RT Journal Article
SR Electronic
T1 Regulation of Multidrug Resistance Protein 1 (Mrp1) by Tumor Necrosis Factor Alpha (TNF-α) in Cultured Glial Cells: Involvement of Nuclear Factor-κB (NF-κB) and c-Jun N-terminal Kinase (JNK) Signaling Pathways
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.059410
DO 10.1124/mol.109.059410
A1 Patrick T. Ronaldson
A1 Tamima Ashraf
A1 Reina Bendayan
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/01/05/mol.109.059410.abstract
AB 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., TNF-α, 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 if 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 BCECF, an Mrp substrate, was reduced in TNF-α treated astrocytes, suggesting increased Mrp-mediated transport. Pharmacological inhibition of 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 pre-treated with SP600125, an established 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 regulation of Mrp1 during an HIV-1 associated inflammatory response.The American Society for Pharmacology and Experimental Therapeutics