Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis

Kelly, Catriona; Williams, Mark Thomas Shaw; Elborn, J. Stuart; Ennis, Madeleine; Schock, Bettina

doi:10.1016/j.jcf.2012.10.009

Cited by 17 publications

(23 citation statements)

References 18 publications

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“…antibiotics, but augmented CFTR function failed to reduce inflammatory markers in sputum (e.g., IL-1, -6, -8) (26), and heterogeneous responses to the treatment have been reported (27), suggesting that CFTR correction/potentiation may not directly improve the underlying compromised immune response. The negative NF-κB regulator A20 (TNFAIP3) is reduced in CF airway epithelial cells, basally and after LPS stimulation (23), and is associated with markers of inflammation and decreased lung function (12). A20 silencing increased TRAF6 and NF-κB activity (18), and A20 overexpression had protective effects in airway inflammation in asthmatic mice (28), suggesting that A20 augmentation normalizes the inflammatory response in the airways.…”

Section: Discussionmentioning

confidence: 99%

“…A common feature of CF is the heightened, chronic inflammatory response to Pseudomonas aeruginosa, driven by constitutive NF-κB activation in airway and peripheral blood cells (2,3,11). Primary nasal epithelial cells (PNECs) from patients with the common Phe508del/Phe508del mutation and a milder genotype (R117H/ Phe508del) show a significant increase in NF-κB(p65), which correlates with disease severity (12). A20 [TNFα-induced protein 3 (TNFAIP3)] is a central negative regulator of NF-κB activation following stimulation of TLRs and/or TNF receptor and regulates different signaling pathways such as NF-κB and IFN regulatory factor signaling (13).…”

Section: Cf Airway Inflammationmentioning

confidence: 99%

“…A20 [TNFα-induced protein 3 (TNFAIP3)] is a central negative regulator of NF-κB activation following stimulation of TLRs and/or TNF receptor and regulates different signaling pathways such as NF-κB and IFN regulatory factor signaling (13). A20 modifies classical immune cells (14,15) as well as epithelial cells (12), endothelial cells (16), embryonic fibroblasts (17), osteoclasts (18), and pancreatic beta cells (19) and diverse roles have been suggested for A20 in innate immunity, apoptosis, autophagy and Significance This study reports that publicly available gene array expression data together with statistically significant connections' map successfully predicts licensed drugs able to modify genes of interest. We used this method to predict drugs able to induce A20 [TNFα-induced protein 3 (TNFAIP3)], which is reduced in cystic fibrosis (CF) airway cells, and thus normalize the inflammatory response.…”

Section: Cf Airway Inflammationmentioning

confidence: 99%

“…In cultured human airway epithelial cells, A20 is rapidly induced by viral or bacterial compounds (21) and is essential for termination of the TLR4 signal (22). PNECs stimulated with P. aeruginosa LPS show a transient increase in A20, but CF PNECs display lower A20 expression basally and after LPS stimulation (12,23).…”

Section: Cf Airway Inflammationmentioning

confidence: 99%

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Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.A20 | NF-κB | connectivity mapping | drug repositioning | CF airway inflammation

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Section: Discussionmentioning

confidence: 99%

Section: Cf Airway Inflammationmentioning

confidence: 99%

Section: Cf Airway Inflammationmentioning

confidence: 99%

Section: Cf Airway Inflammationmentioning

confidence: 99%

See 2 more Smart Citations

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Enhanced A20 mRNA expression occurs following infection of mice with P. aeruginosa [22] We have previously shown that the prolonged NF-κB driven inflammatory response in CF airway epithelial cells is associated with reduced expression of A20 [23] and most importantly this lack of A20 correlates with reduced lung function in patients with CF [24]. Onose et al described virus induced induction of A20 in human bronchial epithelial cell lines and mouse lung homogenates.…”

Section: A20 In the Airwaysmentioning

confidence: 99%

Chronic Inflammation in CF Airways - A Persistent Issue for A20

McCallum¹,

A²,

Ennis³

et al. 2016

J Genet Syndr Gene Ther

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Cystic Fibrosis (CF) is characterised by prolonged and exaggerated airways inflammation. Despite recent developments to overcome the underlying functional defect in CFTR (cystic fibrosis transmembrane conductance regulator); there is still an unmet need to reduce the inflammatory response. The NF-κB regulator A20 is a key target to normalise the inflammatory response and is reduced in CF. Here, we describe the plethora of functions of A20 as they apply to innate immune function within the airways. Pharmacological compounds can enhance A20 mRNA and protein expression, but we observed a blunted effect in CF primary epithelial cells. In CF cells pre-treatment with gibberellic acid (GA3) shows anti-inflammatory effects only in some patients. We show that cells with higher basal p38 expression respond with an increase in pro-inflammatory cytokines. Furthermore, all CF PNECs show increased p38 mRNA when stimulated in the presence of GA3. Our results suggest that those patients may benefit from therapeutics targeting p38.

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Proinflammatory mediators alter expression of nuclear factor kappa B–regulating deubiquitinases in sinonasal epithelial cells

Wang

Turner

2015

Int Forum Allergy Rhinol

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Introduction NF-Kappa B (NF-κB) is a vital transcription factor that is activated by numerous inflammatory stimuli. Its activity is tightly regulated by a family of deubiquitinating enzymes (A20, Cezanne, CYLD) that function in a negative-feedback loop, a process that prevents chronic and systemic inflammation. This study seeks to characterize the expression and functional role of NF-κB-regulating deubiquitinases in the sinonasal epithelium. Methods Expression of A20, Cezanne, and CYLD was assessed in normal sinonasal tissue using immunohistochemistry. Cultured sinonasal epithelial cells were stimulated with pro-inflammatory cytokines (TNF-α, IL-4, IL-13) or LPS and changes in NF-κB activation and deubiquitinase expression were assessed using western blots and quantitative real-time PCR, respectively. Results NF-kB was activated in response to LPS and TNF-α, but not IL-4 or IL-13. A20, Cezanne, and CYLD were all expressed in sinonasal tissue, primarily along the apical surface of the epithelium. Pro-inflammatory mediators primarily affected expression of A20, with upregulation by LPS and TNF-α and downregulation by IL-4 and IL-13. Conclusions The NF-κB-regulating deubiquitinases A20, Cezanne, and CYLD are expressed in sinonasal tissue and are differentially induced by pro-inflammatory cytokines and microbial antigens. These results suggest an important role for NF-κB-regulating deubiquitinases in mucosal immunity and homeostasis.

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Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis

Abstract: A20 expression is reduced in CF and is proportional to FEV1. Pending confirmation in a larger study, A20 may prove a novel predictor of CF inflammation/disease severity.

Cited by 17 publications

References 18 publications

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Chronic Inflammation in CF Airways - A Persistent Issue for A20

Proinflammatory mediators alter expression of nuclear factor kappa B–regulating deubiquitinases in sinonasal epithelial cells

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