Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells Journal Articles uri icon

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  • AbstractGrowing evidence implicates CD40, a member of the TNFR superfamily, as contributing to the pathogenesis of many neurodegenerative diseases. Thus, strategies to suppress its expression may be of benefit in those disorders. To this aim, we investigated the effect of guanosine, a purine nucleoside that exerts neurotrophic and neuroprotective effects. CD40 expression and function are increased by exposure of mouse microglia cultures or the N9 microglia cell line to IFN-γ (10 ng/ml) plus TNF-α (50 ng/ml) or β amyloid (Aβ) peptide (Aβ1–42; 500 nM). Culture pretreatment with guanosine (10–300 μM), starting 1 h before cytokine or Aβ addition, dose-dependently inhibited the CD40-induced expression as well as functional CD40 signaling by suppressing IL-6 production promoted by IFN-γ/TNF-α challenge in the presence of CD40 cross-linking. Moreover, guanosine abrogated IFN-γ-induced phosphorylation on Ser727 and translocation of STAT-1α to the nucleus as well as TNF-α-/Aβ-induced IκBα and NF-κB p65/RelA subunit phosphorylation, thus inhibiting NF-κB-induced nuclear translocation. Guanosine effects were mediated by an increased phosphorylation of Akt, a PI3K downstream effector, as well as of ERK1/2 and p38 in the MAPK system, because culture pretreatment with selective ERK1/2, p38 MAPK, and PI3K antagonists (U0126, SB203580, or LY294002, respectively) counteracted guanosine inhibition on IFN-γ/TNF-α-induced CD40 expression and function as well as on STAT-1α or NF-κB nuclear translocation. These findings suggest a role for guanosine as a potential drug in the experimental therapy of neuroinflammatory/neurodegenerative diseases, particularly Alzheimer’s disease.


  • D’Alimonte, Iolanda
  • Flati, Vincenzo
  • D’Auro, Mariagrazia
  • Toniato, Elena
  • Martinotti, Stefano
  • Rathbone, Michel Piers
  • Jiang, Shucui
  • Ballerini, Patrizia
  • Di Iorio, Patrizia
  • Caciagli, Francesco
  • Ciccarelli, Renata

publication date

  • January 15, 2007

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