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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, Zuzanna; Blumer, Tanja; Duong, François H T; La Monica, Nicola; Kandimalla, Ekambar R; Heim, Markus H.
Afiliação
  • Makowska Z; Department of Biomedicine, University of Basel, Basel, Switzerland.
J Hepatol ; 58(4): 743-9, 2013 Apr.
Article em En | MEDLINE | ID: mdl-23207140
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-α/ß receptor-deficient and interferon-γ-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-α 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-α/ß 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-γ producers, such as T cells and natural killer cells. Interferon-γ-deficient mice showed a transient response to IMO, demonstrating the central role of interferon-γ 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Interferon Tipo I / Interferon gama / Receptor Toll-Like 9 / Fígado Limite: Animals Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Interferon Tipo I / Interferon gama / Receptor Toll-Like 9 / Fígado Limite: Animals Idioma: En Ano de publicação: 2013 Tipo de documento: Article