Pdx1 overexpression sensitizes to IL-1b-induced apoptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Morten Tonnesen
PROVIDER: E-GEOD-40642 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Cytokines have been shown to play a key role in the destruction of beta cells. In the rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (Pdx1) increases sensitivity to Interleukin 1b (IL-1b). To elucidate mechanisms of action underlying Pdx1 driven potentiation of beta-cell sensitivity to IL-1β, we performed a microarray analysis of INS-1ab cells with and without Pdx1 overexpression exposed to IL-1β between 2h and 24h.
2012-09-20 | GSE40642 | GEO
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Project description:Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1b production is detrimental during Salmonella infection. Mice lacking IL-1b (IL-1b -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1b -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1b induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1b loss prevented mortality in Salmonella-infected IL-1b -/- mice. Finally, we found that IL-1b expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1b signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1b signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.
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Project description:Pdx1 overexpression sensitizes to IL-1b-induced apoptosis
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Project description:ILC2s regulate type2 immune responses and protect against helminth infection. We found that ILC2s can be expanded in the presence of a combination of cytokines IL-2 and IL-1b. To better understand the functional and phenotypic consequence of IL-1β activation of ILC2s, we utilized whole transcriptome sequencing (RNA-seq) of freshly isolated ILC2s and IL-1β-primed ILC2s. Differential expression analysis revealed a substantial number of genes underwent significant change between the two conditions (total 4,744 gene, FDR<0.01, Fold change >2), among which 3,871 genes were upregulated in IL-1β –primed ILC2s.
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Project description:IL-1B is an important cytokine that is often found to be up-regulated during osteoarthritic and rheumatoid joint diseases. It is viewed as a catabolic factor, inducing enzymes that allow for the degradation of the cartilage extracellular matrix and also has essential roles as an autocrine and paracrine factor in fibronectin fragment-mediated degradation. It can also reduce the synthesis of the major cartilage components, type II collagen and aggrecan. On the other hand, IL-1B also has the ability to induce the growth and morphogenic factor BMP-2. During joint diseases, IL-1B is synthesized by both synovial cells and chondrocytes. Addition of IL-1 biological antagonists such as IL-1 receptor antagonists can suppress cartilage degradation in vitro. Thus, the production of IL-1B could act as the first step in mediating a cascade of other mediators in cartilage which could be relevant to the fate of the cartilage. In order to obtain a global picture of the effect of IL-1B production on human adult articular chondrocytes, we analyzed changes in gene expression induced by IL-1B by microarray analysis. We found that IL-1B has a diverse effect on gene expression profile in chondrocytes. One of the predominant responses that we observed in adult human articular chondrocytes on exposure to IL-1B is a dramatic increase in a large set of chemokines and other genes related to the inflammatory cascade. Keywords: Gene response to IL-1B (10 ng/ml) Cartilage was obtained from adult human tissue donors with above the knee amputations due to chondrosarcoma or traumatic injury or from autopsy. Chondrocytes were isolated following established protocols, maintained in high density, and treated with IL-1B (10 ng/ml). Chondrocytes treated with buffer only served as the untreated control. The experiment was carried out in duplicate. Total RNA was extracted from these chondrocytes, labeled with fluorophores (Cy3 or Cy5) and analyzed for expression changes using the Human Operon/Qiagen v3.0 oligonucleotide array. The analysis was repeated with the fluorophore dyes exchanged between the untreated and experimental RNAs.
2008-05-14 | E-GEOD-11427 | biostudies-arrayexpress
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
2023-10-30 | GSE246507 | GEO
Project description:Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
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