Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells

James A Reihill, Bethany Malcomson, Anne Bertelsen, S Cheung, A Czerwiec, R Barsden, J Stuart Elborn, H Dürkop, B Hirsch, Madeleine Ennis, Catriona Kelly, Bettina C Schock

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16 Citations (Scopus)

Abstract

Background and Purpose
NF‐κB‐driven inflammation is negatively regulated by the zinc finger protein A20. Gibberellic acid (GA3) is a plant‐derived diterpenoid with documented anti‐inflammatory activity, which is reported to induce A20‐like zinc finger proteins in plants. Here, we sought to investigate the anti‐inflammatory effect of GA3 in airway epithelial cells and determine if the anti‐inflammatory action relates to A20 induction.

Experimental Approach
Primary nasal epithelial cells and a human bronchial epithelial cell line (16HBE14o‐) were used. Cells were pre‐incubated with GA3, stimulated with Pseudomonas aeruginosa LPS; IL‐6 and IL‐8 release, A20, NF‐κB and IκBα expression were then evaluated. To determine if any observed anti‐inflammatory effect occurred via an A20‐dependent mechanism, A20 was silenced using siRNA.

Key Results
Cells pre‐incubated with GA3 had significantly increased levels of A20 mRNA (4 h) and protein (24 h), resulting in a significant reduction in IL‐6 and IL‐8 release. This effect was mediated via reduced IκBα degradation and reduced NF‐κB (p65) expression. Furthermore, the anti‐inflammatory action of GA3 was abolished in A20‐silenced cells.

Conclusions and Implications
We showed that A20 induction by GA3 attenuates inflammation in airway epithelial cells, at least in part through its effect on NF‐κB and IκBα. GA3 or gibberellin‐derived derivatives could potentially be developed into anti‐inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction.
Original languageEnglish
Pages (from-to)778-789
Number of pages12
JournalBritish Journal of Pharmacology
Volume173
Issue number4
Early online date25 May 2015
DOIs
Publication statusPublished - 4 Feb 2016

Keywords

  • Airways
  • Inflammation
  • A20
  • NF-kB

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    Reihill, J. A., Malcomson, B., Bertelsen, A., Cheung, S., Czerwiec, A., Barsden, R., Elborn, J. S., Dürkop, H., Hirsch, B., Ennis, M., Kelly, C., & Schock, B. C. (2016). Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells. British Journal of Pharmacology, 173(4), 778-789. https://doi.org/10.1111/bph.13200