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Beta cell overexpression of HSD11B1 in high fat fed mice

ABSTRACT: To model the potential diabetogenic effects of higher level of HSD11B1 in b-cells of the pancreas in vivo, we created a transgenic model overexpressing HSD11B1 under the mouse insulin I promoter (MIP-HSD1) in diabetes-prone C57Bl/KsJ mice. KsJ wild type and MIP-HSD1 heterozygous mice have been high fat fed for 12 weeks. Pancreata have been perfused with collagenase and islets isolated by hand picking. Isolated islets (around 500) coming from at least 3 mice (around 200/mice) have been directly lysed in Trizol. Total RNA have been extracted by Trizol plus RNA Purification Kit (invitrogen).

ORGANISM(S): Mus musculus

PROVIDER: GSE23161 | GEO | 2011/06/30

SECONDARY ACCESSION(S): PRJNA131549

REPOSITORIES: GEO

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Beta cell overexpression of HSD11B1 in high fat fed mice

Project description:To model the potential diabetogenic effects of higher level of HSD11B1 in b-cells of the pancreas in vivo, we created a transgenic model overexpressing HSD11B1 under the mouse insulin I promoter (MIP-HSD1) in diabetes-prone C57Bl/KsJ mice. KsJ wild type and MIP-HSD1 heterozygous mice have been high fat fed for 12 weeks. Pancreata have been perfused with collagenase and islets isolated by hand picking. Isolated islets (around 500) coming from at least 3 mice (around 200/mice) have been directly lysed in Trizol. Total RNA have been extracted by Trizol plus RNA Purification Kit (invitrogen). Four biological replicates per group: Wild type KsJ mice on High Fat diet (KsJ1, KsJ2, KsJ3, KsJ4) and MIP-HSD1 transgenic mice on High Fat diet (MIP1, MIP2, MIP3, MIP4) were used to prepare RNA for microarray analysis.

2011-06-30 | E-GEOD-23161 | biostudies-arrayexpress

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth

Project description:Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). Here we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded with increased frequencies of tumor-infiltrating CD8+ T cells (TIL) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of Tconv activation in tumor-infiltrating Treg. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.

2023-09-20 | GSE231303 | GEO

Effects of Hsd11b1 overexpressing in mc3T3-e1 pre-osteoblastic cell lines under glucocorticoid excess

Project description:To explore the mechanism by which osteoblastic 11β-HSD1 regulates bone formation and glucose handling, we transfected the mouse MC3T3-E1 osteoblastic cells with a plasmid carrying the exogenous Hsd11b1 or EGFP gene to construct the 11β-HSD1-overexpressed and control osteoblastic cells (hereafter MC3T3-HSD1 and MC3T3-GFP cells), respectively. After incubating with 11-DHC,we then employed RNA sequencing (RNA-seq) to examine the gene expression profile between MC3T3-HSD1 and MC3T3-GFP cells.

2024-09-25 | GSE274790 | GEO

Effects of Hsd11b1 overexpressing in mc3T3-e1 pre-osteoblastic cell lines under glucocorticoid excess (ATAC-Seq)

Project description:To explore the mechanism by which osteoblastic 11β-HSD1 regulates bone formation and glucose handling, we transfected the mouse MC3T3-E1 osteoblastic cells with a plasmid carrying the exogenous Hsd11b1 or EGFP gene to construct the 11β-HSD1-overexpressed and control osteoblastic cells (hereafter MC3T3-HSD1 and MC3T3-GFP cells), respectively. After incubating with 11-DHC,we then employed assay for transposase-accessible chromatin with sequencing (ATAC-seq) to examine the gene expression profile between MC3T3-HSD1 and MC3T3-GFP cells.

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Ubiquitin Thioesterase OTUB2 is An Endoplasmic Reticulum Stress-associated β Cell Autoantigen Targeted by CD8+ T cells in Type 1 Diabetes

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2024-05-24 | PXD041227 | Pride

Examination of inflammatory transcripts during a transfer model of type I diabetes.

Project description:In an accompanying paper we found specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intra-islet dendritic cells bearing the β-cell-peptide-MHC complex. Here we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. VCAM-1 expression was notable in blood vessels and so was ICAM-1. ICAM-1 was also found on β-cells. These expression changes induced the entry of non-specific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of non-specific T cells required a chemokine response and VCAM-1 expression by the islets. Interferon-gamma was important for the early gene expression changes in the islets. By microarray analysis we detected up-regulation of a group of interferon-inducible genes as early as 8 hours post T cell transfer. These studies provide a baseline to examine the development of therapeutics that can modulate islet localization of diabetogenic T cells to control this autoimmune disease. 20 total samples

2011-02-16 | E-GEOD-26147 | biostudies-arrayexpress

Examination of inflammatory transcripts during a transfer model of type I diabetes.

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