Fragmented hyaluronan induces transcriptional up-regulation of the multidrug resistance-1 gene in CD4+ T cells.
P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in multidrug resistance. We found previously that interleukin-2, a lymphocyte-activation cytokine, induces P-glycoprotein expression on lymphocytes. Lymphocyte activation involves adhesion with the extracellular matrix, such as hyaluronan, through adhesion molecules on lymphocytes. We investigated the transcriptional regulation of MDR-1 in lymphocytes by fragmented hyaluronan. Fragmented hyaluronan (especially the 6.9-kDa form), not native high molecular hyaluronan, induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into the nucleus and resulted in the transcription of MDR-1 and the expression of P-glycoprotein on lymphocytes in a dose-dependent manner. Transfection of YB-1 antisense oligonucleotides inhibited P-glycoprotein expression induced by fragmented hyaluronan. The fragmented hyaluronan induced significant P-glycoprotein expression on only activated CD4+ T cells, which highly expressed CD69, and resulted in excretion of intracellular dexamethasone added in vitro. Cyclosporin A, a competitive P-glycoprotein inhibitor, restored intracellular dexamethasone levels in CD4+ T cells. Anti-CD44 monoclonal antibody (Hermes-1) inhibited fragmented hyaluronan-induced YB-1 activation and P-glycoprotein expression in CD4+ T cells. We provide the first evidence that binding of fragmented hyaluronan to CD44 induces YB-1 activation followed by P-glycoprotein expression in accordance with activation of CD4+ T cells. Our findings imply that CD4+ T cell activation by fragmented hyaluronan, induced by characteristic extracellular matrix changes in inflammation, tumors, and other conditions, results in P-glycoprotein-mediated multidrug resistance.
Tsujimura
Shizuyo
S
First Department of Internal Medicine and Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
Saito
Kazuyoshi
K
Kohno
Kimitoshi
K
Tanaka
Yoshiya
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000493:pharmacokinetics; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008970:Molecular Weight; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D051840:Y-Box-Binding Protein 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D003907:Dexamethasone; D006820:Hyaluronic Acid