Browse
Submit Data
Databases
API
Help

Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-kB Signaling

ABSTRACT: The bacterial product lipopolysaccharide (LPS) stimulates nuclear factor kB (NF-kB) signaling, which results in the production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), as part of the immune response. NF-kB target genes also include those encoding proteins that inhibit NF-kB signaling through negative feedback loops. By simultaneously studying the dynamics of the nuclear translocation of the NF-kB subunit RelA and the activity of a Tnf-driven reporter in a mouse macrophage cell line, Sung et al. found that the gene encoding RelA was also a target of NF-kB. Synthesis of RelA occurred only at higher concentrations of LPS and constituted a positive feedback loop that dominated over existing negative feedback mechanisms. Genes expressed in response to a high concentration of LPS were enriched for those involved in innate immune responses. Together, these data suggest that the RelA-dependent positive feedback loop enables macrophages to mount an effective immune only above a critical concentration of LPS. Bone-marrow-derived macrophage (BMDM) cells were stimulated with zero, low, and high concentration of LPS separately for 4hrs. Two replicates for each condition.

ORGANISM(S): Mus musculus

SUBMITTER: Timothy Myers

PROVIDER: E-GEOD-53810 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-kB Signaling

Project description:The bacterial product lipopolysaccharide (LPS) stimulates nuclear factor kB (NF-kB) signaling, which results in the production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), as part of the immune response. NF-kB target genes also include those encoding proteins that inhibit NF-kB signaling through negative feedback loops. By simultaneously studying the dynamics of the nuclear translocation of the NF-kB subunit RelA and the activity of a Tnf-driven reporter in a mouse macrophage cell line, Sung et al. found that the gene encoding RelA was also a target of NF-kB. Synthesis of RelA occurred only at higher concentrations of LPS and constituted a positive feedback loop that dominated over existing negative feedback mechanisms. Genes expressed in response to a high concentration of LPS were enriched for those involved in innate immune responses. Together, these data suggest that the RelA-dependent positive feedback loop enables macrophages to mount an effective immune only above a critical concentration of LPS.

2014-01-14 | GSE53810 | GEO

Immune differentiation regulator p100 tunes NF-kB responses to TNF

Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.

2020-08-22 | GSE119961 | GEO

Human RELA haploinsufficiency results in autosomal dominant chronic mucocutaneous ulceration: the transcriptional profile of RelA haploinsufficient patients

Project description:The treatment of chronic mucocutaneous ulceration is challenging and only some patients respond selectively to inhibitors of tumor necrosis factor-alpha (TNF-a). TNF-a activates opposing pathways leading to caspase-8-mediated apoptosis as well as NF-kB-dependent cell survival. We investigated the etiology of autosomal dominant mucocutaneous ulceration in a family whose proband was dependent on anti-TNF-a therapy for sustained remission. A heterozygous mutation in RELA (NM_021975: c.559+1G>A), encoding the NF-kB subunit RelA (p65), segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients’ fibroblasts exhibited increased apoptosis in response to TNF-a, impaired NF-kB activation, and defective expression of NF-B-dependent anti-apoptotic genes. We show that Rela+/- mice have similarly impaired NF-kB activation, develop cutaneous ulceration from TNF-a exposure, and exhibit severe dextran sodium sulfate-induced colitis ameliorated by TNF-a inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-a-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF-a inhibition in this disease.

2017-05-09 | GSE98624 | GEO

LPS-induced genome-wide RELA binding sites and H3K27ac changes in phraryngeal epithelial cells

Project description:Gram negative endotoxin Lypopolysaccharide (LPS) leads to a strong innate immune response through TLR4 signalling. This latter pathway activates cannonical NF-kB pathway, including its member RELA. Here, we want to investigate the RELA response in terms of DNA binding as well as epigenetic changes induced by LPS recognition.

2019-06-01 | GSE132018 | GEO

LPS-induced gene expression changes in phraryngeal epithelial cells

Project description:Gram negative endotoxin Lypopolysaccharide (LPS) leads to a strong innate immune response through TLR4 signalling. This latter pathway activates cannonical NF-kB pathway, including its member RELA. Here, we want to investigate the gene expression response induced by LPS recognition.

2019-06-01 | GSE132019 | GEO

An epithelial Nfkb2 pathway exacerbates intestinal inflammation by supplementing latent RelA complexes to the canonical NF-kB module

Project description:The canonical NF-kB module induces nuclear translocation of RelA heterodimers from the latent cytoplasmic complexes. RelA directs inflammatory immune responses against microbial entities. However, aberrant RelA activity also triggers destructive inflammation, including those associated with inflammatory bowel disease (IBD). What provokes this pathological RelA activity remains unclear. As such, the noncanonical NF-kB pathway activates RelB heterodimers and mediates immune organogenesis. Because NF-kB-activating pathways are interlinked, we asked if noncanonical NF-kB signaling exacerbated intestinal inflammation. Our investigation revealed recurrent engagement of the noncanonical pathway in human IBD. In a mouse model of chemical colitis, the noncanonical NF-kB signaling gene Nfkb2 aggravated inflammation by amplifying the RelA activity induced in intestinal epithelial cells. Our mechanistic studies clarified that noncanonical signaling augmented the abundance of latent RelA complexes leading to hyperactive canonical NF-kB response in the colitogenic gut. In sum, latent dimer homeostasis appears to link noncanonical NF-kB signaling to RelA-driven inflammatory pathologies.

2021-07-07 | GSE148577 | GEO

AhmedMobeen2021 - NF-kB Activation Model

Project description:NF-kappaB Activation Model includes the activation of both NFKB1:RELA and NFKB2:RELB for Canonical and Non-Canonical Pathway respectively. The model includes the pathway model integrated with post-translational modifications of NF-kB subunits that regulate the NFKB1:RELA and NFKB2:RELB activity. The processes that are regulated by NF-kB pathway can be monitored through following readouts NFKB1:RELA Activity, NFKB2:RELB Activity, Degraded RelA, Degraded RelB, Degraded IkB, Degraded NIK, Apoptosis, Tumour, Antiviral Activity, B Cell Growth and Cell Migration. However, last 5 processes above are also influenced by other pathways too, therefore while making predictions, caution has to be exercised.

2022-05-27 | MODEL2001290001 | BioModels

Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging- Related Transcriptional Networks (ChIP-chip)

Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-?B. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, RelA -/- and Sirt6-/- MEF cells

2011-05-11 | E-GEOD-28638 | biostudies-arrayexpress

Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging- Related Transcriptional Networks (Illumina)

Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, Sirt6-/- and Sirt6-/- RelA-/- MEF cells

2011-05-11 | E-GEOD-28585 | biostudies-arrayexpress

Developmental LTbR synergistically activates TLR4 mediated inflammatory RelA/NF-kB response

Project description:Developmental signals are known to modulate inflammation. How ever, the mechanistic insight that links developmental and inflammatory signaling remains elusive. In the current study, we identifya critical role of NF-kB system in mediating stimulus specific crosstalk that allows developmental LTbR signals to sustain inflammatory TLR4 induced RelA/NF-kB response and gene expression. LTbR activated non-canonical signaling targets canonical TLR4 induced, nfkb2 encoded p100 not only to deplete inhibitory IkBd/(p100)2, but also to supplement RelA:p52/NF-kB dimers. Robust crosstalk in the gut epithelial cells are important, as crosstalk-defective nfkb2-/- mice succumbed to gut infection by Citrobacter rodentium due to hypo-inflammatory responses. Finally, we present evidence for a crosstalk motif that integrates tissue microenvironment derived developmental cues to ameliorate the pathogen response. Total RNA from WT early passage MEFs stimulated with ligands LPS, LTbR and LPS+LTbR for 24hrs were analyzed for global gene expression levels

2015-05-01 | E-GEOD-62301 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data