Funding sources for the study: American Rhinologic Society New Investigator Grant.
P-glycoprotein promotes epithelial T helper 2–associated cytokine secretion in chronic sinusitis with nasal polyps
Article first published online: 5 MAR 2014
© 2014 ARS-AAOA, LLC
International Forum of Allergy & Rhinology
Volume 4, Issue 6, pages 488–494, June 2014
How to Cite
How to Cite this Article: P-glycoprotein promotes epithelial T helper 2–associated cytokine secretion in chronic sinusitis with nasal polyps. Int Forum Allergy Rhinol. 2014;4:488–494., , , et al.
Potential conflict of interest: B.S.B. is an inventor on a patent application assigned to the Massachusetts Eye and Ear Infirmary regarding modulation of efflux pumps for the treatment of sinusitis.
- Issue published online: 3 JUN 2014
- Article first published online: 5 MAR 2014
- Manuscript Accepted: 28 JAN 2014
- Manuscript Revised: 17 JAN 2014
- Manuscript Received: 6 AUG 2013
- American Rhinologic Society New Investigator Grant
- chronic sinusitis with nasal polyps;
- nasal epithelium;
- Th2 inflammation
Sinonasal epithelial cells are recognized as drivers of inflammation in chronic sinusitis with nasal polyps (CRSwNP) through secretion of T helper 2 (Th2)-promoting cytokines. P-glycoprotein (P-gp) is overexpressed in nasal polyps and modulates epithelial cytokine secretion in healthy mucosa. The objective of this study is to determine whether P-gp overactivity promotes Th2-associated cytokine secretion in CRSwNP.
Polyp explants (n = 4) and primary epithelial cell cultures (n = 5) were cultivated from patients with CRSwNP. Explant P-gp activity was determined using a calcein assay. In culture, P-gp was quantified by enzyme-linked immunosorbent assay (ELISA) and sensitivity to PSC-833 inhibition was determined using a calcein assay. Lipopolysaccharide (LPS)-stimulated cytokine secretion of interleukin 6 (IL-6), IL-8, IL-25, and granulocyte macrophage colony stimulating factor (GM-CSF) were quantified by ELISA and compared to secretion following P-gp inhibition. Differences in P-gp expression and cytokine secretion were compared using a Mann-Whitney U test. Secretion was correlated with P-gp expression using a Pearson correlation coefficient.
Calcein retention is increased in P-gp inhibited vs uninhibited polyp explants (mean ± standard deviation [SD]; 5.17 ± 1.76 vs 2.55 ± 0.62; p < 0.05) but not in controls, indicating increased nasal polyp P-gp activity. P-gp is sensitive to dose-dependent P-gp inhibition with PSC-833 in vitro. LPS-stimulated secretion of normalized GM-CSF (45.21 ± 41.39) and IL-6 (63.16 ± 36.37) were significantly reduced following P-gp inhibition (8.47 ± 3.28; p < 0.01, and 39.94 ± 31.07; p < 0.05; respectively) and secretion was highly correlated with P-gp expression(r = 0.824, p < 0.05, and r = 0.833, p < 0.05; respectively).
P-gp overactivity promotes Th2-associated epithelial cytokine secretion in nasal polyps, suggesting a novel mechanism for maintaining chronic inflammation in CRSwNP.