SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179190 | GEO | 2022/02/01
REPOSITORIES: GEO
Similar Datasets
Project description:Gastric mucosa responds to the pathogen Helicobacter pylori (H. pylori) by producing and release of pro-inflammatory cytokines that activate the innate immune system mainly through activation of the transcription factor NF-κB. Although NF-κB signaling is well studied for many possible inducers, induction by H. pylori remains poorly understood. Here, we performed a high-throughput genome-wide RNAi screen for genes influencing H. pylori-induced NF-κB activation. In comparison to TNFα or IL‐1β NF‐κB signaling, we identified 21 proteins unique necessary for H. pylori NF-κB pathway and 24 factors that inhibited the activation. Furthermore, we present here the R/Bioconductor package Nested Effect Model for systematic use in high-throughput screens to classify newly identified factors. We identified alpha kinase 1 (ALPK1) as particular important for the H. pylori NF‐κB pathway without affecting TNFα or IL‐1β signaling. ALPK1 silencing inhibits activity of TAK1 and the IκB kinases (IKKs), degradation of the NF‐κB inhibitor IκBα, nuclear translocation of the NF‐κB subunit p65, and transcription of the NF‐κB target genes, e.g. IL‐8. Thus, we identify ALPK1 as a novel inflammatory regulator functioning particularly in the NF‐κB signaling network activated by H. pylori.
2019-09-02 | GSE89613 | GEO
Project description:We found that NB expression of TNFR2 and monocyte mTNFα are required for monocyte activation and IL-6 production, while NB TNFR1 and monocyte sTNFα are required for NB NF-κB activation. Treatment of NB-monocyte co-cultures with clinical-grade etanercept completely abrogated release of IL-6, G-CSF, IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNFα signaling in NB patients that relapsed.
2023-02-02 | GSE218915 | GEO
Project description:Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling. Gene expression comparison of wild type ras-transformed keratinocytes untreated (n=3) or treated (n=3) in vitro with the IL1R antagonist Anakinra.
2011-08-28 | E-GEOD-22777 | biostudies-arrayexpress
Project description:Autocrine IL-1α mediates NF-κB activation by oncogenic ras in keratinocytes
| PRJNA128083 | ENA
Project description:The virulence factor HlyA of Uropathogenic Escherichia coli (UPEC) could modulate host cell metabolism and inhibits NF-κB signaling pathway. However, whether there is a link between these two processes remains elusive. Here, we demonstrated UPEC could suppress metabolic enzyme ATP citrate lyase (ACLY) that resulted into histone deacetylation by decreasing the levels of acetyl-CoA. The level of histone acetylation was rescued supplementation of acetate. Furthermore, using H3 Lysine9 acetylation (H3K9ac) immunoprecipitation coupled next generation sequencing (ChIP-seq), we found that UPEC cause site specific regulation of H3K9ac which correlates with the expression of pro-inflammatory cytokines and chemokines. To be more specific, the expression of pro-inflammatory cytokines and chemokines like IL 8, CXCL2, and IL-1α are suppressed by UPEC mediated decreasing of H3K9ac at TSS-promoter region. Thus, this study established that UPEC manipulate host cell metabolism to impact histone acetylation at specific loci, correlating with cytokines and chemokines expression, as a means to inhibit NF-κB signaling.
2019-05-22 | GSE131560 | GEO
Project description:<p><strong>BACKGROUND:</strong> Cryopyrin-Associated Periodic Syndrome (CAPS) is an autoinflammatory condition consequence of monoallelic variants in the NLRP3 gene that exacerbate IL-1β production. These variants are gain-of-function, but the exact regulatory mechanism of the NLRP3 CAPS-inflammasome is not well yet understood. It is considered as a hypersensitive inflammasome triggered by cell priming, but patients with CAPS and animal disease models present inflammatory flares in the absence of external triggers.</p><p><strong>OBJECTIVES:</strong> To study the regulation and activation of the NLRP3 inflammasome in CAPS.</p><p><strong>METHODS:</strong> CAPS derived blood samples and genetically modified macrophages expressing different NLRP3 CAPS-associated variants were used to assess NLRP3 function dissociated from cell priming and cell metabolism.</p><p><strong>RESULTS:</strong> We found that CAPS-associated variants constitutively result in active NLRP3 inflammasomes, that induce a basal cleavage of gasdermin D, IL-18 release and pyroptosis. The constitutive active NLRP3 inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, being further regulated by deubiquitination. We also showed that activation of NF-κB with lipopolysaccharide or other endogenous host-derived molecules (palmitate, S100A9 or IL-6) further modulated the activation of the NLRP3 CAPS inflammasome and expanded the repertoire of molecules secreted from CAPS macrophages to IL-1β, IL-1α, HMGB1, cystatin B and the P2X7 receptor, identifying novel proteins involved in CAPS pathogenesis. NLRP3 inflammasomes with CAPS associated variants affected the immunometabolism of the myeloid compartment and impaired glycolysis.</p><p><strong>CONCLUSIONS:</strong> These findings demonstrate that NLRP3 CAPS-associated variants form a constitutive active inflammasome that induce basal pyroptosis and IL-18 release without cell priming, suggesting a priming-independent mechanism for the initiation of CAPS flares characterized with a profound affection in the immunometabolism.</p>
2024-01-09 | MTBLS7872 | MetaboLights
Project description:Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 hours after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of CCL2 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signalling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-B-dependent cytokine and chemokine release during HCMV infection , thereby impacting downstream immune responses.
2020-07-08 | PXD018328 | Pride
Project description:Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-α and IL-6 inhibitors. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. This is the first report on the potent anti-inflammatory activity of the compound. Chlorojanerin was shown to be significantly effective in inhibiting TNF-α and IL-6 production in LPS induced THP-1 cells (TNF-α, IC50 = 3µM and IL-6, IC50 = 0.8µM). The compound also blocked TNF-α and IL-6 production from LPS induced human monocytes and synovial cells from RA patients. Chlorojanerin also inhibited the binding of NF-κB in a GFP reporter assay system. Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of genes involved in activating the transcription factor – NF-κB. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-κB. Thus, this study clearly delineated 8 targets specific for the effect of chlorojanerin on NF-κB induced signaling at the mRNA level. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases. Single dye labelling with Cy3 for all treatment RNA samples. Treatments included unstimulated, LPS stimulated, Chlorjanerin treatment and dexamethasone treatment.
2011-12-14 | E-GEOD-34180 | biostudies-arrayexpress
Project description:Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of lncRNAs induced by inflammatory signaling via TNFα. TNFα regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. RNA profiles of wild type (WT) MEFs treated with TNF-alpha were generated by deep sequencing using Illumina GAIIx. Examination of H3K4me3 histome modification in MEF.
2013-08-05 | E-GEOD-47494 | biostudies-arrayexpress
Project description:The Alzheimer's Disease and Parkinson's Disease risk locus Fyn kinase is implicated in protein pathophysiology and NF-κB microglia inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Gene expression analyses reveal reduction in neuroprotective genes, and elevated inflammatory cytokines Il-1β, IL-12 and TNF-α and genes associated with oxidative stress. These phenotypes correlate with microglia activation in the larval brain. Chemical inhibition demonstrates dopaminergic neuron loss is dependent on Fyn and NF-κB/Caspase 1 signaling. We identify Stat3 activation as a novel downstream effector of Fyn signaling that acts synergistically with NF-κB in dopaminergic neuron degeneration. These results show Fyn drives neurodegeneration through NF-κB inflammatory signaling and Stat3 pathways. Activation of Stat3 provides a potential link from Fyn to mitochondrial dysfunction associated with dopaminergic neuron loss.
2024-11-25 | GSE271955 | GEO