Sequential induction of type I and II interferons mediates a long-lasting gene induction in the liver in response to a novel toll-like receptor 9 agonist

Makowska, Z. and Blumer, T. and Duong, F. H. and La Monica, N. and Kandimalla, E. R. and Heim, M. H.. (2013) Sequential induction of type I and II interferons mediates a long-lasting gene induction in the liver in response to a novel toll-like receptor 9 agonist. Journal of hepatology, Vol. 58, H. 4. pp. 743-749.

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Official URL: http://edoc.unibas.ch/dok/A6338542

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BACKGROUND & AIMS: The toll-like receptor 9 (TLR9) agonist IMO-2125 is currently evaluated in clinical trials for chronic hepatitis C therapy. The aim of this study was to investigate the in vivo mode of action of a closely related compound, referred to as immunomodulatory oligonucleotide (IMO). METHODS: We analyzed the Jak-STAT pathway activation and induction of interferon-stimulated genes in the liver of wild type, interferon-alpha/beta receptor-deficient and interferon-gamma-deficient mice, after administration of IMO. RESULTS: IMO induced a prolonged activation of the Jak-STAT pathway and upregulation of interferon-stimulated genes in the mouse liver. Contrary to the response observed after interferon-alpha injection, the signalling induced by IMO was not abrogated following repeated administration. At early time points after IMO injection, STAT1 phosphorylation and interferon-stimulated gene induction required a functional interferon-alpha/beta receptor, whereas at the later time points, the activation was type I interferon-independent. Microarray analysis revealed that IMO induced a broad transcriptional response in the mouse liver. This included upregulation of cytokine and chemokine genes responsible for recruitment of IFN-gamma producers, such as T cells and natural killer cells. Interferon-gamma-deficient mice showed a transient response to IMO, demonstrating the central role of interferon-gamma in sustained activation of Jak-STAT pathway by IMO. CONCLUSIONS: The bimodal kinetics of response to IMO in the mouse liver are driven by the sequential endogenous production of type I and II interferons. The lack of refractoriness to IMO, combined with the long-lasting induction of interferon-stimulated genes, reveals a favourable pharmacodynamics profile of this novel TLR9 agonist for the treatment of chronic viral hepatitis.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
UniBasel Contributors:Heim, Markus H.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:14
Deposited On:10 Apr 2015 09:14

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