Genome-wide analysis of interleukin (IL) -6 and IL-11 responsive genes in murine gastric tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE43800 | GEO | 2013/08/10
SECONDARY ACCESSION(S): PRJNA187455
REPOSITORIES: GEO
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Project description:We performed micrarrays to analyse gene expression in spontaneously arising gastric tumors from gp130Y757F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human IL-6 or IL-11. The present study was designed to assess differences in gene expression in response to IL-6 and IL-11, two cytokines which both activate the shared gp130 receptor and downstream Stat3 signalling pathway. Since gastric tumorigenesis in gp130Y757F/F mice is strictly dependent on IL-11, but not IL-6 signalling (Ernst et al., 2008) the study aimed to identify IL-6 and IL-11 specific target genes which may account for the IL-11 dependent tumor development. Total RNA was obtained from gastric tumor tissue of gp130Y575F/F mice collected 60 min after a single systemic (i.p.) administration of PBS (vehicle control), recombinant human IL6 or IL11 (5 ug). The gene expression profile of the IL-6 and IL-11 treated samples were separately compared to the PBS (vehicle) treated control samples, resulting in two lists of responsive genes (”IL-6 vs control” and “IL-11 vs control”).
2013-08-10 | E-GEOD-43800 | biostudies-arrayexpress
Project description:All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common b receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130 binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R deficient mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.
2023-04-19 | GSE226064 | GEO
Project description:Background and aims: Here we investigate the role of IL-11 signalling in the pathogenesis of nonalcoholic steatohepatitis (NASH). Methods: HSCs or hepatocytes were stimulated with IL-11 and effects assessed using cellular and high content imaging, immunoblotting, ELISA and invasion assays. Genetic and pharmacological IL-11 gain- or loss-of-function experiments were performed in vitro and in vivo. IL-11 signaling was studied using ERK inhibitors. The effects of anti-IL-11 or anti-IL11RA therapy were assessed in three preclinical NASH models using methionine/choline deficient diets or a Western diet with liquid fructose. Phenotyping was performed using hydroxyproline assay, qPCR, RNA-seq, Western blotting, histology, CyTOF, lipid and metabolic biomarkers. Results: When stimulated with NASH factors HSCs secrete IL-11, which drives an autocrine, ERK-dependent signaling loop required for the HSC-to-myofibroblast transformation. IL-11 is upregulated in human and murine NASH, Il-11 injection causes liver damage, inflammation and fibrosis in mice and Il11ra1 deleted mice are protected from NASH in two preclinical models. Therapeutic antibodies against IL11RA or IL-11 consistently inhibit and reverse fibrosis and steatosis in three murine NASH models. Unexpectedly, IL-11 causes hepatocyte damage and promotes stromal-mediated inflammation and anti-IL-11 therapies reverse NASH-associated hepatotoxicity and hepatitis. Genetic or pharmacologic inhibition of IL-11 signaling in NASH is associated with lower serum triglyceride, cholesterol and glucose. Conclusion: We show an unappreciated and central role for IL-11 in liver pathobiology. Targeting IL-11 signalling with neutralizing antibodies reverses fibrosis, steatosis, hepatocyte death and inflammation across the spectrum of NASH. This novel therapeutic approach is associated with a favorable cardiometabolic profile.
2019-06-22 | GSE128940 | 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 | 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:The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the CNS. We report that IL-11 is produced at highest frequency by myeloid cells among the PBMC cell subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes and IL-11R+ neutrophils in comparison to matched healthy controls (HCs). IL-11+ and GM-CSF+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single cell RNA sequencing (scRNAseq), revealed the highest number of differentially expressed genes (DEGs) in classical monocytes, including upregulated NFKB1, NLRP3 and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly upregulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with aIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates and demyelination. aIL-11 mAb treatment decreased the numbers of NFkBp65+, NLRP3+ and IL-1b+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.
2023-06-21 | GSE233917 | GEO
Project description:126 gastric tissues (90 tumor, 14 lymphnode and 22 normal) assayed using 44K human arrays against common reference (CRG). Published by Leung et al, PNAS, 2002 (PubMed ID 12456890) and Chen et al, MBC, 2003. A clinical history design type is where the organisms clinical history of diagnosis, treatments, e.g. vaccinations, surgery etc. Series_overall_design: Using regression correlation Keywords: other
2005-05-25 | GSE2701 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here we show that IL-11 is upregulated in the lung of IPF patients, associated with disease severity and is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive, ACTA2+ve, collagen secreting myofibroblasts, in an ERK-dependent fashion. In mice, fibroblast-specific transgenic expression or administration of Il-11 drives lung fibroblast-to-myofibroblast transformation and causes lung fibrosis. Il11ra1 deleted mice, whose lung fibroblasts are unresponsive to pro-fibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11 neutralising antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment both prevented and reversed lung fibrosis, which was accompanied by diminished Erk activation. These data prioritise IL-11 as a drug target for lung fibrosis and IPF.
2022-05-06 | GSE130983 | GEO
Project description:Interleukin (IL) 11 is upregulated in a number of fibro-inflammatory diseases and cancer, where it binds the cognate IL11 receptor alpha subunit (IL11RA) to form a hexameric IL11:IL11RA:gp130 signalling complex. Primary cells such as hepatic stellate cells, fibroblasts, and hepatocytes are ideal experimental systems to study IL11 signalling in vitro. In contrast to immortalized cell lines, primary cells better capture physiologically relevant cellular physiology and pathobiology. This collection of protocols details experimental and culturing conditions for primary cells that preserve meaningful cellular states and physiological responses ex vivo in conventional 2D cell culture systems. Our data suggest that cell type, cell culture conditions, passage number, concentrations of stimuli, timing, and other factors have major implications for studies of IL11 signalling. In vitro experiments with primary cell material need to be planned and executed with great caution. Otherwise, physiologically relevant mechanisms may become dysfunctional, and reproducible experimental artefacts can obscure our view of true cytokine biology.
2021-09-28 | GSE180652 | 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