Title of article :
Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation
Bannon, Aidan Queen’s University Belfast - School of Medicine, Centre for Infection and Immunity, Dentistry and Biomedical Sciences, UK , Zhang, Shu-Dong Queen’s University Belfast - School of Medicine, Centre for Cancer Research and Cell Biology, UK , Schock, Bettina C. Queen’s University Belfast - School of Medicine, Centre for Infection and Immunity, UK , Ennis, Madeleine Queen’s University Belfast - School of Medicine, Centre for Infection and Immunity, UK
Cystic fibrosis (CF) is a lifelong, inflammatory multi-organ disease and the most common lethal, genetic condition in Caucasian populations, with a median survival rate of 41.5 years. Pulmonary disease, characterized by infective exacerbations, bronchiectasis and increasing airway insufficiency is the most serious manifestation of this disease process, currently responsible for over 80% of CF deaths. Chronic dysregulation of the innate immune and host inflammatory response has been proposed as a mechanism central to this genetic condition, primarily driven by the nuclear factor κB (NF-κB) pathway. Chronic activation of this transcription factor complex leads to the production of pro-inflammatory cytokines and mediators such as IL-6, IL-8 and TNF-α. A20 has been described as a central and inducible negative regulator of NF-κB. This intracellular molecule negatively regulates NF- κB-driven pro-inflammatory signalling upon toll-like receptor activation at the level of TRAF6 activation. Silencing of A20 increases cellular levels of p65 and induces a pro-inflammatory state. We have previously shown that A20 expression positively correlates with lung function (FEV 1 %) in CF. Despite improvement in survival rates in recent years, advancements in available therapies have been incremental. We demonstrate that the experimental use of naturally occurring plant diterpenes such as gibberellin on lipopolysaccharide- stimulated cell lines reduces IL-8 release in an A20-dependent manner. We discuss how the use of a novel bio-informatics gene expression connectivity-mapping technique to identify small molecule compounds that similarly mimic the action of A20 may lead to the development of new therapeutic approaches capable of reducing chronic airway inflammation in CF.
Cystic fibrosis · Nuclear factor κB · A20 · Anti , inflammatory effects · Gene connectivity mapping · Drug repositioning
Journal title :
Medical Principles and Practice