Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. Nov-Dec 2017;43(9-10):417-425.
doi: 10.1080/01902148.2017.1393707. Epub 2017 Dec 11.

Quercetin Restores Corticosteroid Sensitivity in Cells From Patients With Chronic Obstructive Pulmonary Disease

Affiliations
Free PMC article

Quercetin Restores Corticosteroid Sensitivity in Cells From Patients With Chronic Obstructive Pulmonary Disease

Akihisa Mitani et al. Exp Lung Res. .
Free PMC article

Abstract

Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected from patients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence or absence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC from patients with COPD showed corticosteroid insensitivity compared with those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD.

Keywords: adenosine monophosphate-activated protein kinase; chronic obstructive pulmonary disease; corticosteroid sensitivity; quercetin.

Figures

Figure 1.
Figure 1.
Quercetin (QT) improved steroid sensitivity in U937 cells. U937 cells were treated with QT for 4 h and incubated with CSE for additional 2h. Cells were washed with PBS and seeded in the presence of the different concentrations of dexamethasone for 1 h before overnight stimulation with 10 ng/mL TNFα. CXCL8 expression in supernatant was measured by ELISA. (A) The concentration of CXCL8 released after TNFα stimulation. (B and C) The inhibition rate of CXCL8 by dexamethasone was calculated, and corticosteroid sensitivity was determined. *; p < 0.05, ***; p < 0.001.
Figure 2.
Figure 2.
The time course of AMPK activity and Nrf2 expression after quercetin (QT) treatment in U937 cells. (A and B) U937 cells were treated with QT at different time points (2 to 24 hr), and phosphorylated AMPK (p-AMPK) levels (A) and Nrf2 levels (B) were determined by Western blotting. *; p < 0.05, **; p < 0.01, ***; p < 0.001. (compared to NT).
Figure 3.
Figure 3.
Analysis of PBMC samples from healthy volunteers (HV) and patients with COPD (COPD). (A and B) PBMCs were incubated with the different concentrations of dexamethasone, and stimulated with 1ng/ml TNFα. Corticosteroid sensitivity of PBMC was measured using CXCL8 inhibition rate by dexamethasone as IC40 (A) and Emax (B), and plotted individually. (C) AMPK activity was evaluated as phosphorylated AMPK (p-AMPK). (D) Nrf2 expression was also measured by Western blotting. (E) The correlation with AMPK activity to Nrf2 expression level was analyzed by Spearman correlation test. **; p < 0.01.
Figure 4.
Figure 4.
Treatment with quercetin(QT) to the PBMC. (A and B) PBMCs were incubated with 10 μM of quercetin (QT) for 4h, and AMPK activity and Nrf2 level were calculated. (C) CXCL8 release caused by overnight TNFα stimulation with or without QT pre-treatment. (D and E) PBMC were treated with QT for 6h before measuring corticosteroid sensitivity. *; p < 0.05, ***; p < 0.001 (compared to NT if not indicated).

Similar articles

See all similar articles

Cited by 4 articles

References

    1. Lopez AD, Murray CC. The global burden of disease, 1990–2020. 1998;4(11):1241–1243. doi:10.1038/3218. - DOI - PubMed
    1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. 2006;3(11):e442. doi:10.1371/journal.pmed.0030442. - DOI - PMC - PubMed
    1. Barnes PJ, Kleinert S. COPD–a neglected disease. 2004;364(9434):564–565. doi:10.1016/S0140-6736(04)16866-9. - DOI - PubMed
    1. Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. 2009;135(1):173–180. doi:10.1378/chest.08-1419. - DOI - PubMed
    1. Ito K, Mercado N. STOP accelerating lung aging for the treatment of COPD. 2014;59:21–27. doi:10.1016/j.exger.2014.03.014. - DOI - PubMed

Publication types

Feedback