Antidepressants inhibit interferon-γ-induced microglial production of IL-6 and nitric oxide

Sadayuki Hashioka, Andis Klegeris, Akira Monji, Takahiro Kato, Makoto Sawada, Patrick L. McGeer, Shigenobu Kanba

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-γ (IFN-γ)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells with 100 U/ml of IFN-γ resulted in an eightfold increase in IL-6 and a tenfold increase in NO into the culture medium. Pretreatment with the selective serotonin reuptake inhibitor fluvoxamine, the relatively selective noradrenaline reuptake inhibitor reboxetine, or the non-selective monoaminergic reuptake inhibitor imipramine, significantly inhibited IL-6 and NO production in a dose-dependent manner. These inhibitions were reversed significantly by SQ 22536, a cyclic adenosine monophosphate (cAMP) inhibitor, and, except for reboxetine, by the protein kinase A (PKA) inhibitor Rp-adenosine3′,5′-cyclic monophosphorothioate triethylammonium salt (Rp-3′,5′-cAMPS). Lithium chloride, which is believed to act by inhibiting the calcium-dependent release of noradrenaline, had a different spectrum of action on microglial 6-3 cells. It enhanced IFN-γ-stimulated IL-6 production and inhibited NO production. The inhibitory effect of lithium chloride was not reversed by either SQ 22536 or Rp-3′,5′-cAMPS. These results suggest that antidepressants have inhibitory effects on IFN-γ-activated microglia and these effects are, at least partially, mediated by the cAMP-dependent PKA pathway. On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-γ-induced microglial activation.

Original languageEnglish
Pages (from-to)33-42
Number of pages10
JournalExperimental Neurology
Volume206
Issue number1
DOIs
Publication statusPublished - Jul 2007

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

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