Dependency of ISG expression on IFNAR1 and Tyk2
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75203 | GEO | 2015/11/20
SECONDARY ACCESSION(S): PRJNA302792
REPOSITORIES: GEO
Similar Datasets
Project description:We analyze the expression profile of ISGs in the context of IFNAR1-KO primary murine B cells and macrophages. These analses were used to define ISG gene sets that are under tonic control. Furthermore, these analyses enabled the definition of ISGs that are dependent on Tyk2 signaling. Male C57BL/6 IFNAR1-KO mice were injected subcutaneously with 10,000U IFNa for 2hrs. Splenic B cells and peritoneal macrophages were sorted by FACS directly into TriZol and gene expression profiling was performed on Affymetrix Mouse Gene 1.0 ST Arrays.
2015-11-20 | E-GEOD-75203 | biostudies-arrayexpress
Project description:ISG induction in IFNAR2 mutant, IFNAR1 KO and wild type THP1
2023-01-25 | GSE211502 | GEO
Project description:Inborn errors of TLR3-dependent IFN-α/β- and -λ-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β- and -λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3’UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the induction of IFN-stimulated genes (ISGs). Transcriptome analysis revealed a complete abolition of genome-wide ISG induction in response to IFN-α2b in IFNAR1-deficient fibroblasts from the patient. These fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This experiment of Nature indicates that IFN-α/β are essential for anti-HSV-1 immunity in the CNS.
2020-09-24 | GSE157948 | GEO
Project description:Define the impact of Tyk2 and Tyk2K923E on the transcriptome of NK cells Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2-/- ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2-/- mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2-/- and Tyk2K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2-/- NK cells (and to a lesser extent of Tyk2K923E NK cells) is impaired. In contrast, the production of interferon ? (IFN?) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2K923E NK cells against a range of target cells in vitro is higher than that of Tyk2-/- NK cells. Consistently, Tyk2K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2’s kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy. Splenic NK cells derived from WT, Tyk2-/- and Tyk2K923E mice (DX5-MACS enriched from 3-4 mice per genotype) were grown in the presence rhIL-2 (5000 U/ml) for 7 days. Three independent expreiments (= biological replicates)
2015-04-28 | E-GEOD-68294 | biostudies-arrayexpress
Project description:Define the impact of Tyk2 and Tyk2K923E on the transcriptome of NK cells Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2-/- ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2-/- mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2-/- and Tyk2K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2-/- NK cells (and to a lesser extent of Tyk2K923E NK cells) is impaired. In contrast, the production of interferon γ (IFNγ) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2K923E NK cells against a range of target cells in vitro is higher than that of Tyk2-/- NK cells. Consistently, Tyk2K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2’s kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.
2015-04-28 | GSE68294 | GEO
Project description:We previously identified a subset of interferon stimulated genes (ISGs), including Irf7, Irf1, Oas1a and Oas1b, upregulated by a West Nile virus (WNV) infection in wildtype mouse embryo fibroblasts (MEFs) after viral proteins had inhibited type 1 interferon (IFN)-mediated JAK-STAT signaling and also in WNV-infected STAT1-/-, STAT2-/-, IFNAR-/-, IRF3-/-, IRF7-/-, and IRF3/7-/- MEFs. In this study, ISG upregulation by WNV infection was inhibited in RIG-I/MDA5-/- but not in single knockout MEFs. ISGs upregulation was detected in WNV-infected IRF1-/- and IRF5-/- but was minimal in IRF3/5/7-/- MEFs, suggesting redundant IRF involvement. ISG upregulation by WNV infection in IFNAR-/- MEFs was confirmed by RNA-seq. We previously showed that a single proximal interferon stimulated response element (ISRE) in the Oas1a and Oas1b promoters bound the ISGF3 complex during IFN-dependent upregulation. In this study, we used wild-type and mutant promoter luciferase reporter constructs to identify critical regions in the Oas1b and Ifit1 promoters for IFN-independent transcriptional regulation. Two ISREs were required for both promoters. Mutation of these ISREs in an Ifit1 promoter DNA probe reduced in vitro complex formation. An NF-κB inhibitor decreased Ifit1 promoter activity in cells and in vitro complex formation. IRF3 and p50 binding was detected by ChIP for four upregulated ISGs with two proximal ISREs in their promoters. The data indicate that IFN-independent ISG expression of some ISGs is upregulated by two ISREs functioning cooperatively and the binding of a complex consisting of IRF3, 5, and/or 7 and an NF-κB component(s) as well as other as yet unknown factors.
2021-08-31 | GSE182446 | GEO
Project description: Not available
| S-EPMC1479745 | biostudies-other
Project description:Stimulator of Interferon Genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFN and IFN-I Interferon Stimulated Genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to RANKL in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation settings, we sought to determine whether basal STING signaling contributes to bone homeostasis, an unexplored area. Using whole-body and myeloid-specific deficiency, we show that STING signaling prevents trabecular bone loss in mice over time and that myeloid-restricted STING activity is sufficient for this effect. STING-deficient osteoclast precursors differentiate with greater efficiency than wildtypes. RNA sequencing of wildtype and STING-deficient osteoclast precursor cells and differentiating osteoclasts reveals novel clusters of ISGs including a previously undescribed ISG set expressed in RANKL naïve precursors (tonic expression) and downregulated during differentiation. We identify a 50 gene tonic ISG signature that is STING-dependent and shapes osteoclast differentiation. From this list, we identify Interferon Stimulated Gene 15 (ISG15) as a tonic STING-regulated ISG that limits osteoclast formation. Thus, STING is an important upstream regulator of tonic IFN-I signatures shaping the commitment to osteoclast fates, providing evidence for a nuanced and novel role for this pathway in bone homeostasis.
2023-04-19 | GSE226625 | GEO
Project description:Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK kinase activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of IL-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the anti-apoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. Human T-ALL cell line JURKAT cells were transduced with TYK2 (TYK2#2 or #3), STAT1 (STAT1#2 or #3) or control shRNAs (GFP and Luc). Experiment was done in biological duplicate ("dup1" and "dup2") . A total of 12 RNA samples (4 control, 4 TYK2 knockdown and 4 STAT1 knockdown) were used for microarray gene expression analysis.
2013-03-18 | E-GEOD-44652 | biostudies-arrayexpress