title: Anti-inflammatory effects of noradrenaline on LPS-treated microglial cells: Suppression of NFκB nuclear translocation and subsequent STAT1 phosphorylation.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Yamaizumi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Ayu
authors.initials: A
authors.lastname: Kawakami
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Afsana
authors.initials: A
authors.lastname: Islam
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Choudhury
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan; Center for Advanced Research and Education, Asahikawa Medical University, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan. Electronic address: jtanaka@m.ehime-u.ac.jp.
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D009569:Nitric Oxide; D009638:Norepinephrine
keywords: Adrenergic receptor; IRF; JAK; Phenylephrine; TLR4; cAMP