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

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• 作者：Zuzanna Makowska¹ ; Tanja Blumer¹ ; Franç ; ois H.T. Duong¹ ; Nicola La Monica² ; Ekambar R. Kandimalla² ; Markus H. Heim¹ ; ³ ; ^{markus.heim@unibas.ch}
• 关键词：HCV ; hepatitis C virus ; IFN ; interferon ; TLR ; Toll-like receptor ; Jak-STAT ; Janus kinase-signal transducer and activator of transcription ; ISG ; interferon-stimulated gene ; PBMCs ; peripheral blood mononuclear cells ; IMO ; immunomodulatory oligonucleotide ; K
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：58
• 期：4
• 页码：743-749
• 全文大小：1510 K

文摘

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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-¦Á/¦Â receptor-deficient and interferon-¦Ã-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-¦Á 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-¦Á/¦Â 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-¦Ã producers, such as T cells and natural killer cells. Interferon-¦Ã-deficient mice showed a transient response to IMO, demonstrating the central role of interferon-¦Ã 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.