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P‐glycoprotein functions as an immunomodulator in healthy human primary nasal epithelial cells
Author(s) -
Bleier Benjamin S.,
Nocera Angela L.,
Iqbal Hufsa,
Hoang John D.,
Feldman Rachel E.,
Han Xue
Publication year - 2013
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.21166
Subject(s) - medicine , cytokine , thymic stromal lymphopoietin , p glycoprotein , immunology , lipopolysaccharide , secretion , pharmacology , biology , microbiology and biotechnology , multiple drug resistance , antibiotics
Background P‐glycoprotein (P‐gp) is an adenosine triphosphate (ATP)‐dependent efflux pump that confers chemotherapeutic resistance in cancer cells. Recent studies suggest that P‐gp may also function as an immunomodulator through regulation of cytokine transport. Sinonasal epithelial cells have been recognized as drivers of local innate and adaptive immunity and are known to overexpress P‐gp in the setting of inflammation. The objective of this study is to therefore determine whether P‐gp participates in the regulation of cytokine secretion in sinonasal epithelial cells. Methods Primary nasal epithelial cell cultures (PNECCs) were cultivated from 5 healthy patients. Membranous P‐gp was quantified through quantitative fluorescent immunohistochemistry (Q‐FIHC) and confirmed by enzyme‐linked immunosorbent assay (ELISA). Sensitivity to inhibition was determined using a rhodamine 123 accumulation assay. Baseline and lipopolysaccharide (LPS)‐stimulated cytokine secretion of interleukin 6 (IL‐6), IL‐8, granulocyte macrophage colony stimulating factor (GM‐CSF), and thymic stromal lymphopoietin (TSLP) were quantified by ELISA and compared to LPS stimulated secretion in the setting of P‐gp–specific inhibition. Differences in P‐gp expression and cytokine secretion were compared using 2‐tailed Student t tests with post hoc testing using the Bonferroni procedure. Results Membranous P‐gp is detectable in PNECCs and upregulated following LPS exposure. P‐gp is sensitive to inhibition by both PSC 833 and verapamil in a dose‐dependent fashion. LPS stimulated secretion of normalized IL‐6 (mean, 95% confidence interval [CI]) (79.67, 42.26–117.07), GM‐CSF (39.92, 7.90–71.94), and TSLP (6.65, 5.35–7.96) was significantly reduced following P‐gp inhibition (37.60, 11.54–63.65, p = 0.023; 7.64, 2.25–13.03, p = 0.044; and 5.13, 4.44–5.82, p = 0.038; respectively). Conclusion P‐gp is functionally active in PNECCs. P‐gp participates in modulation of epithelial secretion of LPS stimulated IL‐6, GM‐CSF, and TSLP.