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P‐glycoprotein promotes epithelial T helper 2–associated cytokine secretion in chronic sinusitis with nasal polyps
Author(s) -
Bleier Benjamin S.,
Nocera Angela L.,
Iqbal Hufsa,
Hoang John D.,
Alvarez Ulises,
Feldman Rachel E.,
Han Xue
Publication year - 2014
Publication title -
international forum of allergy and rhinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.503
H-Index - 46
eISSN - 2042-6984
pISSN - 2042-6976
DOI - 10.1002/alr.21316
Subject(s) - nasal polyps , medicine , cytokine , secretion , tumor necrosis factor alpha , endocrinology , interleukin 8 , immunology
Background 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. Methods 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. Results 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). Conclusion P‐gp overactivity promotes Th2‐associated epithelial cytokine secretion in nasal polyps, suggesting a novel mechanism for maintaining chronic inflammation in CRSwNP.