Journal
INTERNATIONAL IMMUNOLOGY
Volume 18, Issue 3, Pages 485-493Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxh389
Keywords
T cells; cytokines; Multidrug Resistance Protein-1 (MRP1); peroxisome proliferator-activated receptor-c (PPARc)
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Multidrug resistance protein-1 (MRP1) belongs to subfamily C of the ATP-binding cassette transporters, and exports leukotriene C-4 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.
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