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

Content Provider	Springer Nature : BioMed Central
Author	Vogl, Claus Flatt, Thomas Fuhrmann, Bernd Hofmann, Elisabeth Wallner, Barbara Stiefvater, Rita Kovarik, Pavel Strobl, Birgit Müller, Mathias
Abstract	Background 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. Results 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. Conclusions 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.
Related Links	https://bmcgenomics.biomedcentral.com/counter/pdf/10.1186/1471-2164-11-199.pdf
Ending Page	19
Page Count	19
Starting Page	1
File Format	HTM / HTML
ISSN	14712164
DOI	10.1186/1471-2164-11-199
Journal	BMC Genomics
Issue Number	1
Volume Number	11
Language	English
Publisher	BioMed Central
Publisher Date	2010-03-25
Access Restriction	Open
Subject Keyword	Life Sciences Microarrays Proteomics Animal Genetics and Genomics Microbial Genetics and Genomics Plant Genetics and Genomics Gene Ontology Metabolic Gene Expression Putative TFBSs Tyk2 Deficiency
Content Type	Text
Resource Type	Article
Subject	Biotechnology Genetics
Journal Impact Factor	3.5/2023
5-Year Journal Impact Factor	4.1/2023

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