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P‐glycoprotein regulates Staphylococcus aureus enterotoxin B–stimulated interleukin‐5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants
Author(s) -
Bleier Benjamin S.,
Singleton Amy,
Nocera Angela L.,
Kocharyan Armine,
Petkova Victoria,
Han Xue
Publication year - 2016
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.21566
Subject(s) - thymic stromal lymphopoietin , medicine , enterotoxin , secretion , staphylococcus aureus , microbiology and biotechnology , immunology , explant culture , stromal cell , inflammation , pathology , bacteria , in vitro , biology , gene , escherichia coli , biochemistry , genetics
Background T‐helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P‐glycoprotein (permeability glycoprotein, P‐gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL‐5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P‐gp–mediated secretory pathways. Methods Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P‐gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P‐gp expression was measured using real‐time polymerase chain reaction (RT‐PCR) and enzyme‐linked immunosorbent assay (ELISA). IL‐5, IL‐8, and TSLP secretion were quantified using ELISA. Results P‐gp protein was overexpressed in CRSwNP (28.32 ± 25.94 ng/mL per mg explant) as compared to CRS (10.74 ± 8.61; p = 0.01, 2‐tailed Mann‐Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL‐5 and TSLP but not IL‐8 secretion relative to control in the CRSwNP explants only. Subsequent P‐gp inhibition significantly reduced IL‐5 and TSLP secretion ( p = 0.04 for both, 2‐tailed Student t test) to control levels. The concentration of IL‐5 and TSLP secretion were strongly and significantly correlated to the concentration of P‐gp within the same explant (IL‐5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2‐tailed Spearman's rank‐order correlation). Conclusion P‐gp protein is expressed at higher concentrations in CRSwNP as compared to CRS. This overexpression directly contributes to the relative hypersecretion of IL‐5 and TSLP. These findings suggest a novel mechanism for Th2 skewing in CRSwNP.