Mus musculus
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR040620_1.fastq.gz | Fastqsanger.gz | |||
| DRR040620_2.fastq.gz | Fastqsanger.gz | |||
| DRR040621_1.fastq.gz | Fastqsanger.gz | |||
| DRR040621_2.fastq.gz | Fastqsanger.gz | |||
| DRR040622_1.fastq.gz | Fastqsanger.gz |
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Project description:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Gene expression in BMDMs obtained from wild-type and Keap1-CKO mice. In Keap1-CKO (Keap1 flox/flox::LysM-Cre) BMDMs, Nrf2 transcription factor is activated due to Keap1-deficiency. BMDMs were obtained by a culture of bone marrow cells in the presence of M-CSF for7 days. M1-activated BMDMs were obtained by stimulation with LPS and IFNg for 6 hours, while M2-activated BMDMs were obtained by a stimulation with IL-4 for 6 hours. Two independent BMDM cultures were performed, and each experiment contains samples obtained from one wild-type and one Keap1-CKO mice, respectively.
2016-05-12 | E-GEOD-71263 | biostudies-arrayexpress
Project description:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
2016-05-12 | GSE71263 | GEO
Project description:In this paper we investigate one of the lesser studied TRIM family proteins, TRIM16, to determine if it might impact the ability of different viruses to replicate productively in host cells. TRIM16 is unique compared to other TRIM proteins in that it mediates E3 ligase activity despite lacking the catalytic RING domain present in other TRIM proteins. TRIM16 has been shown to play a role in innate immunity by increasing the secretion proinflammatory cytokine Il-1 in macrophages through interactions with components of the inflammasome complex (procaspase-1 and NALP-1). TRIM16 also mediates ubiquitination and aggregation of misfolded proteins which are subsequently degraded through the autophagic pathway in cells under proteotoxic and oxidative stress11. It does so through interactions with the p62-KEAP-NRF2 complex and stabilization of the NRF2 protein through multiple mechanisms11. Interestingly the NRF2 protein has been implicated in antiviral immunity, as previous studies have shown that infection of NRF2 (-/-) mice with respiratory syncytial virus (RSV) resulted in significantly higher viral titres in the lungs compared to NRF2 (+/+) mice. In addition to these clues in the literature, a recent study from our group examining transcriptional signatures in type II airway epithelial cells (AEC II) isolated from mock versus IAV-infected mice indicated that TRIM16 was upregulated in AECII following IAV infection in vivo.
2023-06-21 | PXD039241 | Pride
Project description:Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
| PRJNA290721 | ENA
Project description:Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/ p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.
2025-03-31 | GSE292969 | GEO
Project description:We investigated the regulatory role of alloferon in the development of psoriasis in an imiquimod (IMQ)-induced psoriasis model through the regulation of IL-22Rα expression. Psoriasis is an immune-mediated inflammatory skin disease. IL-22, a proinflammatory cytokine, is implicated in psoriasis pathogenesis; however, there is currently no established biological treatment targeting IL-22 or its receptor, IL-22Rα. Alloferon is a short peptide that has an anti inflammatory effect on skin disorders; however, little is known about its anti-inflammatory activity in psoriasis. This study demonstrate that alloferon could be an effective potential drug for the treatment of psoriasis by interrupting IL-22 signaling and factors related to skin inflammation.
2025-03-05 | GSE285640 | GEO
Project description:The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), is directly involved and required for the acute activation of the inflammatory gene program. Here we show that the major transactivating subunit of NF?B, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high occupancy sites within super-enhancers. Based on these data we have developed models that with high accuracy predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell type-specific manner. Our results propose a novel paradigm for NF?B-mediated repression, whereby NF?B selectively redistributes cofactors from high occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes. Genome-wide assesment of the acute transcriptional response to TNF in human SGBS adipocytes using RNA- ChIP- and DHS-seq. Total RNA-seq and RNAPII-ChIP seq for vehicle and TNF treated adipocytes are available under GSE60462
2015-06-17 | E-GEOD-64233 | biostudies-arrayexpress
Project description:Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4 binding protein 1 (N4BP1) was recently identified as a critical suppressor of proinflammatory cytokine production1, whose mode of action remained unknown. Here, we show that N4BP1 is a novel linear ubiquitin receptor that negatively regulates NFB signalling by its unique dimerization-dependent ubiquitin-binding module. N4BP1 homo-oligomerization strategically positions two non-selective ubiquitin-binding domains, ensuring exclusive recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex where it, through linear ubiquitin binding, regulates stability of the TNFR1 signalling complex and duration of proinflammatory signalling. N4BP1 deficiency accelerates TNF-induced cell death by increasing complex II assembly. Under proapoptotic conditions, Caspase-8 mediates proteolytic processing of N4BP1 and the resulting cleavage fragment of N4BP1, which retains the ability to bind linear ubiquitin, is rapidly degraded by the 26S proteasome, accelerating apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a unique linear ubiquitin reader that ensures timely and coordinated regulation of TNFR1-mediated inflammation and cell death.
2024-05-22 | PXD024355 | Pride
Project description:Hayashi2013 - TNF-induced Signaling Dynamics Model (Model A)
Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases.
This model is described in the article:
Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246.
Abstract:
Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted.
Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired.
Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
Figure 2B, obtained from the simulation of TNFR1 Model A, is highlighted here.
This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.
2025-02-19 | MODEL2502170001 | BioModels
Project description:Hayashi2013 - Extended TNF-induced Signaling with Gene Expression Dynamics (Model B)
Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases.
This model is described in the article:
Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246.
Abstract:
Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted.
Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired.
Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
Figure S3, obtained from the simulation of TNFR1 Model B, is highlighted here.
This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.
2025-02-19 | MODEL2502170002 | BioModels