Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway

ABSTRACT: MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling. While STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1); miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122–RTKs/STAT3–IRF1–IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge about miR-122’s function and have important implications for treating hepatitis viruses. We used microarrays to analyze which genes were down-regulated by miR-122.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99663 | GEO | 2019/02/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IRF1 mass-spectrometry primary fibroblasts non-stimulated or stimulated with IFNg for 24h

Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-a/b immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-a/b in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-a/b immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-a/b immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.

2023-01-19 | PXD037759 | Pride

Opposing tumor cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in anti-tumor immunity

Project description:Type I interferons (IFN-I) and IFN- foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these responses are incompletely understood. Herein, we describe how Interferon Regulatory Factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumors blocked Toll-like receptor and IFN-I-dependent host antitumor immunity by preventing IFN stimulated gene (ISG) programs and effector programs in dendritic cells and T cells. In contrast, expression of IRF1 in the host, but not IRF3 or IFN-, was also required for antitumor immunity to wildtype and Irf1-/- tumors. Mechanistically, tumor cell IRF1 regulated major histocompatibility class I expression and bound uniquely or together with STAT1 at many ISGs, contributing to expression of immunosuppressive but not immunostimulatory ISGs. Overexpression of PD-L1 in Irf1-/- tumors only partially restored tumor growth, suggesting that the negative effects of tumor IRF1 on antitumor immunity are multifactorial. Thus, we identify tumor cell IRF1 expression as a previously unrecognized selective inhibitor of host IFN-I dependent antitumor immunity, while host IRF1 and IFN-I are critical drivers of antitumor immune responses.

2024-05-01 | GSE246923 | GEO

miR-122-dependent binding of TNRC6 to HCV RNA

Project description:The liver-specific microRNA, miR-122, is an essential host factor for replication of hepatitis C virus (HCV), an important infectious cause of chronic liver disease and hepatocellular carcinoma. miR-122 stabilizes the positive-strand HCV RNA genome and promotes viral RNA synthesis by binding two closely spaced sites (S1 and S2) near the 5’ end of the genome in association with Ago2. Ago2 is essential for both host factor activities, but whether other host proteins are involved is unknown. Using a quantitative proteomics approach, we identified TNRC6A (GW182) and its paralogs (TNRC6B and TNRC6C), as functionally important components of the miR-122/Ago2 host factor complex binding HCV RNA. Depletion of any two TNRC6 proteins reduced HCV replication in Huh-7.5 cells,but did not reduce viral RNA stability or translational activity, but rather dampened miR-122 stimulation of viral RNA synthesis. However, TNRC6 depletion had no effect on replication of HCV in which S2 was mutated so that miR-122 binds only S1, whereas it significantly enhanced replication when S1 was mutated and only S2 bound by miR-122. Consistent with this, we found that TNRC6 proteins preferentially associate with the S1 site, and that the association of Ago2 with S2 is increased in TNRC6-depleted cells. Collectively, these data suggest a model in which TNRC6 proteins, which are known to interact with Ago2, preferentially direct the miR-122/Ago2 complex to S1 while restricting its association with S2, thereby fine tuning the spatial organization of miR-122/Ago2 complexes bound to the viral RNA.

2019-04-24 | PXD013054 | Pride

Transcription profiling of wild type mouse embryonic fibroblasts treated with interferon to study interferon-regulated gene expression.

Project description:A number of IFN-induced proteins are believed to be responsible for the antiviral state induced by IFNs. Our microarray analysis of IFN-regulated genes in MEFs from wild-type mice identified 124 probe sets that were differentially regulated upon IFN treatment. This group consisted of many known ISGs such as Ifit1, Gbp2, mx1, Isg15, Stat1, nmi, mx2, If204, Adar, Irf1, and protein kinase R. Experiment Overall Design: 3 control and 3 IFNb-treated biological replicates were analyzed.

2007-10-12 | E-GEOD-3400 | biostudies-arrayexpress

Primary human hepatocytes treated with IFNalpha and IL28B

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN, IL28b and T-PolyC after 6 or 24 hours respectively

2012-03-09 | E-GEOD-31264 | biostudies-arrayexpress

Transcription profiling by array of primary human hepatocytes derived from hepatitis C patients treated with type III interferons (IFNs) for 6 or 24 hours

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN or IL28b after 6 or 24 hours with three replications

2012-03-09 | E-GEOD-31193 | biostudies-arrayexpress

Primary human hepatocytes treated with IL28B and the HCV JFH1 Genotype 2A clone.

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with JFHA, and IL28b respectively with three biological replication.

2013-08-16 | E-GEOD-31455 | biostudies-arrayexpress

Human IRF1 governs phagocytic IFN-gamma immunity to mycobacteria

Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-/ immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-/ immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-/ in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-/ immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-/ immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.

2023-01-12 | GSE218033 | GEO

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Project description:Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

2023-05-12 | GSE203220 | GEO

Human IRF1 governs phagocytic IFN-γ immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses [CITEseq]

Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, while inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-γ than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-γ. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in mononuclear myeloid cells.

2023-01-12 | GSE216488 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data