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Coordinated binding of NF-kappaB family members in the response of human cells to lipopolysaccharide.

ABSTRACT: The NF-kappaB family of transcription factors plays a critical role in numerous cellular processes, particularly the immune response. Our understanding of how the different NF-kappaB subunits act coordinately to regulate gene expression is based on a limited set of genes. We used genome-scale location analysis to identify targets of all five NF-kappaB proteins before and after stimulation of monocytic cells with bacterial lipopolysaccharide (LPS). In unstimulated cells, p50 and p52 bound to a large number of gene promoters that were also occupied by RNA polymerase II. After LPS stimulation, additional NF-kappaB subunits bound to these genes and to other genes. Genes that became bound by multiple NF-kappaB subunits were the most likely to show increases in RNA polymerase II occupancy and gene expression. This study identifies NF-kappaB target genes, reveals how the different NF-kappaB proteins coordinate their activity, and provides an initial map of the transcriptional regulatory network that underlies the host response to infection.

SUBMITTER: Schreiber J

PROVIDER: S-EPMC1426243 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Chromatin immunoprecipitation of human cells after lipopolysaccharide stimulation, to identify binding of NF-KappaB family members

Project description:The NF-KappaB family of transcription factors plays a critical role in numerous cellular processes, particularly the immune response. Our understanding of how the different NF-kappaB subunits act coordinately to regulate gene expression is based on a limited set of genes. We used genome-scale location analysis to identify targets of all five NF-kappaB proteins before and after stimulation of monocytic cells with bacterial lipopolysaccharide (LPS). In unstimulated cells, p50 and p52 bound to a significant number of gene promoters. p50 occupied genes together with RNA polymerase II and defined a set of genes to which other NF-kappaB proteins bound after LPS induction. In stimulated cells, genes bound by multiple NF-kappaB subunits exhibited the greatest increases in RNA polymerase II occupancy and gene expression. This study identifies novel NF-kappaB target genes, reveals how the different NF-kappaB proteins coordinate their activity and maps transcriptional regulatory networks that underlie the host response to infection.

2006-05-09 | E-WMIT-6 | biostudies-arrayexpress

A noisy paracrine signal determines the cellular NF-kappaB response to lipopolysaccharide.

Project description:Nearly identical cells can exhibit substantially different responses to the same stimulus. We monitored the nuclear localization dynamics of nuclear factor kappaB (NF-kappaB) in single cells stimulated with tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). Cells stimulated with TNF-alpha have quantitative differences in NF-kappaB nuclear localization, whereas LPS-stimulated cells can be clustered into transient or persistent responders, representing two qualitatively different groups based on the NF-kappaB response. These distinct behaviors can be linked to a secondary paracrine signal secreted at low concentrations, such that not all cells undergo a second round of NF-kappaB activation. From our single-cell data, we built a computational model that captures cell variability, as well as population behaviors. Our findings show that mammalian cells can create "noisy" environments to produce diversified responses to stimuli.

| S-EPMC2778577 | biostudies-other

Human variation in PolII and NF-KappaB binding (ChIP-seq study with NF-KappaB)

Project description:We examined genome-wide variation in transcription factor binding in different individuals and a chimpanzee using chromatin immunoprecipitation followed by massively-parallel sequencing (ChIP-Seq). The binding sites of RNA Polymerase II (Pol II) as well as a key regulator of immune responses, NFkB, were mapped in ten HapMap lymphoblastoid cell lines derived from individuals of African, European, and Asian ancestry, including a parent-offspring trio. We also mapped gene expression in all ten human cell lines for two treatment conditions: a) no treatment and b) following induction by TNF-alpha.

2010-03-22 | GSE19485 | GEO

Distribution of NF-kappaB-binding sites across human chromosome 22.

Project description:We have mapped the chromosomal binding site distribution of a transcription factor in human cells. The NF-kappaB family of transcription factors plays an essential role in regulating the induction of genes involved in several physiological processes, including apoptosis, immunity, and inflammation. The binding sites of the NF-kappaB family member p65 were determined by using chromatin immunoprecipitation and a genomic microarray of human chromosome 22 DNA. Sites of binding were observed along the entire chromosome in both coding and noncoding regions, with an enrichment at the 5' end of genes. Strikingly, a significant proportion of binding was seen in intronic regions, demonstrating that transcription factor binding is not restricted to promoter regions. NF-kappaB binding was also found at genes whose expression was regulated by tumor necrosis factor alpha, a known inducer of NF-kappaB-dependent gene expression, as well as adjacent to genes whose expression is not affected by tumor necrosis factor alpha. Many of these latter genes are either known to be activated by NF-kappaB under other conditions or are consistent with NF-kappaB's role in the immune and apoptotic responses. Our results suggest that binding is not restricted to promoter regions and that NF-kappaB binding occurs at a significant number of genes whose expression is not altered, thereby suggesting that binding alone is not sufficient for gene activation.

| S-EPMC218744 | biostudies-literature

Human variation in PolII and NF-KappaB binding

Project description:This SuperSeries is composed of the SubSeries listed below.

2010-03-22 | GSE19486 | GEO

Human variation in PolII and NF-KappaB binding (ChIP-seq study with NF-KappaB)

2010-03-22 | E-GEOD-19485 | biostudies-arrayexpress

Piperlongumine Improves Lipopolysaccharide-Induced Amyloidogenesis by Suppressing NF-KappaB Pathway.

Project description:Amyloidogenesis is known to cause Alzheimer's disease. Our previous studies have found that lipopolysaccharide (LPS) causes neuroinflammation and amyloidogenesis through activation of nuclear factor kappaB (NF-?B). Piperlongumine (PL) is an alkaloid amide found naturally in long pepper (Piper longum) isolates; it was reported to have inhibitory effects on NF-?B activity. We therefore investigated whether PL exhibits anti-inflammatory and anti-amyloidogenic effects by inhibiting NF-?B. A murine model of LPS-induced memory impairment was made via the intraperitoneal (i.p.) injection of LPS (0.25 mg/kg/day, i.p.). We then injected PL (1.5 or 3.0 mg/kg/day, i.p.) for 7 days in three groups of mice to observe effects on memory. We also conducted an in vitro study with astrocytes and microglial BV-2 cells, which were treated with LPS (1 µg/mL) or PL (0.5 or 1.0 or 2.5 µM). Results from our behavioral tests showed that PL inhibited LPS-induced memory. PL also prevented LPS-induced beta-amyloid (A?) accumulation and inhibited the activities of ?- and ?-secretases. The expression of inflammatory proteins also was decreased in PL-treated mice, cultured BV-2, and primary astrocyte cells. These effects were associated with the inhibition of NF-?B activity. A docking model analysis and pull-down assay showed that PL binds to p50. Taken together, our findings suggest that PL diminishes LPS-induced amyloidogenesis and neuroinflammation by inhibiting NF-?B signaling; PL therefore demonstrates potential for the treatment of Alzheimer's disease.

| S-EPMC6097046 | biostudies-literature

Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-kappaB oncogenesis.

Project description:Cell transformation by the v-rel oncogene is mediated by the aberrant expression of genes that are normally tightly regulated by other Rel/NF-kappaB family members. Although a number of genes inappropriately activated or suppressed by v-Rel have been identified, their contributions to the v-Rel transformation process have been poorly characterized. Here, we examine the role of individual AP-1 proteins in v-Rel-mediated transformation. v-Rel-transformed cells exhibit elevated RNA and protein expression of c-Fos, c-Jun and ATF2 and sustained repression of Fra-2. c-Fos and c-Jun are essential in both the initiation and maintenance of v-Rel-mediated transformation, whereas Fra-2 is dispensable. By employing a c-Jun dimerization mutant, we further identified Fos/Jun heterodimers as major contributors to the v-Rel transformation process. The inability of c-Rel to induce the expression of c-Fos and c-Jun contributes to its weaker oncogenic potential relative to v-Rel. Our studies also demonstrate that v-Rel may induce AP-1 members by directly upregulating gene expression (c-fos and ATF2) and by activating pathways that stimulate AP-1 activity. Although elevated expression of ATF2 is also required for v-Rel-mediated transformation, its ectopic overexpression is inhibitory. Investigating the mode of ATF2 regulation revealed a positive feedback mechanism whereby ATF2 induces p38 MAPK phosphorylation to further induce its own activity. In addition, these studies identified Ha-Ras as an effector of v-Rel-mediated transformation and reveal a novel role for ATF2 in the inhibition of the Ras-Raf-MEK-ERK signaling pathway. Overall, these studies reveal distinct and complex roles of AP-1 proteins in Rel/NF-kappaB oncogenesis.

| S-EPMC2932816 | biostudies-literature

Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB.

Project description:Inflammatory mediators activate the transcriptional complex HIF-1 (hypoxia-inducible factor-1), the key regulator of hypoxia-induced gene expression. Here we report that bacterial LPS (lipopolysaccharide) induces HIF-1alpha mRNA expression and HIF-1alpha protein accumulation in human monocytes as well as in non-differentiated and differentiated cells of the human monocytic cell line THP-1 under normoxic conditions. LPS and hypoxia synergistically activated HIF-1. Whereas LPS increased HIF-1alpha mRNA expression through activation of a NF-kappaB (nuclear factor kappaB) site in the promoter of the HIF-1alpha gene, hypoxia post-translationally stabilized HIF-1alpha protein. HIF-1alpha activation was followed by increased expression of the HIF-1 target gene encoding ADM (adrenomedullin). Knocking down HIF-1alpha by RNA interference significantly decreased ADM expression, which underlines the importance of HIF-1 for the LPS-induced ADM expression in normoxia. Simultaneously with HIF-1 activation, an increase in p44/42 MAPK (mitogen-activated protein kinase) phosphorylation was observed after incubation with LPS. In cells pretreated with the p44/42 MAPK inhibitor PD 98059 or with RNAi (interfering RNA) directed against p44/42 MAPK, LPS-induced HIF-1alpha accumulation and ADM expression were significantly decreased. From these results we conclude that LPS critically involves the p44/42 MAPK and NF-kappaB pathway in the activation of HIF-1, which is an important transcription factor for LPS-induced ADM expression.

| S-EPMC1482811 | biostudies-literature

Bee venom ameliorates lipopolysaccharide-induced memory loss by preventing NF-kappaB pathway.

Project description:BackgroundAccumulation of beta-amyloid and neuroinflammation trigger Alzheimer's disease. We previously found that lipopolysaccharide (LPS) caused neuroinflammation with concomitant accumulation of beta-amyloid peptides leading to memory loss. A variety of anti-inflammatory compounds inhibiting nuclear factor kappaB (NF-κB) activation have showed efficacy to hinder neuroinflammation and amyloidogenesis. We also found that bee venom (BV) inhibits NF-κB.MethodsA mouse model of LPS-induced memory loss used administration of BV (0.8 and 1.6 μg/kg/day, i.p.) to ICR mice for 7 days before injection of LPS (2.5 mg/kg/day, i.p.). Memory loss was assessed using a Morris water maze test and passive avoidance test. For in vitro study, we treated BV (0.5, 1, and 2 μg/mL) to astrocytes and microglial BV-2 cells with LPS (1 μg/mL).ResultsWe found that BV inhibited LPS-induced memory loss determined by behavioral tests as well as cell death. BV also inhibited LPS-induced increases in the level of beta-amyloid (Aβ), β-and γ-secretases activities, NF-κB and its DNA-binding activity and expression of APP, and BACE1 and neuroinflammation proteins (COX-2, iNOS, GFAP and IBA-1) in the brain and cultured cells. In addition, pull-down assay and molecular modeling showed that BV binds to NF-κB.ConclusionsBV attenuates LPS-induced amyloidogenesis, neuroinflammation, and therefore memory loss via inhibiting NF-κB signaling pathway. Thus, BV could be useful for treatment of Alzheimer's disease.

| S-EPMC4501073 | biostudies-literature

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