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β-arrestin 2 mediates the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells

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Abstract

Recent evidence has suggested that microglial activation plays an important role in the pathogenesis of depression. Activated microglia can secrete various pro-inflammatory cytokines, which may contribute to the development and maintenance of depression. Thus, inhibition of microglial activation may have a therapeutic benefit in the treatment of depression. In the present study, we found that fluoxetine significantly inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α), interleukin- 6 (IL-6) and nitric oxide (NO) and reduced the phosphorylation of transforming growth factor-beta-activated kinase 1 (TAK1) and nuclear factor-kappa B (NF-κB) p65 nuclear translocation in microglia. We further found that fluoxetine increased the expression of β-arrestin 2 and enhanced the association of β-arrestin 2 with TAK1-binding protein 1 (TAB1) and disrupted TAK1-TAB1 interaction. Moreover, β-arrestin 2 knock-down abolished the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells. Collectively, our findings suggest that β-arrestin 2 is necessary for the anti-inflammatory effects of fluoxetine and offers novel drug targets in the convergent fluoxetine/β-arrestin 2 and inflammatory pathways for treating microglial inflammatory neuropathologies like depression.

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Acknowledgments

This work was supported by the grant from the Key Program of Basic Research of Chaoyang hospital.

Conflict of Interest

None declared.

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Authors and Affiliations

  1. Department of Neurology, Chaoyang Hospital, 15 Renmingnan Road, Huainan, Anhui, 232007, People’s Republic of China

    Ren-Wei Du & Wen-Guang Bu

  2. Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People’s Republic of China

    Ren-Hong Du

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  1. Ren-Wei Du
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Correspondence to Ren-Hong Du or Wen-Guang Bu.

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Du, RW., Du, RH. & Bu, WG. β-arrestin 2 mediates the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells. J Neuroimmune Pharmacol 9, 582–590 (2014). https://doi.org/10.1007/s11481-014-9556-y

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  • DOI: https://doi.org/10.1007/s11481-014-9556-y

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