Regulation of P-glycoprotein by human immunodeficiency virus-1 in primary cultures of human fetal astrocytes

Tamima Ashraf, Patrick T Ronaldson, Yuri Persidsky, Reina Bendayan

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

P-glycoprotein (P-gp), a drug efflux pump, is known to alter the bioavailability of antiretroviral drugs at several sites, including the brain. We have previously shown that human immunodeficiency virus-1 (HIV-1) glycoprotein 120 (gp120) induces proinflammatory cytokine secretion and decreases P-gp functional expression in rat astrocytes, a cellular reservoir of HIV-1. However, whether P-gp is regulated in a similar way in human astrocytes is unknown. This study investigates the regulation of P-gp in an in vitro model of gp120-triggered human fetal astrocytes (HFAs). In this system, elevated levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α were detected in culture supernatants. Pretreatment with CCR5 neutralizing antibody attenuated cytokine secretion, suggesting that gp120-CCR5 interaction mediated cytokine production. Treatment with gp120 (R5-tropic) resulted in reduced P-gp expression (64%) and function as determined by increased (1.6-fold) cellular accumulation of [ 3H]digoxin, a P-gp substrate. Exposure to R5 or R5/X4-tropic viral isolates led to a downregulation in P-gp expression (75% or 90%, respectively), and treatment with IL-6 also showed lower P-gp expression (50%). Moreover, IL-6 neutralizing antibody blocked gp120-mediated P-gp downregulation, suggesting that IL-6 is a key modulator of P-gp. Gp120- or IL-6-mediated downregulation of P-gp was attenuated by SN50 (a nuclear factor-κB [NF-κB] inhibitor), suggesting involvement of NF-κB signaling in P-gp regulation. Our results suggest that, similarly to the case with rodent astrocytes, pathophysiological stressors associated with brain HIV-1 infection have a downregulatory effect on P-gp functional expression in human astrocytes, which may ultimately result in altered antiretroviral drug accumulation within brain parenchyma.

Original languageEnglish (US)
Pages (from-to)1773-1782
Number of pages10
JournalJournal of Neuroscience Research
Volume89
Issue number11
DOIs
Publication statusPublished - Nov 2011

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Keywords

  • Astrocyte
  • Gp120
  • HIV-1
  • Inflammation
  • Interleukin-6
  • NF-κB
  • P-glycoprotein

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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