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 activity of the NF-kappa B transcription factor is controlled through cytoplasmic retention by either of two types of molecules: the inhibitor I kappa B alpha/MAD3 or the p105 and p100 precursors of the p50 and p52 DNA-binding subunits. Treatment of cells with classical NF-kappa B inducers such as tumor necrosis factor, interleukin-1, phorbol myristate acetate, and lipopolysaccharide results in MAD3 degradation followed by nuclear translocation of NF-kappa B. On the other hand, the mechanisms involved in the dissociation of the cytoplasmic p105/p100-containing complexes are largely unknown. The Tax protein encoded by human T-cell leukemia virus type 1 is a potent activator of viral and cellular gene transcription. It does not bind DNA directly but seems to activate transcription indirectly either by enhancing the activities of the transcription factors that recognize responsive elements located in the promoters of the Tax-responsive genes or by forming ternary complexes with these factors and DNA. It has been previously shown that Tax is able to induce nuclear translocation of NF-kappa B. We demonstrate here that Tax can induce translocation of members of the NF-kappa B family retained in the cytoplasm through their interaction with either p105 or p100. On the other hand, Tax induces no apparent degradation of MAD3, although experiments using cycloheximide indicate that it decreases the half-life of MAD3. However, this activity is shared by a mutant of Tax which is unable to activate NF-kappa B. These results suggest that Tax activates NF-kappa B essentially through the p105/p100 retention pathway.
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PMID:Tax induces nuclear translocation of NF-kappa B through dissociation of cytoplasmic complexes containing p105 or p100 but does not induce degradation of I kappa B alpha/MAD3. 796 93

The NF-kappa B/Rel family of at least five transcription factor polypeptides is thought to function both as a developmental regulator in B cells and as a rapid response system in all cells. To examine this notion in more detail, we determined the protein contents of both the inducible and constitutive NF-kappa B/Rel activities in a pre-B-cell line, 70Z/3, and a mature B-cell line, WEHI 231. NF-kappa B p50/p65 is the major inducible nuclear complex after lipopolysaccharide or phorbol myristate acetate treatment of 70Z/3 cells. The constitutive and inducible complexes in WEHI 231 cells are mainly composed of p50 and Rel. The constitutive or induced activities are all sensitive to I kappa B-alpha, but this inhibitor is very short-lived in WEHI 231 cells, suggesting that the balance between synthesis and degradation of I kappa B-alpha determines whether a particular cell lineage has constitutive activity. A patterned expression of the NF-kappa B/Rel activator proteins emerges from an analysis of other B-lineage cell lines and splenic B cells: mainly p50 and p65 in pre-B (and non-B) cells, a predominance of Rel and p50 in mature B cells, and expression of p52 and RelB in plasmacytoma lines. This ordered pattern of regulators may reflect the requirement for expression of different genes during terminal B-cell differentiation because different combinations of NF-kappa B/Rel family members preferentially activate distinct kappa B sites in reporter constructs.
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PMID:Sequential induction of NF-kappa B/Rel family proteins during B-cell terminal differentiation. 803 13

Inducible vascular cell adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMC) exposed to lipopolysaccharide (LPS) in vitro involves the activation of nuclear factor-kappa B (NF-kappa B) and its interaction with the proximal VCAM-1 promoter. We used a murine model to assess the effect of the antioxidant, N-acetyl cysteine on GMC activation in vivo. Single intraperitoneal administration of N-acetyl cysteine completely suppressed LPS-induced VCAM-1 expression on the GMC surface. When an oligonucleotide spanning the NF-kappa B binding region of the VCAM-1 promoter was incubated with extracts from the renal cortex of LPS-treated animals, a single nucleoprotein complex formed. This complex was composed of p50 and p65, but not p52, c-Rel, or RelB, and its formation was dramatically inhibited by pretreatment with N-acetyl cysteine, D,L-Buthionine-[S,R]-sulfoximide, a compound that depletes glutathione, augmented VCAM-1 expression inducible with a suboptimal amount of LPS to levels comparable with using 50 micrograms of LPS alone, D,L-Buthionine-[S,R]-sulfoximide also potentiated the p50-p65 binding activity induced with a suboptimal amount of LPS. These data provide a redox-sensitive, transcriptional link between NF-kappa B and VCAM-1 in GMC in vivo and implicate oxidative stress as an important regulatory signal in the pathogenesis of glomerular mesangial cell disorders.
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PMID:N-acetyl cysteine blocks mesangial VCAM-1 and NF-kappa B expression in vivo. 935 47

PGG-Glucan (Betafectin) is a novel soluble beta-glucan immunomodulator that enhances leukocyte microbicidal activities without inducing inflammatory cytokines. Although several different receptors for soluble and particulate beta-glucans have been described, the signal transduction pathway(s) used by soluble beta-glucans have not been elucidated. We report that in a murine monocytic cell line (BMC2.3) PGG-Glucan activates nuclear factor-kappaB (NF-kappaB)-like and NF-interleukin-6 (IL-6)-like transcription factors. Electrophoretic mobility shift assays showed that PGG-Glucan activation of the factors is time- and concentration-dependent. The NF-kappaB-like complex includes subunit p65 (rel-A) as one of its components, but apparently not p50 (kappaB1), p52 (kappaB2), p68 (rel-B), or p75 (C-rel) family members. The NF-IL-6-like complex contains subunit C/EBP-beta (NF-IL-6alpha) as one of its components, but apparently not C/EBP-alpha or C/EBP-delta (NF-IL-6beta). As expected, lipopolysaccharide (LPS) activated p65/p50 NF-kappaB and C/EBP-beta NF-IL-6 complexes, increased the nuclear titer of p65 and p50 antigens, and increased cytokine (IL-1beta, tumor necrosis factor alpha) mRNA production. In contrast, PGG-Glucan increased the nuclear titer of p65, but apparently not p50, and did not induce cytokine mRNA production. These data demonstrate that PGG-Glucan utilizes signal transduction pathways different from those used by LPS. The data suggest that activation of the PGG-Glucan-stimulated factors is not sufficient to stimulate cytokine mRNA transcription.
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PMID:PGG-Glucan activates NF-kappaB-like and NF-IL-6-like transcription factor complexes in a murine monocytic cell line. 940 Aug 29

P-selectin, an adhesion receptor for leukocytes, is constitutively expressed in megakaryocytes and endothelial cells. Tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) increases synthesis of P-selectin in murine but not in human endothelial cells. To identify potential species-specific and conserved mechanisms for regulation of expression of P-selectin, we cloned the 5'-flanking region of the murine P-selectin gene and compared its features with those previously reported for the human gene. The murine and human genes shared conserved Stat-like, Hox, Ets, GATA, and GT-IIC elements. In the murine gene, a conserved GATA element bound to GATA-2 and functioned as a positive regulatory element, whereas a conserved Ets element bound to GA-binding protein and functioned as a negative regulatory element. Significantly, the murine P-selectin gene had several features not found in the human gene. These included an insertion from -987 to -649 that contained tandem GATA and tandem AP1-like sequences, which resembled enhancers in beta-globin locus control regions. Both tandem elements bound specifically to nuclear proteins. The murine gene lacked the unique kappaB site specific for p50 or p52 homodimers found in the human gene. Instead, it contained two tandem kappaB elements and a variant activating transcription factor/cAMP response element site, which closely resembled sites in the E-selectin gene that are required for TNF-alpha- or LPS-inducible expression. TNF-alpha or LPS augmented expression of a reporter gene driven by the murine, but not the human, P-selectin promoter in transfected endothelial cells. Deletional analysis of the murine 5'-flanking region revealed several sequences that were required for either constitutive or inducible expression. These data suggest that both species-specific and conserved mechanisms regulate transcription of the human and murine P-selectin genes.
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PMID:Comparison of promoters for the murine and human P-selectin genes suggests species-specific and conserved mechanisms for transcriptional regulation in endothelial cells. 954 53

Cytokine secretion by mesangial cells (MC) plays a major role in the pathogenesis of glomerulonephritis. To define signaling events that occur during the activation of MC, the cell-specific transcriptional regulation of the interleukin-6 (IL-6) gene was studied. Stimulation with lipopolysaccharide and IL-1beta resulted in the full induction of IL-6 expression only if the cells were coincubated with cAMP agonists; this effect was attenuated by protein kinase A inhibitors. In reporter gene experiments, the IL-6 promoter showed a stimulation pattern comparable to that of the endogenous gene. Elimination of individual transcription factor binding sites provided evidence for functional roles for four cis-acting elements, i.e., activator protein-1, cAMP response element-binding protein (CREB), nuclear factor for IL-6 expression (NF-IL6), and nuclear factor-kappaB (NF-kappaB). Electrophoretic mobility shift assays using nuclear extracts from MC revealed that the DNA-binding activities of activator protein-1 and NF-KB were inducible, whereas no change could be observed for CREB and NF-IL6. The presence of several transcription factor proteins, including JunB, JunD, c-Fos, Fra-1, CREB-1, activating transcription factor-2, NF-KB p50, p52, and p65, and CAAT/enhancer-binding protein-delta, was demonstrated by supershift analysis. Of particular interest was the novel finding of the participation of NF-kappaB p65 in the NF-IL6 complex. In summary, a signal transduction pathway in MC that requires protein kinase A activation in addition to a second signal provided by lipopolysaccharide or IL-1beta was identified.
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PMID:Transcriptional regulation of the interleukin-6 gene in mesangial cells. 1040 2

Cells of the weakly CD14 positive human B cell line RPMI 8226, clone 1, will mobilize NF-kappaB (p50/p65 and p50/p50) proteins and produce TNF mRNA when stimulated with lipopolysaccharide (LPS). When such cells are precultured with a low amount of LPS (50-250 ng/ml) for 3 - 4 days followed by a secondary stimulation with a high dose of LPS (1 microg/ml) then the cytokine expression is strongly reduced, i. e. the cells have become tolerant. Western blot analysis of proteins of the NF-kappaB/rel family demonstrates cytoplasmic p50 and p65 for naive B cells plus a low level of p52. While with tolerance induction the pattern of p50 and p65 proteins remains essentially unchanged, the LPS tolerant 8226 cells show a dramatic increase of both p52 protein and its p100 precursor in the cytosol. This p52 is found strongly upregulated in Western blots of extracts from purified nuclei of tolerant cells. Also, gelshift analysis with the -605 kappaB motif of the human TNF 5'-region shows an additional high mobility complex in LPS tolerant cells -a complex that is supershifted with an anti-p52 antibody. Functional analysis with the -1064 TNF 5'-region in front of the luciferase reporter gene demonstrates that transactivation of the TNF promoter is strongly reduced in tolerant cells. Also, overexpression of p52 will suppress activity of TNF promoter reporter gene constructs. Taken together these data show that tolerance to LPS in the human RPMI 8226 B cell line involves upregulation of the p52 (NF-kappaB2) gene, which appears to be instrumental in the blockade of TNF gene expression.
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PMID:Role of p52 (NF-kappaB2) in LPS tolerance in a human B cell line. 1059 82

An important role for the Rel/NF-kappaB family of transcription factors in the differentiation process of dendritic cells (DC) and macrophages (MAC) was recently suggested by a number of mouse knockout studies but only little information is available for defined populations of human cells. To investigate the role of individual NF-kappaB proteins [p50, p52, p65 (RelA), RelB] in the differentiation of monocyte-derived cell types we analyzed and compared the expression pattern and DNA binding activity of NF-kappaB members in human monocytes (MO), MO-derived MAC, and MO-derived DC. Constitutive expression of p65 and RelB mRNA was found in MO and no significant regulation was observed during differentiation of MO into MAC or immature DC. Only during lipopolysaccharide-induced terminal differentiation of DC was a marked increase in RelB mRNA detected. In DNA binding assays performed with nuclear extracts from blood MO, p50/p50 homodimers were mainly detected, whereas complexes containing p50/RelB and p50/p65 heterodimers were less abundant. DNA-bound protein complexes containing p50/RelB and p50/p65 increased and additional p65/p65 complexes appeared during differentiation of MO into either MAC or immature DC. A strong increase in complexes containing p50/RelB was observed during terminal differentiation of DC. Therefore, gradual differences in the DNA binding activities of different NF-kappaB homo- and heterodimers correlate with differentiation stages of MO, MAC, and DC and are probably important for the biological role of these cells.
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PMID:Differential expression of the transcription factor NF-kappaB during human mononuclear phagocyte differentiation to macrophages and dendritic cells. 1065 20

Dendritic cell (DC) maturation is essential for the initiation of T-dependent immune responses. Nuclear factor kappa B/Rel (NF kappa B/Rel) transcription factors are ubiquitously expressed signalling molecules, known to regulate the transcription of a large number of genes involved in immune responses, including cytokines such as IL-1, IL-6, TNF-alpha and cell surface molecules (MHC class I and II, B7.2). In this study, we have compared the activation of five members of the NF-kappa B family, p65, c-Rel, p50, RelB and p52, during DC maturation in response to lipopolysaccharide (LPS) and to Salmonella typhimurium. We have shown that although the translocation of NF-kappa B occurred very early, 30 min after treatment with both S. typhimurium and LPS, bacteria-induced NF-kappa B activation was more pronounced. Four out of five members, i.e. p65, c-Rel, p50 and RelB, were similarly activated upon the two stimuli but with different kinetics. Indeed, we have observed that p65, c-Rel and p50 were translocated early, whereas RelB was translocated later in DC activation. This differential regulation suggests that the various members of NF-kappa B family can mediate distinct functions of DC physiology.
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PMID:Differential activation of NF-kappa B subunits in dendritic cells in response to Gram-negative bacteria and to lipopolysaccharide. 1133 42

NF-kappaB/Rel transcription factors have been implicated in the differentiation of monocytes to either dendritic cells (DCs) or macrophages, as well as in the maturation of DCs from antigen-processing to antigen-presenting cells. Recent studies of the expression pattern of Rel proteins and their inhibitors (IkappaBs) suggest that their regulation during this differentiation process is transcriptional. To investigate differential gene expression between macrophages and DCs, we used commercially available gene microarrays (GEArray KIT), which included four of the NF-kappaB/Rel family genes (p50/p105, p52/p100, RelB, and c-rel) and 32 additional genes either in the NF-kappaB signal transduction pathway or under transcriptional control of NF-kappaB/Rel factors. To generate macrophages and DCs, human adherent peripheral blood monocytes were cultured with M-CSF or GM-CSF + IL-4 respectively for up to 8 days. DCs (and in some experiments, macrophages) were treated with lipopolysaccharide (LPS) for the last 48 h of culture to induce maturation. Cells were harvested after 7 days, cDNA was prepared and radiolabeled with alpha-(32)P-dCTP, then hybridized to gene arrays containing specific gene probes. beta-actin and GAPDH or PUC18 oligonucleotides served as positive or negative controls, respectively. The expression of all four NF-kappaB/Rel family genes examined was significantly upregulated in maturing DCs compared to macrophages. The strongest difference was observed for c-rel. RT-PCR determinations of c-rel, RelB, and p105 mRNAs confirmed these observations. Among the 32 NF-kappaB/Rel pathway genes, 14 were upregulated in mature DCs compared to macrophages. These genes were IkappaBalpha, IKK-beta, NIK, ICAM-1, P-selectin, E-selectin, TNF-alpha, TNFR2, TNFAIP3, IL-1alpha, IL-1R1, IL-1R2, IRAK, and TANK. By contrast, only mcp-1 (monocyte chemotactic protein 1) was upregulated in macrophages compared to DCs. NF-kappaB pathway genes upregulated in DCs compared to macrophages were constitutively expressed in monocytes then selectively downregulated during macrophage but not DC differentiation. LPS did not induce expression of most of these genes in macrophages but LPS did induce upregulation of IL-8 in mature macrophages. We conclude that NF-kappaB/Rel family genes, especially c-rel, are selectively expressed during differentiation of monocytes towards DCs. Moreover, this differential expression is associated both with activation of different NF-kappaB signal transduction pathways in DCs and macrophages and with expression of a unique subset of genes in DCs that are transcriptionally targeted by NF-kappaB/Rel factors. The results illustrate the ability of the NF-kappaB pathway to respond to differentiation stimuli by activating in a cell-specific manner unique signalling pathways and subsets of NF-kappaB target genes.
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PMID:Expression of different NF-kappaB pathway genes in dendritic cells (DCs) or macrophages assessed by gene expression profiling. 1157 45


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