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Research ArticleMetabolism, Transport, and Pharmacogenomics

Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia

Christopher J. Gibson, Muhammad M. Hossain, Jason R. Richardson and Lauren M. Aleksunes
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 650-660; DOI: https://doi.org/10.1124/jpet.112.196543
Christopher J. Gibson
Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (C.J.G., L.M.A.); Environmental and Occupational Health Sciences Institute, a Joint Institute of Robert Wood Johnson Medical School and Rutgers, the State University of New Jersey, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey (M.M.H., J.R.R.)
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Muhammad M. Hossain
Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (C.J.G., L.M.A.); Environmental and Occupational Health Sciences Institute, a Joint Institute of Robert Wood Johnson Medical School and Rutgers, the State University of New Jersey, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey (M.M.H., J.R.R.)
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Jason R. Richardson
Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (C.J.G., L.M.A.); Environmental and Occupational Health Sciences Institute, a Joint Institute of Robert Wood Johnson Medical School and Rutgers, the State University of New Jersey, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey (M.M.H., J.R.R.)
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Lauren M. Aleksunes
Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (C.J.G., L.M.A.); Environmental and Occupational Health Sciences Institute, a Joint Institute of Robert Wood Johnson Medical School and Rutgers, the State University of New Jersey, Piscataway, New Jersey (J.R.R., L.M.A.); and Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey (M.M.H., J.R.R.)
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Abstract

ATP-binding cassette (ABC) efflux transporters, including multidrug resistance protein 1 (Mdr1), breast cancer resistance protein (Bcrp), and multidrug resistance-associated proteins (Mrps) extrude chemicals from the brain. Although ABC transporters are critical for blood-brain barrier integrity, less attention has been placed on the regulation of these proteins in brain parenchymal cells such as microglia. Prior studies demonstrate that inflammation after lipopolysaccharide (LPS) treatment alters transporter expression in the livers of mice. Here, we sought to determine the effects of inflammation on the expression and function of transporters in microglia. To test this, the expression and function of ABC efflux transport proteins were quantified in mouse BV-2 microglial cells in response to activation with LPS. Intracellular retention of fluorescent rhodamine 123, Hoechst 33342, and calcein acetoxymethyl ester was increased in LPS-treated microglia, suggesting that the functions of Mdr1, Bcrp, and Mrps were decreased, respectively. LPS reduced Mdr1, Bcrp, and Mrp4 mRNA and protein expression between 40 and 70%. Conversely, LPS increased expression of Mrp1 and Mrp5 mRNA and protein. Immunofluorescent staining confirmed reduced Bcrp and Mrp4 and elevated Mrp1 and Mrp5 protein in activated microglia. Pharmacological inhibition of nuclear factor κB (NF-κB) transcriptional signaling attenuated down-regulation of Mdr1a mRNA and potentiated up-regulation of Mrp5 mRNA in LPS-treated cells. Together, these data suggest that LPS stimulates microglia and impairs efflux of prototypical ABC transporter substrates by altering mRNA and protein expression, in part through NF-κB signaling. Decreased transporter efflux function in microglia may lead to the retention of toxic chemicals and aberrant cell-cell communication during neuroinflammation.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK080774]; the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES020522, ES015991, ES007148, ES005022]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS072097].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.196543.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ABC
    ATP binding cassette
    Mdr
    multidrug resistance protein
    Mrp
    multidrug resistance-associated protein
    Bcrp
    breast cancer resistance protein
    LPS
    lipopolysaccharide
    NF-κB
    nuclear factor κB
    IκB
    inhibitor of κB
    Nrf2
    nuclear factor-e2 related factor 2
    TNFα
    tumor necrosis factor-α
    IL
    interleukin
    Nqo1
    NAD(P)H quinone oxidoreductase 1
    NSAID
    nonsteroidal anti-inflammatory drug
    AM
    acetoxymethyl ester
    PBS
    phosphate-buffered saline
    Rpl13a
    ribosomal protein l13a
    Gapdh
    glyceraldehyde-3-phosphate dehydrogenase
    qPCR
    quantitative polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    BAY 11-7082
    3-(4-methylphenylsulfonyl)-2-propenenitrile
    PSC833
    6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporin A
    MK-571
    5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoic acid sodium salt hydrate
    Ko143
    (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester hydrate.

  • Received May 20, 2012.
  • Accepted August 30, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Transporter Function in Activated Microglia

Christopher J. Gibson, Muhammad M. Hossain, Jason R. Richardson and Lauren M. Aleksunes
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 650-660; DOI: https://doi.org/10.1124/jpet.112.196543

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Transporter Function in Activated Microglia

Christopher J. Gibson, Muhammad M. Hossain, Jason R. Richardson and Lauren M. Aleksunes
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 650-660; DOI: https://doi.org/10.1124/jpet.112.196543
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