Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A toxic dose of the nitric oxide (NO) donor S-nitrosoglutathione (GSNO; 1 mM) promoted apoptotic cell death of RAW 264.7 macrophages, which was attenuated by cellular preactivation with a nontoxic dose of GSNO (200 microM) or with lipopolysaccharide, interferon-gamma, and NG-monomethyl-L-arginine (LPS/IFN-gamma/NMMA) for 15 h. Protection from apoptosis was achieved by expression of cyclooxygenase-2 (Cox-2). Here we investigated the underlying mechanisms leading to Cox-2 expression. LPS/IFN-gamma/NMMA prestimulation activated nuclear factor (NF)-kappaB and promoted Cox-2 expression. Cox-2 induction by low-dose GSNO demanded activation of both NF-kappaB and activator protein-1 (AP-1). NF-kappaB supershift analysis implied an active p50/p65 heterodimer, and a luciferase reporter construct, containing four copies of the NF-kappaB site derived from the murine Cox-2 promoter, confirmed NF-kappaB activation after NO addition. An NF-kappaB decoy approach abrogated not only Cox-2 expression after low-dose NO or after LPS/IFN-gamma/NMMA but also inducible protection. The importance of AP-1 for Cox-2 expression and cell protection by low-level NO was substantiated by using the extracellular signal-regulated kinase inhibitor PD98059, blocking NO-elicited Cox-2 expression, but leaving the cytokine signal unaltered. Transient transfection of a dominant-negative c-Jun mutant further attenuated Cox-2 expression by low-level NO. Whereas cytokine-mediated Cox-2 induction relies on NF-kappaB activation, a low-level NO-elicited Cox-2 response required activation of both NF-kappaB and AP-1.
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PMID:NF-kappaB and AP-1 activation by nitric oxide attenuated apoptotic cell death in RAW 264.7 macrophages. 995 Jun 82

A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease mortality. The phytochemical resveratrol found in wine, derived from grapes, has been thought to be responsible for cardiovascular benefits associated with wine consumption because it was shown to have antioxidant and antiplatelet activities. In the present investigation, we examined the effect of resveratrol on induction of tissue factor (TF) expression in vascular cells that were exposed to pathophysiological stimuli. The data presented herein show that resveratrol, in a dose-dependent manner, inhibited the expression of TF in endothelial cells stimulated with a variety of agonists, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and lipopolysaccharide (LPS). A similar inhibition of TF induction was also seen in LPS stimulated monocytes that were pretreated with resveratrol before their stimulation with LPS. In addition, resveratrol was shown to inhibit the LPS-induced expression of TNFalpha mRNA in endothelial cells and of TNFalpha and IL-1beta mRNA in monocytes. Nuclear run-on analysis in endothelial cells showed that resveratrol inhibited TF expression at the level of transcription. However, resveratrol did not significantly alter the binding of the transcription factors c-Fos/c-Jun and c-Rel/p65, the transcription factors required for the induction of TF promoter in both endothelial cells and monocytes. Similarly, resveratrol had no significant effect on the binding of NF-kappaB in endothelial cells stimulated with IL-1beta, TNFalpha, and LPS. Overall, our data show that resveratrol could effectively suppress the aberrant expression of TF and cytokines in vascular cells, but it requires further investigation to understand how resveratrol exerts its inhibitory effect.
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PMID:Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells : A possible mechanism for the cardiovascular benefits associated with moderate consumption of wine. 997 27

Protein kinase C (PKC)-alpha, -betaI, and -delta are known to be involved in the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. The role of mitogen-activated protein kinases (MAPK) p44/42 and p38 in the LPS effect was studied further. LPS-mediated NO release and the inducible form of NO synthase expression were inhibited by the p38 inhibitor, SB 203580, but not by the MAPK kinase inhibitor, PD 98059. Ten-minute treatment of cells with LPS resulted in the activation of p44/42 MAPK, p38, and c-Jun NH2-terminal kinase. Marked or slight activation, respectively, of p44/42 MAPK or p38 was also seen after 10-min treatment with 12-O-tetradecanoylphorbol-13-acetate, but c-Jun NH2-terminal kinase activation did not occur. Tyrosine kinase inhibitor, genestein, attenuated the LPS-induced activation of both p44/42 MAPK and p38, whereas the PKC inhibitors, Ro 31-8220 and calphostin C, or long-term treatment with 12-O-tetradecanoylphorbol-13-acetate resulted in inhibition of p44/42 MAPK activation, but had only a slight effect on p38 activation, indicating that LPS-mediated PKC activation resulted in the activation of p44/42 MAPK. Nuclear factor-kappaB (NF-kappaB)-specific DNA-protein-binding activity in the nuclear extracts was enhanced by 10-min, 1-h, or 24-h treatment with LPS. Analysis of the proteins involved in NF-kappaB binding showed translocation of p65 from the cytosol to the nucleus after 10-min treatment with LPS. The onset of NF-kappaB activation correlated with the cytosolic degradation of both inhibitory proteins of NF-kappaB, IkappaB-alpha and IkappaB-beta. IkappaB-alpha was resynthesized rapidly after loss (1-h LPS treatment), whereas IkappaB-beta levels were not restored until after 24-h treatment. SB 203580 but not PD 98059 inhibited the LPS-induced stimulation of NF-kappaB DNA-protein binding. Thus, activation of p38 but not p44/42 MAPK by LPS resulted in the stimulation of NF-kappaB-specific DNA-protein binding and the subsequent expression of inducible form of NO synthase and NO release in RAW 264.7 macrophages.
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PMID:p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. 1005 31

Macrophages are targeted by environmental pollutants and play a role in allergic inflammation. We explored the molecular basis for induction of RANTES (regulated upon activation, normal T-cells expressed and secreted) mRNA by lipopolysaccharide (LPS) and the redox-active quinone, tert-butylhydroxyquinone (tBHQ). We demonstrate that transcriptional activation of the human RANTES promoter by LPS is dependent on specific AP-1 and NF-kappaB response elements, which are regulated by c-Jun N-terminal kinase (JNK) and NF-kappaB kinase cascades, respectively. The transcriptional activation of the TRE3/4 site is mediated through the transcriptional activation of c-Jun by JNK. A c-Jun mutant which lacks a transcriptional activation domain interfered in the activation of the RANTES promoter. Similarly, kinase-inactive NF-kappaB inducing kinase interfered in the activation of the RANTES promoter. While activation of the RANTES promoter could also be blocked by the downstream kinase-inactive IkappaB kinases, only IKKalpha appears to be LPS-inducible. tBHQ also exerted subtle effects on the human RANTES promoter and induced mRNA expression in parallel with generating NF-kappaB shift complexes.
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PMID:Activation of the human RANTES gene promoter in a macrophage cell line by lipopolysaccharide is dependent on stress-activated protein kinases and the IkappaB kinase cascade: implications for exacerbation of allergic inflammation by environmental pollutants. 1007 57

We investigated whether vascular endothelial growth factor (VEGF) production by human pulp cells (HPC) is regulated by lipopolysaccharide (LPS) in relation to the pathogenesis of pulpitis. Although HPC incubated with medium alone only marginally expressed VEGF mRNA and produced a low level of VEGF as detected by enzyme-linked immunosorbent assay, the VEGF mRNA expression and VEGF production were markedly enhanced upon stimulation with LPS from Escherichia coli. Prevotella intermedia LPS, phorbol 12-myristate 13-acetate, and interleukin-6 also induced VEGF mRNA expression in HPC. A simian virus 40-infected HPC line also exhibited increased VEGF mRNA expression in response to E. coli LPS, but lung and skin fibroblasts did not. Fetal bovine serum (FBS) increased the sensitivity of HPC to LPS in a dose-dependent manner. HPC did not express membrane CD14 on their surfaces. However, the anti-CD14 monoclonal antibody MY4 inhibited VEGF induction upon stimulation with LPS in HPC cultures in the presence of 10% FBS but not in the absence of FBS. LPS augmented the VEGF production in HPC cultures in the presence of recombinant human soluble CD14 (sCD14). To clarify the mechanisms of VEGF induction by LPS, we examined the possible activation of the transcription factor AP-1 in HPC stimulated with LPS, by a gel mobility shift assay. AP-1 activation in HPC was clearly observed, whereas that in skin fibroblasts was not. The AP-1 inhibitor curcumin strongly inhibited LPS-induced VEGF production in HPC cultures. In addition, a protein synthesis inhibitor, cycloheximide, inhibited VEGF mRNA accumulation in response to LPS. These results suggest that the enhanced production of VEGF in HPC induced by LPS takes place via an sCD14-dependent pathway which requires new protein synthesis and is mediated in part through AP-1 activation.
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PMID:Lipopolysaccharide enhances the production of vascular endothelial growth factor by human pulp cells in culture. 1008 96

The involvement of ceramide in lipopolysaccharide-mediated activation of mouse macrophages was studied. Lipopolysaccharide, cell-permeable ceramide analogs, and bacterial sphingomyelinase led to phosphorylation of the extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 kinase and induced AP-1 DNA binding in C3H/OuJ (Lpsn) but not in C3H/HeJ (Lpsd) macrophages. Lipopolysaccharide and ceramide mimetics showed distinct kinetics of mitogen-activated protein kinase phosphorylation and AP-1 induction and activated AP-1 complexes with different subunit compositions. Lipopolysaccharide-activated AP-1 consisted of c-Fos, Jun-B, Jun-D, and c-Jun, while C2-ceramide induced Jun-D and c-Jun only. Lipopolysaccharide and, less potently, C2-ceramide or sphingomyelinase, stimulated AP-1-dependent reporter gene transcription in RAW 264.7 cells. Unlike lipopolysaccharide, C2-ceramide failed to activate NF-kappaB and did not induce production of tumor necrosis factor or interleukin-6. The lipopolysaccharide antagonist, Rhodobacter sphae-roides diphosphoryl lipid A, inhibited lipopolysaccharide activation of NF-kappaB and AP-1 but did not block C2-ceramide-induced AP-1. Pretreatment of C3H/OuJ macrophages with C2-ceramide greatly diminished AP-1 induction following subsequent C2-ceramide stimulation. However, lipopolysaccharide-induced transcription factor activation and cytokine release were not influenced. In contrast, lipopolysaccharide pretreatment inhibited both lipopolysaccharide- and C2-ceramide-mediated responses. Thus, ceramide partially mimics lipopolysaccharide in activating the mitogen-activated protein kinases and AP-1 but not in mediating NF-kappaB induction or cytokine production, suggesting a limited role in lipopolysaccharide signaling.
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PMID:Limited role of ceramide in lipopolysaccharide-mediated mitogen-activated protein kinase activation, transcription factor induction, and cytokine release. 1009 12

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.
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PMID:Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. 1019 Sep 4

Peptidoglycan (PGN), the major cell wall component of Gram-positive bacteria, induces secretion of cytokines in macrophages through CD14, the pattern recognition receptor that binds lipopolysaccharide and other microbial products. To begin to elucidate the mechanisms that regulate the transcription of cytokine genes, we wanted to determine which transcription factors are activated by PGN in mouse RAW264.7 and human THP-1 macrophage cells. Our results demonstrated that: (i) PGN induced phosphorylation of the transcription factors ATF-1 and CREB; (ii) ATF-1 and CREB bound DNA as a dimer and induced transcriptional activation of a CRE reporter plasmid, which was inhibited by dominant negative CREB and ATF-1; (iii) PGN induced phosphorylation of c-Jun, protein synthesis of JunB and c-Fos, and transcriptional activation of the AP-1 reporter plasmid, which was inhibited by dominant negative c-Fos; and (iv) PGN-induced activation of CREB/ATF and AP-1 was mediated through CD14. This is the first study to demonstrate activation of CREB/ATF and AP-1 transcription factors by PGN or by any other component of Gram-positive bacteria.
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PMID:Bacterial peptidoglycan induces CD14-dependent activation of transcription factors CREB/ATF and AP-1. 1031 14

1. The intracellular transport of leukotriene C4 (LTC4) in hematopoietic cells such as human monocytes is controlled by an ATP dependent carrier encoded by the multidrug resistance protein1 (MRPI) gene whose function can be blocked by the compound MK-571. Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRPI mediated function by MK-571 might affect cytokine production. 2. MK-571 strongly enhanced IL-6 expression at mRNA and protein level in lipopolysaccharide (LPS) and interleukin-1 (IL-1) stimulated human monocytes giving rise to 2.0+/-0.4 (x+/-s.d.) and 5.7+/-3.5 fold induction of IL-6 protein secretion. The increase in IL-6 secretion was accompanied by an enhanced phosphorylation of p38 but not of c-Jun-N terminal kinase. 3. The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 signalling route. MK-571 mediated upregulation of IL-6 in the presence of IL-1 was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK-571 did not affect the IL-1 induced DNA binding activity of Activator Protein-1 and Nuclear Factor-kappaB but rather enhanced the transactivational activity of an IL-6 promoter construct. Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC). 4. These results indicate that the membrane transporter MRP1 is involved in the regulation of IL-6 expression in activated human peripheral blood monocytes.
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PMID:Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1. 1038 44

Tumor necrosis factor (TNF) is a highly pleiotropic cytokine whose activity is at least partially regulated by the redox status of the cell. The cellular redox status is controlled primarily by glutathione, a major cellular antioxidant, whose synthesis is regulated by the rate-limiting enzyme gamma-glutamylcysteine synthetase (gamma-GCS). In the present report we investigated the effect of gamma-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-kappa B and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with gamma-GCS cDNA blocked TNF-induced NF-kappa B activation, cytoplasmic I kappa B alpha degradation, nuclear translocation of p65, and NF-kappa B-dependent gene transcription. gamma-GCS overexpression also completely suppressed NF-kappa B activation induced by phorbol ester and okadaic acid, whereas that induced by H2O2, ceramide, and lipopolysaccharide was minimally affected. gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF-induced activation of JNK and mitogen-activated protein kinase kinase. TNF-mediated cytotoxicity and activation of caspase-3 were both abrogated in gamma-GCS-overexpressing cells. Overall, our results indicate that most of the pleiotropic actions of TNF are regulated by the glutathione-controlled redox status of the cell.
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PMID:Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1. 1043 45


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