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Transcriptional regulation of multidrug resistance‐1 gene by interleukin‐2 in lymphocytes
Author(s) -
Tsujimura Shizuyo,
Saito Kazuyoshi,
Nakayamada Shingo,
Nakano Kazuhisa,
Tsukada Junichi,
Kohno Kimitoshi,
Tanaka Yoshiya
Publication year - 2004
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2004.00803.x
Subject(s) - biology , p glycoprotein , multiple drug resistance , intracellular , cytotoxic t cell , microbiology and biotechnology , immunology , cancer research , in vitro , drug resistance , biochemistry , genetics
P‐glycoprotein, encoded by the multidrug resistance (MDR)‐1 gene, expels various drugs from cells resulting in drug resistance. However, its functional relevance to lymphocytes and the regulatory mechanism remain unclear. Although MDR‐1 is known to be induced by various cytotoxic stimuli, it is poorly understood whether the activation stimuli such as cytokines induce MDR‐1 transcription. We investigated the transcriptional regulation of MDR‐1 in lymphocytes by activation stimuli, particularly by interleukin (IL)‐2. IL‐2 induced translocation of YB‐1, a specific transcriptional factor for MDR‐1, from the cytoplasm into nucleus of lymphocytes in a dose‐dependent manner and resulted in the sequential events; transcription of MDR‐1, expression of P‐glycoprotein on the cell surface, and excretion of the intracellular dexamethasone added in vitro . Transfection of YB‐1 anti‐sense oligonucleotides inhibited P‐glycoprotein expression induced by IL‐2. Cyclosporin A, a competitive inhibitor of P‐glycoprotein, recovered intracellular dexamethasone levels in lymphocytes. We provide the first evidence that IL‐2, a representative lymphocyte‐activation stimulus, induces YB‐1 activation followed by P‐glycoprotein expression in lymphocytes. Our findings imply that lymphocytes activation by IL‐2 in vivo , in the context of the pathogenesis of autoimmune diseases, results in P‐glycoprotein‐mediated multidrug resistance, and that P‐glycoprotein could be an important target for the treatment of refractory autoimmune diseases.