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


  • Funding sources for the study: Funded in part by a American Rhinologic Society New Investigator Grant.

  • 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.

Correspondence to: Benjamin S. Bleier, MD, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA, 02114; e-mail:



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.


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.


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).


P-gp is functionally active in PNECCs. P-gp participates in modulation of epithelial secretion of LPS stimulated IL-6, GM-CSF, and TSLP.

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