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

J Hepatol. 2013 Apr;58(4):743-9. doi: 10.1016/j.jhep.2012.11.038. Epub 2012 Dec 1.


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/β 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/β 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokines / genetics
  • Cytokines / genetics
  • Immunologic Factors / pharmacology
  • Interferon Type I / biosynthesis*
  • Interferon-gamma / biosynthesis*
  • Liver / drug effects*
  • Liver / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligodeoxyribonucleotides / pharmacology
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 9 / agonists*
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Transcriptional Activation / drug effects
  • Up-Regulation / drug effects


  • Chemokines
  • Cytokines
  • Immunologic Factors
  • Interferon Type I
  • Oligodeoxyribonucleotides
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Receptor, Interferon alpha-beta
  • Interferon-gamma