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)

The nuclear factor-kappaB (NF-kappaB) family of transcription factors have been implicated in the inducible expression of genes involved in inflammatory and immune responses. As such, a specific inhibitor of NF-kappaB would be a useful therapeutic agent in a variety of inflammatory disorders. The marine natural product hymenialdisine was evaluated as an inhibitor of NF-kappaB in U937 cells. U937 cells were transfected with either a luciferase reporter plasmid containing the human immunodeficiency virus long terminal repeat or the interleukin-8 (IL-8) core promoter, both of which are activated by NF-kappaB. Hymenialdisine caused a concentration-dependent decrease in luciferase production from both reporters when the cells were stimulated with tumor necrosis factor-alpha, lipopolysaccharide or phorbol myristate acetate. An electrophoretic mobility shift assay confirmed its activity by inhibiting DNA binding of NF-kappaB. Hymenialdisine was shown to be a selective inhibitor of NF-kappaB in that it had no effect on the binding of other transcription factors to their DNA concensus motifs; these included activator protein-1, CCAAT/enhancer binding protein and Sp1. Functional studies showed hymenialdisine to be an inhibitor of IL-8 production and IL-8 mRNA formation in the U937 cell. Investigation into the mechanism of action of hymenialdisine showed that it was not due to inhibition of protein kinase C because the selective protein kinase C inhibitor RO 32-0432 was inactive against tumor necrosis factor-alpha-stimulated luciferase and IL-8 production. The compound also had no effect on IkappaB alpha or IkappaB beta phosphorylation and degradation. Thus, hymenialdisine is a potent inhibitor of NF-kappaB and IL-8 production in U937 cells.
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PMID:The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB. 922 88

Constitutive activation of NF-kappaB in WEHI 231 early mature B cells resembles the persistent activation of NF-kappaB that is observed upon prolonged stimulation of other cells. In both cases, NF-kappaB DNA binding complexes are found in the nucleus, despite the abundance of cytosolic IkappaB alpha. Recently, we have shown that prolonged activation of 70Z/3 cells with lipopolysaccharide results in the degradation of IkappaB beta, followed by its subsequent resynthesis as a hypophosphorylated protein. This protein was shown to facilitate transport of a portion of NF-kappaB to the nucleus in a manner that protects it from cytosolic IkappaB alpha. We now demonstrate that the most abundant form of IkappaB beta in WEHI 231 cells is a hypophosphorylated protein. This hypophosphorylated IkappaB beta is found in a stable complex with NF-kappaB in the cytosol and is also detected in NF-kappaB DNA binding complexes in the nucleus. It is likely that hypophosphorylated IkappaB beta in WEHI 231 cells also protects NF-kappaB from IkappaB alpha, thus leading to the continuous nuclear import of this transcription factor.
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PMID:Regulation of IkappaB beta in WEHI 231 mature B cells. 923 97

A concerted activation of transcription factors involved in the transactivation of type II NO synthase (iNOS) gene occurred after partial hepatectomy (PH), resulting in the transient expression of iNOS. The corresponding mRNA and protein levels of iNOS reached a maximum at 4 h and 8 h post-PH respectively. This induction was preceded by an early and transient activation of nuclear factor kappaB (NF-kappaB). Analysis of the kappaB inhibitory (I) proteins showed an important role for IkappaBalpha in the process of NF-kappaB activation, whereas the contribution of IkappaBbeta was less evident. Interferon regulatory factor 1, which has been described as an important activator of iNOS expression, was up-regulated after PH but failed to bind to the corresponding DNA binding sequences of the iNOS promoter. The transcriptional control of iNOS after PH, was compared with the events associated with the hepatic expression of this enzyme in animals challenged with lipopolysaccharide, showing a differential pattern of transcription-factor activation and IkappaB degradation between both models. Transfection of hepatoma cell lines with iNOS promoter constructs, followed by stimulation with post-PH sera, revealed the requirement of NF-kappaB activation for iNOS expression. These data suggest that there is an important role for the restricted NF-kappaB activation in the temporal pattern of iNOS expression in regenerating liver.
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PMID:Nuclear factor kappaB is required for the transcriptional control of type II NO synthase in regenerating liver. 930 29

To elucidate the molecular action of the NFkappaB inhibitor IkappaBbeta, we isolated a number of IkappaBbeta interactors using the yeast two-hybrid system. These include the retinoid X receptor (RXR), whose interaction with IkappaBbeta is significantly stimulated by the RXR ligand 9-cis-retinoic acid, as shown in the yeast system as well as the glutathione S-transferase pull down assays. RXR is a nuclear protein, whereas IkappaBbeta accumulates in the nucleus only in cells stimulated with lipopolysaccharide or other inducers that result in prolonged activation of NFkappaB. Consistent with this, cotransfection with IkappaBbeta specifically repressed the 9-cis-RA-induced transcriptional activities of RXR in an lipopolysaccharide-dependent manner. These results suggest a novel IkappaBbeta-mediated antagonism between the signaling pathways of NFkappaB and RXR.
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PMID:IkappaBbeta interacts with the retinoid X receptor and inhibits retinoid-dependent transactivation in lipopolysaccharide-treated cells. 945 33

The effect of cycloheximide (CHX) on the mRNA expression of the cytokine-inducible, calcium-independent nitric oxide synthase (iNOS) was investigated in fetal hepatocytes stimulated with lipopolysaccharide (LPS) or pro-inflammatory cytokines. In the presence of CHX the LPS-dependent iNOS mRNA levels were reduced, whereas the response to pro-inflammatory cytokines was enhanced. Because iNOS transcription is highly dependent on the activation of nuclear factor kappaB (NF-kappaB), this factor was evaluated by electrophoretic mobility shift assays, and a close correlation between NF-kappaB activity and iNOS mRNA levels was observed. CHX itself potentiated the degradation of the IkappaB alpha and IkappaB beta inhibitory subunits (IkappaB is inhibitory kappaB) of the NF-kappaB complex, and therefore the loss of LPS-dependent iNOS mRNA expression cannot be attributed to a blockage in the activation of NF-kappaB. These results suggest the existence of a CHX-sensitive pathway in the expression of iNOS mediated by LPS, a mechanism that is not involved in the response to pro-inflammatory cytokines.
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PMID:Differential regulation of nitric oxide synthase mRNA expression by lipopolysaccharide and pro-inflammatory cytokines in fetal hepatocytes treated with cycloheximide. 958 61

We studied the signal transduction pathways involved in NF-kappaB activation and the induction of the cytoprotective A20 gene by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVEC). LPS induced human A20 mRNA expression with a maximum level 2 h after stimulation. The proteasome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN) and the tyrosine kinase inhibitor herbimycin A (HMA) blocked A20 mRNA expression and partially inhibited NF-kappaB DNA-binding activity induced by LPS treatment. LPS induced IkappaBalpha degradation at 30-60 min after treatment, but did not induce IkappaBbeta degradation up to 120 min. In contrast, TNF-alpha rapidly induced IkappaBalpha degradation within 5 min and IkappaBbeta degradation within 15 min. Cycloheximide did not prevent LPS-induced IkappaBalpha degradation, indicating that newly synthesized proteins induced by LPS were not involved in LPS-stimulated IkappaBalpha degradation. LPS-induced IkappaBalpha degradation was inhibited by ALLN, confirming that ALLN inhibits NF-kappaB activation by preventing IkappaBalpha degradation. Of note, HMA also inhibited LPS-induced IkappaBalpha degradation. However, tyrosine phosphorylation of IkappaBalpha itself was not elicited by LPS stimulation, suggesting that tyrosine phosphorylation of a protein(s) upstream of IkappaBalpha is required for subsequent degradation. We conclude that in HUVEC, LPS induces NF-kappaB-dependent genes through degradation of IkappaBalpha, not IkappaBbeta, and propose that this degradation is induced in part by HMA-sensitive kinase(s) upstream of IkappaBalpha.
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PMID:Lipopolysaccharide-induced NF-kappaB activation in human endothelial cells involves degradation of IkappaBalpha but not IkappaBbeta. 974 2

Mononuclear phagocytes play a major role in immune and inflammatory responses. Bacterial lipopolysaccharide (LPS) induces monocytes to express a variety of genes by activating the NF-kappaB/Rel transcription factor family. Recently, we have reported that the tumor necrosis factor and interleukin 1 signaling pathways activate two kinases, IKK1 and IKK2. Phosphorylation of the IkappaB cytoplasmic inhibitors, IkappaBalpha, IkappaBbeta, and IkappaBepsilon, by these kinases triggers proteolytic degradation and the release of NF-kappaB/Rel proteins into the nucleus. At present, the role of the IKKs in LPS signaling has not been investigated. Here, we report that LPS induces IKK activity in human monocytes and THP-1 monocytic cells. The kinetics of activation of kinase activity in monocytic cells are relatively slow with maximal activity observed at 60 min, which coincides with the degradation of IkappaBs and the nuclear translocation of NF-kappaB. In transfection experiments, overexpression of wild type IKK1, a dominant negative mutant IKK1 (K44M), or wild type IKK2 did not affect LPS-induced kappaB-dependent transcription in monocytic cells. In contrast, a dominant negative mutant of IKK2 inhibited LPS induction of kappaB-dependent transcription in a dose-dependent manner. These results indicate that LPS induction of kappaB-dependent gene expression in human monocytic cells requires activation of IKK2.
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PMID:Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. 980 6

Oxidized low density lipoprotein (oxLDL) is known to alter the expression of inflammatory gene products in mononuclear phagocytes. The mechanisms involved in this effect were studied by examining the activation of nuclear factor kappaB (NFkappaB), a transcription factor known to be important in controlling the expression of such genes. Pretreatment of peritoneal macrophages with oxLDL modulated the activation of NFkappaB in response to either lipopolysaccharide (LPS) or the combination of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). In macrophages pretreated with oxLDL the nuclear translocation of Rel family members (RelA and c-Rel) is delayed (LPS) or markedly diminished (IFN-gamma/IL-2) and results in delayed or reduced appearance of kappaB binding activity within the nucleus. These changes in NFkappaB activation result from alterations in the stimulus-dependent degradation of IkappaB alpha and IkappaB beta. The effects of oxLDL on NFkappaB activation depend both on the degree of LDL oxidation (most potent with extensive oxidation) and on the time of exposure of the cells to the lipoprotein preparation (a minimal exposure of 6 h is required before inhibitory effects are observed). The modulation of IkappaB/NFkappaB function in cells exposed to oxLDL appears to be responsible for previously reported effects of oxLDL on chemoattractant cytokine gene expression where both inhibition and delay of such stimulus-dependent events has been observed.
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PMID:Oxidized LDL modulates activation of NFkappaB in mononuclear phagocytes by altering the degradation if IkappaBs. 982 73

Previously we reported that 3-deazaadenosine (DZA), a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor-alpha and interleukin-1beta in mouse macrophage RAW 264.7 cells. In this study, we demonstrate the effects of DZA on nuclear factor-kappaB (NF-kappaB) regulation. DZA inhibits the transcriptional activity of NF-kappaB through the hindrance of p65 (Rel-A) phosphorylation without reduction of its nuclear translocation and DNA binding activity. The inhibitory effect of DZA on NF-kappaB transcriptional activity is potentiated by the addition of homocysteine. Taken together, DZA promotes the proteolytic degradation of IkappaBalpha, but not IkappaBbeta, resulting in an increase of DNA binding activity of NF-kappaB in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells. The reduction of IkappaBalpha by DZA is neither involved in IkappaB kinase complex activation nor modulated by the addition of homocysteine. This study strongly suggests that DZA may be a potent drug for the treatment of diseases in which NF-kappaB plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-kappaB.
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PMID:3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-kappaB regulation. Inhibition of NF-kappaB transcriptional activity and promotion of IkappaBalpha degradation. 1038 97

Recently isolated trophoblasts express nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), decreasing the levels of the corresponding mRNAs when the cells were maintained in culture. The sustained expression of COX-2 and NOS-2 in trophoblasts was dependent on the activation of nuclear factor kappaB (NF-kappaB) since proteasome inhibitors and antioxidants that abrogated NF-kappaB activity suppressed the induction of both genes. The time-dependent fall of the mRNA levels of NOS-2 and COX-2 paralleled the inhibition of NF-kappaB, determined by electrophoretic mobility shift assays, and the increase of the IkappaBalpha and IkappaBbeta inhibitory proteins. Isolated trophoblasts synthesized reactive oxygen intermediates (ROI), a process impaired after culturing the cells, and that might be involved in the NF-kappaB activation process. Moreover, treatment of recently isolated cells with ROI scavengers suppressed the expression of COX-2 and NOS-2. Challenge of trophoblasts with interleukin-1beta up-regulated the expression of both proteins, an effect that was potentiated by lipopolysaccharide. These results indicate that the physiological expression of NOS-2 and COX-2 in trophoblasts involves a sustained activation of NF-kappaB which inhibition abrogates the inducibility of both genes.
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PMID:Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts. 1046 30


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