Alterations in P-Glycoprotein Expression and Function Between Macrophage Subsets

Authors

Theodore J. Cory, Department of Clinical Pharmacy, University of Tennessee Health Science Center College of Pharmacy, Memphis, Tennessee, 38163, USA. tcory1@uthsc.edu.
Hui He, Department of Clinical Pharmacy, University of Tennessee Health Science Center College of Pharmacy, Memphis, Tennessee, 38163, USA.
Lee C. Winchester, Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Santosh Kumar, Department of Pharmaceutical Sciences, University of Tennessee Health Science Center College of Pharmacy, Memphis, Tennessee, USA.
Courtney V. Fletcher, Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Abstract

PURPOSE: Macrophages are an important cellular reservoir in HIV, and exist in two phenotypically dissimilar subsets, the pro-inflammatory M1 phenotype, and the anti-inflammatory M2 phenotype. The role of these two subsets is uncertain. We hypothesized that differences in drug efflux transporters exist between the subsets, which would result in altered intracellular drug concentrations between these cells. METHODS: U937 monocytic cells were polarized to the M1 or M2 phenotype via treatment with interferon-gamma and LPS, or interleukins 4, 13, and LPS, respectively. PGP function was assessed with Hoechst 33342, and expression via western blotting. Intracellular lopinavir was assessed via LC-MS/MS. Data was confirmed with primary monocyte derived macrophages. RESULTS: We observed significant differences in intracellular concentrations of lopinavir, a PGP substrate, with higher concentrations in M1 cells. PGP function and expression was higher in the M2 macrophages. These results were confirmed with primary monocyte derived macrophages. CONCLUSIONS: This data shows that there are previously unreported differences in P-glycoprotein expression between macrophage subsets, and suggests that there may be differences for other transporters. These differences can play a role in intracellular drug concentrations in these cells, and may allow for low-level HIV replication.

Publication Title

Pharmaceutical research

Recommended Citation

Cory, T. J., He, H., Winchester, L. C., Kumar, S., & Fletcher, C. V. (2016). Alterations in P-Glycoprotein Expression and Function Between Macrophage Subsets. Pharmaceutical research, 33 (11), 2713-21. https://doi.org/10.1007/s11095-016-1998-x