Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-κB-Mediated Inflammation

Abstract

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 (FEV₁%) 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.

Increased Visfatin Expression Is Associated with Nuclear Factor-κB in Obese Ovalbumin-Sensitized Male Wistar Rat Tracheae

“…Obesity is a low-grade chronic proinflammatory state, identified by enhances in serum levels of various chemokines, cytokines, and soluble cytokine receptors, and results in airway inflammation and asthma severity [27] . Previous reports have indicated that NF-κB has an important role in allergic inflammation of airways [28] . A study conducted by Poynter et al [5] showed that rapid and selective activation of NF-κB occurred in mice airway epithelium challenged and sensitized with antigen.…”

Abscisic Acid as Pathogen Effector and Immune Regulator

“…Similar approaches might also be fruitful for studies of other signaling molecules from plants and phytopathogenic fungi that have been found to show pharmacological effects in animals, like for example gibberellins (Hedden and Thomas, 2012; Annand et al, 2015; Bannon et al, 2015; Reihill et al, 2016) and SA (Klessig et al, 2016). Since no genes are known that regulate intracellular ABA homeostasis in animals, utilizing proteins and pathways known in plants and phytopathogenic fungi could help defining the physiological role of ABA in animals.…”

A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications

“…NF- κ B pathway is an important signal pathway in inflammatory process (Bannon et al. 2015 ). SSa attenuates inflammation mainly by inhibiting the activation of NF- κ B pathway (Wu et al.…”