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International Immunology Advance Access originally published online on February 15, 2006
International Immunology 2006 18(3):485-493; doi:10.1093/intimm/dxh389
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Published by Oxford University Press 2006

Human T cell cytokine responses are dependent on multidrug resistance protein-1

Jinsong Zhang, Marc A. Alston, Hui Huang and Ronald L. Rabin

Center for Biologics Evaluation and Research, US Food and Drug Administration, 29 Lincoln Drive (MSC-4555), Building 29, Room B1, Bethesda, MD 20892-4555, USA

Correspondence to: R. L. Rabin; E-mail: rrabin{at}helix.nih.gov

Multidrug resistance protein-1 (MRP1) belongs to subfamily C of the ATP-binding cassette transporters, and exports leukotriene C4 and organic anions including the fluorescent calcium indicator indo-1. The observation that leukocytes from patients with an autoimmune disease exported indo-1 at a higher rate than controls prompted the hypothesis that MRP1 contributes to the function of activated cells. To test this, we defined the expression of MRP1 on resting and activated human T cells, and determined whether T cell activation is dependent upon MRP1 function. MRP1 is expressed on resting memory but not on naive CD4 and CD8 T cells. After activation through the TCR, cord blood CD4 T cells express high levels of MRP1. Blockade of MRP1 with the specific inhibitor MK-571 abrogated superantigen-induced expression of IFN-{gamma}, tumor necrosis factor-{alpha}, IL-10, IL-2, IL-4 and CD69 by T cells without affecting their viability, and was reversible upon removal of MK-571 from the culture media. Electrophoretic mobility shift assays demonstrate that MRP1 blockade with MK-571 induces activation of the transcriptional repressor peroxisome proliferator-activated receptor-{gamma} in CD4 T cells, thus providing insight into the potential mechanism by which their responses are abrogated.

Keywords: T cells, cytokines, Multidrug Resistance Protein-1 (MRP1), peroxisome proliferator-activated receptor-c (PPARc)

Transmitting editor: W. Strober

Disclaimer

The views in this article are those of the authors and do not reflect the official policy or position of the Food and Drug Administration or the US Government.


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