Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes.
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.
Tsujimura
Shizuyo
S
First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Yahata-nishi, Kitakyushu, Japan.
Saito
Kazuyoshi
K
Nakayamada
Shingo
S
Nakano
Kazuhisa
K
Tsukada
Junichi
J
Kohno
Kimitoshi
K
Tanaka
Yoshiya
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D001483:Base Sequence; D016572:Cyclosporine / Q000494:pharmacology; D016373:DNA, Antisense / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D019450:Genes, MDR; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D009687:Nuclear Proteins; D021381:Protein Transport; D015533:Transcriptional Activation; D015854:Up-Regulation; D051840:Y-Box-Binding Protein 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D003907:Dexamethasone; D016572:Cyclosporine