Anti-inflammatory effects of noradrenaline on LPS-treated microglial cells: Suppression of NFκB nuclear translocation and subsequent STAT1 phosphorylation. (November 2015)

• Record Type: Journal Article
• Authors: Ishii, Yurika; Yamaizumi, Ayaka; Kawakami, Ayu; Islam, Afsana; Choudhury, Mohammed E.; Takahashi, Hisaaki; Yano, Hajime; Tanaka, Junya
• Is Part Of: Neurochemistry international. Volume 90(2015)
• Page Start: 56
• Page End: 66
• Publication Date: 2015-11
• Subjects: Adrenergic receptor -- Phenylephrine -- cAMP -- JAK -- IRF -- TLR4; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2015.07.010
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Noradrenaline (NA) has marked anti-inflammatory effects on activated microglial cells. The present study was conducted to elucidate the mechanisms underlying the NA effects using rat primary cultured microglial cells. NA, an α1 agonist, phenylephrine (Phe) and a β2 agonist, terbutaline (Ter) suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) release by microglia and prevented neuronal degeneration in LPS-treated neuron-microglia coculture. The agents suppressed expression of mRNA encoding proinflammatory mediators. Both an α1-selective blocker terazocine and a β2-selective blocker butoxamine overcame the suppressive effects of NA. cAMP-dependent kinase (PKA) inhibitors did not abolish the suppressive NA effects. LPS decreased IκB leading to NFκB translocation into nuclei, then induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1). NA inhibited LPS-induced these changes. When NFκB expression was knocked down with siRNA, LPS-induced STAT1 phosphorylation and IRF1 expression was abolished. NA did not suppress IL-6 induced STAT1 phosphorylation and IRF1 expression. These results suggest that one of the critical mechanisms underlying the anti-inflammatory effects of NA is the inhibition of NFκB translocation. Although inhibitory effects of NA on STAT1 phosphorylation and IRF1 expression may contribute to the overall suppressive effects of NA, these may be the downstream events of inhibitory effects on NFκB. Since NA, Phe and Ter exerted almost the same effects and PKA inhibitors did not show significant antagonistic effects, the suppression by NA might not be dependent on specific adrenergic receptors and cAMP-dependent signaling pathway. Highlights: Noradrenaline (NA) suppresses microglial activation independently of cAMP. The inhibition of NFκB nuclear translocation is an important mechanism of NA action. NA inhibits STAT1 phosphorylation secondarily to inhibition of NFκB.