Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes

<p>Abstract</p> <p>Background</p> <p>Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin...

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Main Authors: Kovarik Pavel, Stiefvater Rita, Wallner Barbara, Hofmann Elisabeth, Fuhrmann Bernd, Flatt Thomas, Vogl Claus, Strobl Birgit, Müller Mathias
Format: Article
Language:English
Published: BMC 2010-03-01
Series:BMC Genomics
Online Access:http://www.biomedcentral.com/1471-2164/11/199
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spelling doaj-ef657fb40dcb4e8894aacafa03dc14db2020-11-25T00:09:24ZengBMCBMC Genomics1471-21642010-03-0111119910.1186/1471-2164-11-199Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genesKovarik PavelStiefvater RitaWallner BarbaraHofmann ElisabethFuhrmann BerndFlatt ThomasVogl ClausStrobl BirgitMüller Mathias<p>Abstract</p> <p>Background</p> <p>Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin shock induced by lipopolysaccharide (LPS), and Tyk2 deficient macrophages fail to efficiently induce interferon α/β after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we examine the regulatory role of Tyk2 in basal and inflammatory transcription by comparing gene expression profiles of peritoneal macrophages from Tyk2 mutant and wildtype control mice that were either kept untreated or exposed to LPS for six hours.</p> <p>Results</p> <p>Untreated Tyk2-deficient macrophages exhibited reduced expression of immune response genes relative to wildtype, in particular those that contain interferon response elements (IRF/ISRE), whereas metabolic genes showed higher expression. Upon LPS challenge, IFN-inducible genes (including those with an IRF/ISRE transcription factor binding-site) were strongly upregulated in both Tyk2 mutant and wildtype cells and reached similar expression levels. In contrast, metabolic gene expression was strongly decreased in wildtype cells upon LPS treatment, while in Tyk2 mutant cells the expression of these genes remained relatively unchanged, which exaggerated differences already present at the basal level. We also identified several 5'UR transcription factor binding-sites and 3'UTR regulatory elements that were differentially induced between Tyk2 deficient and wildtype macrophages and that have not previously been implicated in immunity.</p> <p>Conclusions</p> <p>Although Tyk2 is essential for the full LPS response, its function is mainly required for baseline expression but not LPS-induced upregulation of IFN-inducible genes. Moreover, Tyk2 function is critical for the downregulation of metabolic genes upon immune challenge, in particular genes involved in lipid metabolism. Together, our findings suggest an important regulatory role for Tyk2 in modulating the relationship between immunity and metabolism.</p> http://www.biomedcentral.com/1471-2164/11/199
collection DOAJ
language English
format Article
sources DOAJ
author Kovarik Pavel
Stiefvater Rita
Wallner Barbara
Hofmann Elisabeth
Fuhrmann Bernd
Flatt Thomas
Vogl Claus
Strobl Birgit
Müller Mathias
spellingShingle Kovarik Pavel
Stiefvater Rita
Wallner Barbara
Hofmann Elisabeth
Fuhrmann Bernd
Flatt Thomas
Vogl Claus
Strobl Birgit
Müller Mathias
Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
BMC Genomics
author_facet Kovarik Pavel
Stiefvater Rita
Wallner Barbara
Hofmann Elisabeth
Fuhrmann Bernd
Flatt Thomas
Vogl Claus
Strobl Birgit
Müller Mathias
author_sort Kovarik Pavel
title Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
title_short Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
title_full Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
title_fullStr Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
title_full_unstemmed Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes
title_sort transcriptome analysis reveals a major impact of jak protein tyrosine kinase 2 (tyk2) on the expression of interferon-responsive and metabolic genes
publisher BMC
series BMC Genomics
issn 1471-2164
publishDate 2010-03-01
description <p>Abstract</p> <p>Background</p> <p>Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin shock induced by lipopolysaccharide (LPS), and Tyk2 deficient macrophages fail to efficiently induce interferon α/β after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we examine the regulatory role of Tyk2 in basal and inflammatory transcription by comparing gene expression profiles of peritoneal macrophages from Tyk2 mutant and wildtype control mice that were either kept untreated or exposed to LPS for six hours.</p> <p>Results</p> <p>Untreated Tyk2-deficient macrophages exhibited reduced expression of immune response genes relative to wildtype, in particular those that contain interferon response elements (IRF/ISRE), whereas metabolic genes showed higher expression. Upon LPS challenge, IFN-inducible genes (including those with an IRF/ISRE transcription factor binding-site) were strongly upregulated in both Tyk2 mutant and wildtype cells and reached similar expression levels. In contrast, metabolic gene expression was strongly decreased in wildtype cells upon LPS treatment, while in Tyk2 mutant cells the expression of these genes remained relatively unchanged, which exaggerated differences already present at the basal level. We also identified several 5'UR transcription factor binding-sites and 3'UTR regulatory elements that were differentially induced between Tyk2 deficient and wildtype macrophages and that have not previously been implicated in immunity.</p> <p>Conclusions</p> <p>Although Tyk2 is essential for the full LPS response, its function is mainly required for baseline expression but not LPS-induced upregulation of IFN-inducible genes. Moreover, Tyk2 function is critical for the downregulation of metabolic genes upon immune challenge, in particular genes involved in lipid metabolism. Together, our findings suggest an important regulatory role for Tyk2 in modulating the relationship between immunity and metabolism.</p>
url http://www.biomedcentral.com/1471-2164/11/199
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