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Molecular Pharmacology

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Research ArticleArticle

Regulation of Multidrug Resistance Protein 1 by Tumor Necrosis Factor α in Cultured Glial Cells: Involvement of Nuclear Factor-κB and c-Jun N-Terminal Kinase Signaling Pathways

Patrick T. Ronaldson, Tamima Ashraf and Reina Bendayan
Molecular Pharmacology April 2010, 77 (4) 644-659; DOI: https://doi.org/10.1124/mol.109.059410
Patrick T. Ronaldson
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Tamima Ashraf
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Reina Bendayan
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Abstract

Pharmacotherapy of brain HIV-1 infection may be limited by ABC transporters [i.e., P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1)] that export antiretroviral drugs from HIV-1 brain cellular targets (i.e., astrocytes, microglia). Using an in vitro astrocyte model of an HIV-1 associated inflammatory response, our laboratory has shown that cytokines [i.e., tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6], which are secreted in response to HIV-1 envelope glycoprotein gp120 exposure, can decrease P-gp functional expression; however, it is unknown whether these same cytokines can alter expression and/or activity of other ABC transporters (i.e., Mrp1). In primary cultures of rat astrocytes, Mrp1 expression was increased by TNF-α (2.7-fold) but was not altered by IL-1β or IL-6. Cellular retention of 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, an Mrp substrate, was reduced in TNF-α-treated astrocytes, suggesting increased Mrp-mediated transport. Pharmacologic inhibition of nuclear factor-κB (NF-κB) signaling with SN50 prevented both TNF-α release and Mrp1 expression changes in astrocytes triggered with gp120; however, SN50 did not attenuate Mrp1 expression in cells triggered with TNF-α. In contrast, Mrp1 functional expression was not altered in the presence of gp120 or TNF-α when astrocyte cultures were pretreated with 1,9-pyrazoloanthrone (SP600125), an established c-Jun N-terminal kinase (JNK) inhibitor. SP600125 did not affect TNF-α release from cultured astrocytes triggered with gp120. Mrp1 mRNA expression was increased after treatment with gp120 (1.6-fold) or TNF-α (1.7-fold), suggesting altered Mrp1 gene transcription. These data suggest that gp120 and TNF-α can up-regulate Mrp1 expression in cultured astrocytes. Furthermore, our results imply that both NF-κB and JNK signaling are involved in Mrp1 regulation during an HIV-1 associated inflammatory response.

Footnotes

    fn-3
  • This work was supported by the Canadian Institutes of Health Research [Grant MOP-56976] and the Ontario HIV Treatment Network, Ontario Ministry of Health.

  • fn-4
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.059410.

  • fn-5
  • ABBREVIATIONS:

    CNS
    central nervous system
    TNF-α
    tumor necrosis factor
    IL
    interleukin
    ABC
    ATP-binding cassette
    P-gp
    P-glycoprotein
    MRP/Mrp
    multidrug resistance protein
    LPS
    lipopolysaccharide
    NF-κB
    nuclear factor-κB
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun N-terminal kinase
    PSC833
    valspodar
    BCECF
    2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein
    BAY 11-7082
    (E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile
    SP600125
    anthra[1–9cd]pyrazol-6(2H)-one
    SAPK
    stress-activated protein kinase
    ELISA
    enzyme-linked immunosorbent assay
    PVDF
    polyvinylidene difluoride
    PCR
    polymerase chain reaction
    AM
    acetoxymethyl ester.

    • Received July 14, 2009.
    • Accepted January 5, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Regulation of Multidrug Resistance Protein 1 by Tumor Necrosis Factor α in Cultured Glial Cells: Involvement of Nuclear Factor-κB and c-Jun N-Terminal Kinase Signaling Pathways

Patrick T. Ronaldson, Tamima Ashraf and Reina Bendayan
Molecular Pharmacology April 1, 2010, 77 (4) 644-659; DOI: https://doi.org/10.1124/mol.109.059410

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Research ArticleArticle

Regulation of Multidrug Resistance Protein 1 by Tumor Necrosis Factor α in Cultured Glial Cells: Involvement of Nuclear Factor-κB and c-Jun N-Terminal Kinase Signaling Pathways

Patrick T. Ronaldson, Tamima Ashraf and Reina Bendayan
Molecular Pharmacology April 1, 2010, 77 (4) 644-659; DOI: https://doi.org/10.1124/mol.109.059410
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