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

ABSTRACT: 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 alpha/beta 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.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.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.

SUBMITTER: Vogl C

PROVIDER: S-EPMC2864243 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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

Vogl Claus C Flatt Thomas T Fuhrmann Bernd B Hofmann Elisabeth E Wallner Barbara B Stiefvater Rita R Kovarik Pavel P Strobl Birgit B Müller Mathias M

BMC genomics 20100325

<h4>Background</h4>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 alpha/beta after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we e ...[more]

PMID: 20338026

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Project description:BackgroundAs a member of the Janus kinase (JAK) family, which includes JAK1, JAK2 and JAK3, tyrosine kinase 2 (TYK2) plays an important role in signal transduction and immune system regulation. Moreover, it is also involved in the development of many types of inflammatory and autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE). TYK2 is an attractive therapeutic target, and selective inhibition of TYK2 over other JAK family members is critical for the development of TYK2 small molecule inhibitors. However, targeting the catalytic region of the TYK2 ATP-binding site is a major challenge due to the high structural homology between the catalytic regions of the JAK family proteins.ResultsIn this study, we developed a novel small molecule inhibitor (QL-1200186) by targeting the pseudokinase regulatory domain (Janus homology 2, JH2) of the TYK2 protein. The binding sites of QL-1200186 were predicted and screened by molecular docking. The inhibitory effects on IFNα, IL-12 and IL-23 signaling were tested in cell lines, human peripheral blood cells and human whole blood. The pharmacokinetic (PK) and pharmacodynamic properties of QL-1200186 were verified in mice. QL-1200186 showed high affinity for TYK2 JH2 and had no apparent selectivity for the TYK2 and JAK homologous kinase domains; these effects were demonstrated using biochemical binding, signaling pathway transduction (JAK1/2/3) and off-target effect assays. More importantly, we revealed that QL-1200186 was functionally comparable and selectivity superior to two clinical-stage TYK2 inhibitors (BMS-986165 and NDI-034858) in vitro. In the PK studies, QL-1200186 exhibited excellent exposure, high bioavailability and low clearance rates in mice. Oral administration of QL-1200186 dose-dependently inhibited interferon-γ (IFNγ) production after interleukin-12 (IL-12) challenge and significantly ameliorated skin lesions in psoriatic mice.ConclusionThese findings suggest that QL-1200186 is a highly selective and potent inhibitor of TYK2. QL-1200186 could be an appealing clinical drug candidate for the treatment of psoriasis and other autoimmune diseases. Video Abstract.

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

Publications

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

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