LPS hypersensitivity of gp130 mutant mice is independent of elevated hematopoietic TLR4 signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29311 | GEO | 2011/05/17
SECONDARY ACCESSION(S): PRJNA138647
REPOSITORIES: GEO
Similar Datasets
Project description:The inflammatory mediator IL6 induced by LPS, which signals via TLR4, has been shown to feedback and augment TLR4 signaling when over-produced in LPS hypersensitive gp130F/F mice. The identity of the LPS/TLR4 responsive inflammatory signaling pathways and gene networks which are modulated by IL6 are unknown. Therefore, to understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers was performed. The mouse 22K compugen oligo array from the Adelaide Microarray Facility was used to investigate the effect of LPS treatment on the livers of wildtype and gp130F/F mutant mice. Livers of both wildtype mice and gp130F/F mice at 6hr post LPS injection and also control livers wer collected. Each experimental group had 3 independant mice. In total 12 arrays were performed with a total of three biological replicates. A common reference design was used for this experiment. RNA extracted from eight pooled 17.5dpc C57BL/6 mouse embryos was used as the reference sample. 6 wildytpe mice and 6 gp130F/F mice were used in this study, with 3 mice of each genotype treated with LPS.
2011-05-17 | E-GEOD-29311 | biostudies-arrayexpress
Project description:Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by the elevated expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a striking activation of the IL6 signalling pathway in this tumour type, and sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene that encodes the signalling co-receptor gp130. Indeed, ~70% of IHCA harbour small in-frame deletions that target the binding site of gp130 for IL6, and expression of the most frequent gp130 mutant, Delta-STVY190, in hepatocellular cells activates STAT3 in absence of ligand. Further, analysis of hepatocellular carcinomas revealed rare gp130 alterations always accompanied by ß-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas explains their inflammatory phenotype, and suggest that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.
2008-12-24 | GSE11819 | GEO
Project description:Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by the elevated expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a striking activation of the IL6 signalling pathway in this tumour type, and sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene that encodes the signalling co-receptor gp130. Indeed, ~70% of IHCA harbour small in-frame deletions that target the binding site of gp130 for IL6, and expression of the most frequent gp130 mutant, Delta-STVY190, in hepatocellular cells activates STAT3 in absence of ligand. Further, analysis of hepatocellular carcinomas revealed rare gp130 alterations always accompanied by M-CM-^_-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas explains their inflammatory phenotype, and suggest that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation. HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 4 Inflammatory hepatocellular adenomas (IHCA) and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions (Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 8 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, 282(19):14437-46, PMID: 17379603; Rebuissou et al., J Hepatol 2008, 49(1):61-71. PMID: 18466996 and Rebuissou et al., in preparation].
2008-12-24 | E-GEOD-11819 | biostudies-arrayexpress
Project description:The latent transcription factor STAT3 is a point of convergence for numerous oncogenic signaling pathways and is excessively activated in the majority of human epithelial cancers. STAT3 promotes many hallmarks of cancer including enhanced proliferation, increased survival, sustained angiogenesis, immune evasion and tumor-promoting inflammation. We performed chromatin immunoprecipitations (ChIP) followed by next-generation sequencing (ChIP-Seq) to identify genomic Stat3 binding sites in established gastric tumors of gp130F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human interleukin (IL)-6 or IL11. The study was designed to assess differences in Stat3 recruitment in response to IL6 and IL11, two cytokines which both activate Stat3 through the shared IL6 cytokine family receptor subunit gp130. In gp130F/F mice, a robust model for inflammation-associated intestinal-type gastric tumorigenesis, the Y757F knock-in mutation in the gp130 receptor triggers spontaneous gastric tumor formation in a strictly IL11-dependent manner, but independent of IL6 signaling (Ernst et al., 2008). Therefore, the study aimed to identify IL6- and IL11-specific Stat3 target genes. In total, we identified 948 or 961 significant Stat3-DNA interactions in gp130F/F tumors following IL6 or IL11 administration, respectively. These interactions were validated by binding motif analysis which showed that at least 30% of all Stat3-associated genomic regions comprise a Stat3 consensus binding sequence.
2015-10-01 | GSE48287 | GEO
Project description:The latent transcription factor STAT3 is a point of convergence for numerous oncogenic signaling pathways and is excessively activated in the majority of human epithelial cancers. STAT3 promotes many hallmarks of cancer including enhanced proliferation, increased survival, sustained angiogenesis, immune evasion and tumor-promoting inflammation. We performed chromatin immunoprecipitations (ChIP) followed by next-generation sequencing (ChIP-Seq) to identify genomic Stat3 binding sites in established gastric tumors of gp130F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human interleukin (IL)-6 or IL11. The study was designed to assess differences in Stat3 recruitment in response to IL6 and IL11, two cytokines which both activate Stat3 through the shared IL6 cytokine family receptor subunit gp130. In gp130F/F mice, a robust model for inflammation-associated intestinal-type gastric tumorigenesis, the Y757F knock-in mutation in the gp130 receptor triggers spontaneous gastric tumor formation in a strictly IL11-dependent manner, but independent of IL6 signaling (Ernst et al., 2008). Therefore, the study aimed to identify IL6- and IL11-specific Stat3 target genes. In total, we identified 948 or 961 significant Stat3-DNA interactions in gp130F/F tumors following IL6 or IL11 administration, respectively. These interactions were validated by binding motif analysis which showed that at least 30% of all Stat3-associated genomic regions comprise a Stat3 consensus binding sequence.
2015-10-01 | GSE48285 | GEO
Project description:Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
2023-08-07 | GSE237028 | GEO
Project description:Comparison between wild-type and cardiomyocyte-restricted knock-out of IL6 cytokines receptor component gp130 after surgical intervention for pressure-overload induced cardiomyopathy.
2004-06-30 | E-MEXP-104 | biostudies-arrayexpress
Project description:In endothelial cells (ECs), stimulation of Toll-like receptor 4 (TLR4) by the endotoxin lipopolysaccharide (LPS) induces the release of diverse pro-inflammatory mediators beneficial in controlling bacterial infections. However, their systemic secretion is a main driver of sepsis and chronic inflammatory diseases. Since distinct and rapid TLR4 signaling induction is difficult to achieve by LPS due to its poorly controllable binding and non-specific affinity to other surface molecules and receptors, we engineered new light-oxygen-voltage-sensing (LOV) domain-based optogenetic endothelial cell lines (opto-TLR4-LOV LEC and opto-TLR4-LOV HUVEC) that allow precise temporal and reversible activation of TLR4 signaling pathways. Using quantitative mass spectrometry, RT-qPCR and Western Blot analysis, we show that pro-inflammatory proteins were not only expressed differently, but also had a different time course when the cells were stimulated with light or LPS. Additional functional assays demonstrated that light induction promoted chemotaxis of THP-1 cells, disruption of the EC-monolayer and transmigration. In contrast, ECs incorporating a truncated version of the TLR4 extracellular domain (opto-TLR4 ΔECD2-LOV LEC) revealed high basal activity with fast exploitation of cell signaling system upon illumination. We conclude that the established optogenetic cell lines are well suited to induce rapid and precise photoactivation of TLR4, allowing receptor-specific studies.
2023-05-10 | PXD038764 | Pride
Project description:The experiment was designed to determine the gene expression changes cultured brown adipocytes in response to the inflammatory stimulus of LPS treatment. Both wild type and TLR4 knockout cells were applied to enable assessment of the contribution of TLR4 to the response.
2024-03-21 | E-MTAB-12834 | biostudies-arrayexpress
Project description:Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multi-modular scaffold, GIV (a.k.a Girdin) titrates such inflammatory response in macrophages. Upon challenge with microbe-derived lipopolysaccharides (LPS, a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress pro-inflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts.
2020-07-08 | GSE153924 | GEO