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P-glycoprotein functions as an immunomodulator in healthy human primary nasal epithelial cells.


Int Forum Allergy Rhinol. 2013 Mar 20;


Authors: Bleier BS, Nocera AL, Iqbal H, Hoang JD, Feldman RE, Han X


Abstract

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.

PMID: 23520057 [PubMed - as supplied by publisher]