Human T cell cytokine responses are dependent on multidrug resistance protein-1.
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.
Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892-4555, USA.
Jinsong
J
Zhang
Marc A
MA
Alston
Hui
H
Huang
Ronald L
RL
Rabin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D011422:Propionates; D011804:Quinolines; C059141:verlukast; D007371:Interferon-gamma