title: β-Arrestin 2 mediates the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells.
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.
authors.affiliation: Department of Neurology, Chaoyang Hospital, 15 Renmingnan Road, Huainan, Anhui, 232007, People's Republic of China.
authors.forename: Ren-Wei
authors.initials: RW
authors.lastname: Du
authors.forename: Ren-Hong
authors.initials: RH
authors.lastname: Du
authors.forename: Wen-Guang
authors.initials: WG
authors.lastname: Bu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005473:Fluoxetine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019390:Arrestins; D005473:Fluoxetine; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009569:Nitric Oxide; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000099151:MAP Kinase Kinase Kinase 7; C000605258:Arrb2 protein, mouse; C498144:Rela protein, mouse; C531463:Tab1 protein, mouse