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, Reina Bendayan

Research output: Contribution to journalArticle

56 Scopus citations

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-́B (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.

Original languageEnglish (US)
Pages (from-to)644-659
Number of pages16
JournalMolecular pharmacology
Volume77
Issue number4
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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