title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.forename: Tanja
authors.initials: T
authors.lastname: Blumer
authors.forename: François H T
authors.initials: FH
authors.lastname: Duong
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology; D007370:Interferon Type I / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma