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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (neutrophils)

ABSTRACT: Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (neutrophils)

PROVIDER: PRJNA609306 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11197900.fastq.gz	Fastqsanger.gz
	SRR11197871.fastq.gz	Fastqsanger.gz
	SRR11197872.fastq.gz	Fastqsanger.gz
	SRR11197873.fastq.gz	Fastqsanger.gz
	SRR11197874.fastq.gz	Fastqsanger.gz

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection

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Project description:Treating inflammatory diseases with Janus kinase 1/2 (JAK1/2) inhibitors bears the risk that patients acquire viral infections due to unwanted immune suppression. Tyrosine kinase 2 (TYK2), a JAK family member, is required for type I interferon (IFN-α/β) signaling, but its role in type III IFN (IFN-λ) signaling is still under debate. We found that the selective TYK2 inhibitor BMS-986165 blocked potentially noxious type I IFN signaling without altering IFN-λ-mediated gene expression. We show that epithelial cells do not require TYK2 for IFN-λ-mediated signaling or antiviral protection. Lack of TYK2 diminished IFN-α-induced protection against lethal influenza virus infection of mice, but did not impair IFN-λ-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors likely represent a superior treatment option for type I interferonopathies than broadly acting JAK1/2 inhibitors, as selective TYK2 inhibitors may counteract inflammatory responses without abolishing the beneficial antiviral effects of IFN-λ.

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Project description:We have developed a transgenic mouse model for Epstein-Barr virus-associated Burkitt's lymphoma. Transgenic mice that express LMP2A and MYC in B cells develop spontaneous lymph node tumors at different rates. Tumor onset occurs at approximately 40-60 days in LMP2A/λ-MYC mice and at 100-200 days in λ-MYC mice. This study compared total gene expression in the tumor cells from each genotype, as well as in B cells isolated from 3 week old mice prior to tumor onset. Comparison of total gene expression in tumor cells from LMP2A/λ-MYC and λ-MYC transgenic mice identified a short list of differentially expressed genes. Comparison of gene expression in B cells from the spleens of 3 week old mice, in contrast, identified a 10-fold increase in the number of differentially expressed genes.

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