IL-17A-associated IKK-\u03b1 signaling induced TSLP production in epithelial cells of COPD patients

Giulia Anzalone,Fabio Bucchieri,Roberto Marchese,Mirella Profita,Anna Bonanno,Monica Moscato,Loredana Riccobono,Giusy Daniela Albano,Rosalia Gagliardo,Angela Marina Montalbano

doi:10.1038/s12276-018-0158-2

Abstract

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed in the epithelium, involved in the pathogenesis of chronic disease. IL-17A regulates airway inflammation, oxidative stress, and reduction of steroid sensitivity in chronic obstructive pulmonary disease (COPD). TSLP and IL-17A were measured in induced sputum supernatants (ISs) from healthy controls (HC), healthy smokers (HS), and COPD patients by enzyme-linked immunosorbent assay. Human bronchial epithelial cell line (16HBE) and normal bronchial epithelial cells were stimulated with rhIL-17A or ISs from COPD patients to evaluate TSLP protein and mRNA expression. The effects of the depletion of IL-17A in ISs, an anticholinergic drug, and the silencing of inhibitor kappa kinase alpha (IKKα) on TSLP production were evaluated in 16HBE cells. Coimmunoprecipitation of acetyl-histone H3(Lys14)/IKKα was evaluated in 16HBE cells treated with rhIL-17A and in the presence of the drug. TSLP and IL-17A levels were higher in ISs from COPD patients and HS compared with HC. TSLP protein and mRNA increased in 16HBE cells and in normal bronchial epithelial cells stimulated with ISs from COPD patients compared with ISs from HC and untreated cells. IKKα silencing reduced TSLP production in 16HBE cells stimulated with rhIL-17A and ISs from COPD patients. RhIL-17A increased the IKKα/acetyl-histone H3 immunoprecipitation in 16HBE cells. The anticholinergic drug affects TSLP protein and mRNA levels in bronchial epithelial cells treated with rhIL-17A or with ISs from COPD patients, and IKKα mediated acetyl-histone H3(Lys14). IL-17A/IKKα signaling induced the mechanism of chromatin remodeling associated with acetyl-histone H3(Lys14) and TSLP production in bronchial epithelial cells. Anticholinergic drugs might target TSLP derived from epithelial cells during the treatment of COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and by a progressive airflow limitation usually caused by tobacco smoke[1]
Levels of Thymic stromal lymphopoietin (TSLP) and IL-17A in induced sputum supernatants (ISs) TSLP concentrations were significantly higher in ISs from healthy smokers (HS) and COPD patients compared with ISs from healthy controls (HC) (p < 0.001 and p < 0.0001, respectively) and in ISs from COPD patients compared with ISs from HS (p < 0.003) (Fig. 1a)
We described the molecular mechanisms of chromatin remodeling, associated with IL-17A-mediated

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and by a progressive airflow limitation usually caused by tobacco smoke[1]. The inflammation in COPD subjects is often resistant to corticosteroid treatments, and currently, there are no safe and effective alternative anti-. The regular use of β2 adrenergic agonists and anticholinergic bronchodilators is recommended to maximize bronchodilation according to the current guidelines for the treatment of COPD3,4. Several studies provide perspectives on the use of muscarinic receptor antagonists for asthma and COPD, as these drugs acutely affect cholinergic airways obstruction and may have important beneficial effects on β2-agonist responsiveness, airway inflammation, and remodeling[5]. Many studies have proposed novel pharmacological strategies, including the use of anticholinergic drugs (Tiotropium) as anti-inflammatory and anti-remodeling drugs in COPD5–7.

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