Anti-inflammatory action of Gibberellin in lung epithelial cells is mediated by modification of NF-κB related kinase expression

Ruth Barsden, Alexandrina Todd, Catriona Kelly, Madeleine Ennis, Bettina Schock

    Research output: Contribution to journalSpecial issuepeer-review

    Abstract

    Airway inflammation is driven by activation of the transcription factor NF-kB. NF-kB signalling is negatively regulated by the zinc finger protein A20. In Cystic Fibrosis A20 expression / function is significantly reduced and the lack of A20 is associated with reduced lung function (Kelly et al. 2012, 2013). The plant diterpene gibberellin (GA3) has anti-inflammatory properties by induction of A20 and reduction of the NF-κB subunit p65, but A20 itself is NF-κB induced. The pro- and anti-inflammatory effects of NF-κB may be mediated by different activation (phosphorylation) of p65 facilitated by IKKα/β, Glycogen Synthase Kinase 3β (GSK3β) and Tank Binding Kinase 1 (TBK1).

    We hypothesised that the anti-inflammatory action of GA3 is mediated by the p65 phosphorylating kinases.

    Our results with bronchial epithelial cell lines show significantly increased expression of IKKα/β and GSK3β in CF epithelial cells. GA alone induces IKKα/β and TBK1 (8, 4h). Importantly, in CF cells, GA3 reduces the LPS-induced expression of IKKα/β and GSK3β (8h after LPS). GSK3β is a key regulator of inflammation, phosphorylating p65 on Ser536 and Ser468. In non-activated cells, GSK3β is constitutively active, giving rise to p65 Ser468 phosphorylation, which is associated with negative control of NF-kB. Using A20 induction by Hepatocyte Growth Factor, the 'anti-inflammatory ' arm of NF-κB has been described to be mediated by inactivation of GSK3β and suppression of p65 Ser468 phosphorylation (Gong et al. 2008). Further work will investigate the effect of GA3 on p65 phosphorylation and on stimulated epithelial cells from patients with chronic airway disease such as CF and asthma.
    Original languageEnglish
    Pages (from-to)3884
    Number of pages1
    JournalEuropean Respiratory Journal
    Volume44
    Issue number58
    Publication statusPublished online - 1 Sep 2014

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