title: Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Reihill
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: B
authors.initials: B
authors.lastname: Malcomson
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: A
authors.initials: A
authors.lastname: Bertelsen
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: S
authors.initials: S
authors.lastname: Cheung
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: A
authors.initials: A
authors.lastname: Czerwiec
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: R
authors.initials: R
authors.lastname: Barsden
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Elborn
authors.affiliation: Institute für Pathodiagnostik, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Dürkop
authors.affiliation: Charité-University, Institute of Pathology, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hirsch
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ennis
authors.affiliation: Northern Ireland Centre for Stratified Medicine, University of Ulster, Londonderry, UK.
authors.forename: C
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK.
authors.forename: B C
authors.initials: BC
authors.lastname: Schock
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005875:Gibberellins / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005875:Gibberellins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C007842:gibberellic acid; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3