (IC50 = 0.35 microM). In a model of septic shock, i.e. LPS challenge of galactosamine-sensitized mice, a dose-dependent protection against liver injury was observed following oral application of rolipram (ED50 = 0.55 mg/kg) or of zardaverine (ED50 approximately 30 mg/kg). The adenylate cyclase activator forskolin was also protective. Rolipram also protected against TNF-induced liver injury in mice while zardaverine failed to do so. It is concluded that the intracellular cAMP level of macrophages is a critical determinant of LPS-inducible TNF release and therefore modulates the susceptibility to septic shock.
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PMID:Protection by phosphodiesterase inhibitors against endotoxin-induced liver injury in galactosamine-sensitized mice. 839 40

Resting murine B lymphocytes can be induced to proliferate by cross-linking membrane immunoglobulin, the antigen receptor, or by contact with activated helper T lymphocytes in the absence of a signal through membrane immunoglobulin. Little is known about the molecular nature of contact-dependent T cell help. To determine whether helper T cells activate B cells through different signal transduction and second messenger pathways from those used by membrane immunoglobulin, the effects of drugs which block activation of B cells through membrane immunoglobulin were measured on B cell activation by contact with anti-CD3-activated and fixed T helper cells. Cyclosporin A, phorbol esters added at the time of activation, and cAMP agonists all block activation of B cells through membrane immunoglobulin at concentrations at least 100-fold lower than those necessary to block B cell activation by contact with activated Th1 or Th2 helper T cells. Depletion of protein kinase C by pretreatment of B cells with phorbol ester inhibits the proliferative response to anti-immunoglobulin but not the response to contact with activated T cells. The B cell response to lipopolysaccharide is intermediate in sensitivity to cyclosporin A and cAMP agonists, and resembles the response to activated T cells in resistance to phorbol esters and protein kinase C depletion. Various protein kinase inhibitors did not distinguish among these B cell activation pathways, except for the tyrosine kinase inhibitor, herbimycin A, which inhibited anti-immunoglobulin responses at 3- to 5-fold lower concentrations.
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PMID:Antigen and helper T lymphocytes activate B lymphocytes by distinct signaling pathways. 841 91

Compounds suppressing the production of tumor necrosis factor-alpha are protective in animal models of septic shock. Recent studies demonstrated a beneficial effect of xanthine derivatives, which suppress tumor necrosis factor-alpha production by acting as non-specific cAMP phosphodiesterase inhibitors. In this experiment we tested the effect of (+/-)-rolipram (racemate) and its enantiomers on human mononuclear cells stimulated with lipopolysaccharide (LPS). Rolipram has a phenyl-pyrrolidinone structure, unrelated to the methylxanthines, and acts as a specific inhibitor of the type IV phosphodiesterase. Our results identify rolipram as a remarkably potent suppressor of the LPS-induced synthesis of tumor necrosis factor-alpha. When compared to the non-specific inhibitor pentoxifylline, the IC50 of (+/-)-rolipram (130 nM) is more than 500 times lower. The influence of rolipram on tumor necrosis factor-alpha production depended on the steric configuration of the molecule, since the (-)-enantiomer exhibited a five times lower IC50 than the (+)-enantiomer. The inhibitory effect of all substances tested is selective for tumor necrosis factor-alpha rather than interleukin-1 beta, since interleukin-1 beta production is only slightly influenced.
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PMID:The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. 850 51

Transcription factor NF-kappaB is essential for the induction of nitric oxide synthase (NOS) II (iNOS) by bacterial lipopolysaccharide in murine macrophages (Xie, Q. W., Kashiwabara, Y., and Nathan, C. (1994) J. Biol. Chem. 269, 4705-4708). In 3T3 fibroblasts, agents other than cytokines are efficacious inducers of NOS II expression. In addition to cytokines such as interferon-gamma or tumor necrosis factor-alpha, protein kinase C-stimulating agents such as tetradecanoylphorbol-13-acetate, or cyclic AMP-elevating agents such as forskolin and 8-bromo-cAMP markedly increased NOS II mRNA (measured by Sl nuclease and RNase protection analyses), NOS II protein (determined by Western blotting), and NOS activity (measured by chemiluminescence detection of NO2-). Transforming growth factor-beta1 (which is an inhibitor of NOS II induction in other cell types) potentiated NOS II mRNA expression produced by all inducing agents listed, whereas dexamethasone, pyrrolidine dithiocarbamate and 3,4-dichloroisocoumarin (inhibitors of NF-kappaB activation) suppressed NOS II mRNA induction in response to all stimulants. In electrophoretic mobility shift assays, nuclear protein extracts from 3T3 cells stimulated with any of the inducing agents significantly slowed the migration of an NF-kappaB-binding oligonucleotide, whereas nuclear extracts from untreated control cells did not. These experiments indicate that NF-kappaB is the key control element for the induction of NOS II in response to at least three different second messenger pathways in 3T3 cells.
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PMID:In murine 3T3 fibroblasts, different second messenger pathways resulting in the induction of NO synthase II (iNOS) converge in the activation of transcription factor NF-kappaB. 862 88

Cytokines, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), are thought to be responsible for the compromised blood pressure regulation after systemic infection or other antigenic challenge. Because Ca homeostasis is critical for the maintenance of vascular tone, we hypothesized that cytokines may contribute to alterations in blood pressure by a mechanism involving the voltage-sensitive Ca channel in vascular smooth muscle (VSM) cells. Using nystatin-permeabilized patch techniques we examined the effects of IL-1 beta, TNF-alpha, and lipopolysaccharide (LPS) on the Ca channel of VSM cells isolated from rat tail artery. Both IL-1 beta (0.05--1 nM) and TNF-alpha (0.1--1 nM) increased, dose-dependently, the Ba2+ current carried in VSM Ca channels, whereas heat-denatured IL-1 beta was without significant effect on the channel. LPS (0.01--1.0 ng/ml) also increased the Ba2+ current with onset kinetics similar to the two cytokines. Prostaglandins were ruled out as an intermediary in VSM Ca channel modulation, as prostaglandin E2 had no effect and indomethacin (1 microM) failed to block TNF-alpha-induced Ca channel enhancement. The role of cyclic nucleotides in mediating TNF-alpha-induced changes in Ca channel activity was also assessed. Increasing intracellular cAMP via forskolin (1 microM) did not affect the response to TNF-alpha, but pretreatment with the membrane-permeant analog of cGMP, dibutyryl cGMP (100 microM), inhibited the response to TNF-alpha. These data demonstrate that IL-1 beta, TNF-alpha, and LPS have immediate effects on VSM cells via an interaction with the voltage-sensitive Ca channel, and these effects may he regulated by intracellular cGMP. Immunomodulation of Ca channels may represent an early signaling step in VSM cells mediating kinetically slower events, such as changes in gene transcription.
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PMID:Interleukin-1beta, tumor necrosis factor-alpha, and LPS enhance calcium channel current in isolated vascular smooth muscle cells of rat tail artery. 863 96

The costimulatory molecule B7.1 provides a second signal critical for T cell activation. The distribution of this integral membrane protein is restricted to certain tissues where its level of expression is modulated by multiple exogenous stimuli. To identify the molecular basis for specificity and inducibility, the chromatin configuration of the human B7.1 gene was examined in intact nuclei from various cell types. The identification of a tissue-specific deoxyribonuclease I hypersensitive site approximately 3kb upstream of the transcription start site led to the characterization of a cell type-specific enhancer region. This 183-bp region was both cell type specific and responsive to two distinct stimuli, lipopolysaccharide and dibutyryl cAMP, known to regulate B7.1 expression. Deletional and site-directed mutagenesis revealed the presence of multiple functionally critical cis elements within this region, one of which was a nuclear factor (NF)-kappaB consensus sequence. In B7.1-positive B cells, this element bound several members of the NF-kappaB family, transcription factors already implicated in signal transduction pathways relevant to B7.1 expression. This is the first description, to our knowledge, of regulatory elements that control expression of a gene encoding a B7 costimulatory molecule.
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PMID:A cell type-specific enhancer in the human B7.1 gene regulated by NF-kappaB. 864 82


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