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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. 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. The successful pharmacotherapy of various diseases, including tumors and autoimmune diseases, is often limited by multidrug resistance (1Linn S.C. Honkoop A.H. van der Hoekman K. Valk P. Pinedo H.M. Giaccone G. Br. J. Cancer. 1996; 74: 63-68Crossref PubMed Scopus (92) Google Scholar, 3Ueda K. Cardaralli C. Gottesman M.M. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3004-3008Crossref PubMed Scopus (1039) Google Scholar). Among the multiple mechanisms of multidrug resistance, overexpression of P-glycoprotein, a 170-kDa product of the multidrug resistance (MDR) 2The abbreviations used are: MDR, multidrug resistance; YB-1, Y box-binding protein 1; IL, interleukin; PBMC, peripheral blood mononuclear cell; mAb, monoclonal antibody; FACS, fluorescence-activated cell sorter; CMV, cyto-megalovirus; TBS, Tris-buffered saline; RA, rheumatoid arthritis. 2The abbreviations used are: MDR, multidrug resistance; YB-1, Y box-binding protein 1; IL, interleukin; PBMC, peripheral blood mononuclear cell; mAb, monoclonal antibody; FACS, fluorescence-activated cell sorter; CMV, cyto-megalovirus; TBS, Tris-buffered saline; RA, rheumatoid arthritis.-1 gene, has emerged as the major molecule involved in multidrug resistance during chemotherapy for various malignancies (1Linn S.C. Honkoop A.H. van der Hoekman K. Valk P. Pinedo H.M. Giaccone G. Br. J. Cancer. 1996; 74: 63-68Crossref PubMed Scopus (92) Google Scholar, 6List A.F. Kopecky K.J. Willman C.L. Head D.R. Slovak M.L. Douer D. Dakhil S.R. Appelbaum F.R. Blood. 2002; 100: 1910-1912Crossref PubMed Google Scholar). Resistance to chemotherapy induced by P-glycoprotein is closely associated with the prognosis of human malignancies (1Linn S.C. Honkoop A.H. van der Hoekman K. Valk P. Pinedo H.M. Giaccone G. Br. J. Cancer. 1996; 74: 63-68Crossref PubMed Scopus (92) Google Scholar). P-glycoprotein is a member of the ATP-binding cassette transporter superfamily of genes and functions as an energydependent transmembrane efflux pump (7Chen C.J. Chin J.E. Ueda K. Clark D.P. Pastan I. Gottesman M.M. Roninson I.B. Cell. 1986; 47: 381-389Abstract Full Text PDF PubMed Scopus (1712) Google Scholar). Overexpression of P-glycoprotein results in a reduction of intracellular concentrations of xenobiotics, drugs, and poisons, such as vinca alkaloids, anthracyclines, verapamil, colchicines, antimalarials, and corticosteroids (2Tsuruo T. Cancer Treat. Rep. 1983; 67: 889-894PubMed Google Scholar, 3Ueda K. Cardaralli C. Gottesman M.M. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3004-3008Crossref PubMed Scopus (1039) Google Scholar, 8Bourgeois S. Gruol D.J. Newby R.F. Rajah F.M. Mol. Endocrinol. 1993; 7: 840-851Crossref PubMed Scopus (110) Google Scholar). P-glycoprotein is expressed on not only various types of tumor cells but also normal cells such as epithelial cells (9Fojo A.T. Ueda K. Slamon D.J. Poplack D.G. Gottesman M.M. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 265-269Crossref PubMed Scopus (1494) Google Scholar, 11Cordon-Cardo C. O'Brien J.P. Casals D. Rittman-Grauer L. Biedler J.L. Melamed M.R. Bertino J.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 695-698Crossref PubMed Scopus (1587) Google Scholar), CD34+ hematopoietic stem cells (12Chaudhary P.M. Roninson I.B. Cell. 1991; 66: 85-94Abstract Full Text PDF PubMed Scopus (900) Google Scholar), and lymphocytes (13Tsujimura S. Saito K. Nakayamada S. Nakano K. Tsukada J. Kohno K. Tanaka Y. Genes Cells. 2004; 9: 1265-1273Crossref PubMed Scopus (55) Google Scholar). In various tumor cell lines, we and others have reported that transcription of MDR-1 is directly regulated by the human Y box-binding protein-1 (YB-1), an MDR-1 transcription factor, and that activation of YB-1 is induced in response to genotoxic stresses including multiple drugs (14Ohga T. Uchiumi T. Makino Y. Koike K. Wada M. Kuwano M. Kohno K. J. Biol. Chem. 1998; 273: 5997-6000Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 15Kohno K. Sato S. Takano H. Matsuo K. Kuwano M. Biochem. Biophys. Res. Commun. 1989; 165: 1415-1421Crossref PubMed Scopus (207) Google Scholar). In lymphocytes, our group reported previously that the transcription of MDR-1 gene and expression of P-glycoprotein are induced by soluble factors including lymphocyte-activation cytokines such as interleukin (IL)-2, resulting in the activation of YB-1 and induction of its binding to DNA (13Tsujimura S. Saito K. Nakayamada S. Nakano K. Tsukada J. Kohno K. Tanaka Y. Genes Cells. 2004; 9: 1265-1273Crossref PubMed Scopus (55) Google Scholar). In addition to soluble factors, intercellular adhesion or adhesion to the extracellular matrix transduces signals via functional molecules on lymphocytes and these processes are involved in the regulation of immunological reactions (16Sturm A. Krivacic K.A. Fiocchi C. Levine A.D. J. Immunol. 2004; 173: 3889-3900Crossref PubMed Scopus (22) Google Scholar, 17Shimizu Y. Shaw S. FASEB J. 1991; 5: 2292-2299Crossref PubMed Scopus (308) Google Scholar). Hyaluronan, a representative component of extracellular matrix, is a nonsulfated glycosaminoglycan bearing linear repeats of disaccharide-β-d-glucuronyl-β-d-N-acetylglucosamine (18Sugahara K. Schwartz N.B. Dorfman A. J. Biol. Chem. 1979; 254: 6252-6261Abstract Full Text PDF PubMed Google Scholar). The principal known receptor of hyaluronan is CD44 (19Aruffo A. Stamenkovic I. Melnick M. Underhill C.B. Seed B. Cell. 1990; 61: 1303-1313Abstract Full Text PDF PubMed Scopus (2144) Google Scholar). CD44 is a 90-kDa transmembrane glycoprotein widely distributed on T lymphocytes, granulocytes, monocytes, fibroblasts, keratinocytes, and epithelial cells (20Underhill C. J. Cell Sci. 1992; 103: 293-298Crossref PubMed Google Scholar). Stimulation of CD44 with hyaluronan plays a role in various physiological functions, such as cell-cell adhesion, cell-substrate interactions, and lymphocyte recruitment, as well as pathological processes such as chronic inflammation and metastasis of malignant cells (19Aruffo A. Stamenkovic I. Melnick M. Underhill C.B. Seed B. Cell. 1990; 61: 1303-1313Abstract Full Text PDF PubMed Scopus (2144) Google Scholar). Hyaluronan is usually generated as a high molecular weight polymer, a native hyaluronan (18Sugahara K. Schwartz N.B. Dorfman A. J. Biol. Chem. 1979; 254: 6252-6261Abstract Full Text PDF PubMed Google Scholar), but a fragmented hyaluronan, a digested low molecular weight oligomer, is detected in certain pathological conditions, such as inflammation and tumors (21Balazs E.A. Watson D. Duff I.F. Roseman S. Arthritis Rheum. 1967; 10: 357-376Crossref PubMed Scopus (467) Google Scholar, 22Liu D. Pearlman E. Diaconu E. Guo K. Mori H. Haqqi T. Markowitz S. Willson J. Sy M.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7832-7837Crossref PubMed Scopus (202) Google Scholar). Several studies have reported that the biological activities of fragmented hyaluronan markedly differ from native hyaluronan in endothelial cell, various malignant cells, and macrophages (23Lokeshwar V.B. Rubinowicz D. Schroeder G.L. Forgacs E. Minna J.D. Block N.L. Nadji M. Lokeshwar B.L. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. J. 1996; PubMed Scopus Google Scholar). MDR-1 transcription in lymphocytes is induced by various activation such as is on with hyaluronan induces activation and MDR-1 transcription in CD4+ T cells. is also not the of fragmented hyaluronan on activation and regulation of are from native hyaluronan in CD4+ T cells. The to the of fragmented hyaluronan on CD4+ T cell activation and its role in P-glycoprotein-mediated multidrug resistance, in fragmented such as of chronic inflammation or of from peripheral blood mononuclear cells from by Lymphocyte as previously Y. Y. S. H. H. K. Saito K. Tsukada J. van Y. T. S. J. Immunol. Google Scholar, Y. A. K.J. S. M. Saito K. S. I. H. H. Y. S. J. Immunol. Google Scholar). We that of lymphocytes or and of by The by the of the of and of and from in the CD4+ T from T cells by to the by the The of the CD4+ T cell by to and and and native hyaluronan by the of The monoclonal used as in of and of cell or of and specific a specific antibody YB-1 binding protein to the Y and which is for the that MDR-1 gene expression (14Ohga T. Uchiumi T. Makino Y. Koike K. Wada M. Kuwano M. Kohno K. J. Biol. Chem. 1998; 273: 5997-6000Abstract Full Text Full Text PDF PubMed Scopus (217) Google mAb, mAb, mAb, CD44 monoclonal antibody; a for and antibody; and of or CD4+ T cells by as previously a Y. Y. S. H. H. K. Saito K. Tsukada J. van Y. T. S. J. Immunol. Google Scholar, Y. A. K.J. S. M. Saito K. S. I. H. H. Y. S. J. Immunol. Google Scholar). or CD4+ cells with for of and with followed by in of human and the we with mAb, mAb, or CD4+ cells with of with antibody cells detected by on or expression a of binding by a of the cell on cell as reported previously Y. Y. S. H. H. K. Saito K. Tsukada J. van Y. T. S. J. Immunol. Google Scholar, Y. K. A. S. I. H. S. H. K. K. S. S. J. 1996; PubMed Scopus Google Scholar). The used to the of antibody binding The cell on the and the antibody binding by on the the in the the antibody binding to the specific antibody binding for the and antibody binding of the The specific antibody binding is the of cell, to as and expressed in and or CD4+ T cells a and for in the or of 6.9-kDa fragmented hyaluronan in The cells with in for and with in The cells with a specific antibody YB-1 for the cells with concentrations in We of YB-1 a from as previously C. O'Brien J.P. Casals D. Rittman-Grauer L. Biedler J.L. Melamed M.R. Bertino J.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 695-698Crossref PubMed Scopus (1587) Google and with or 6.9-kDa fragmented hyaluronan. In the of protein for in of and of and a the YB-1 binding as previously J.D. Res. 1983; PubMed Scopus Google Scholar). The on in Transfection of of YB-1 in antisense expression as previously T. Koike K. M. Makino Y. Y. M. Kuwano M. Kohno K. Cancer Res. 1996; Google Scholar). We of or into in a a with to the by the H. M. J. 1993; PubMed Scopus Google Scholar, M. K. T. T. PubMed Scopus Google Scholar). the cells for in the or of 6.9-kDa fragmented hyaluronan. of with or of 6.9-kDa fragmented hyaluronan in from CD4+ T cells by a with and the for with specific for MDR-1 and in an for of for for and for The as human human MDR-1 with on with a of in and with of CD4+ T cells, which with or 6.9-kDa fragmented hyaluronan for in with for which is in C. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), a of The CD4+ T cells with and for competitive studies with A, CD4+ T cells with for and with and Cyclosporin in with of with fragmented hyaluronan and A, on of the of and in an for the in and the the the as the and the as the cell The cell with and of The with of of and The of with a The cell to which is an of intracellular and extracellular dexamethasone the in cell in cell in in CD44 cells with or as for to with or 6.9-kDa fragmented hyaluronan, the cells used for the with or 6.9-kDa fragmented hyaluronan, of CD4+ T cells in the of a and The cells to on for which added and The to The of from of CD4+ T cells to The the with and the with The with and with in for in detected a the by the are expressed as used to of and used to or Fragmented Hyaluronan MDR-1 on first the of hyaluronan on P-glycoprotein expression in of P-glycoprotein, as by induced by the addition of the 6.9-kDa fragmented hyaluronan during the In native hyaluronan to P-glycoprotein expression on we the expression of P-glycoprotein a with 6.9-kDa fragmented hyaluronan in the We that expression of P-glycoprotein in a dose-dependent to 6.9-kDa fragmented hyaluronan and Fragmented Hyaluronan of YB-1 in gene expression is by activation and translocation of YB-1 in human lymphocytes (12Chaudhary P.M. Roninson I.B. Cell. 1991; 66: 85-94Abstract Full Text PDF PubMed Scopus (900) Google Scholar). We the intracellular of the transcriptional factor YB-1 in by monoclonal of YB-1 in the cytoplasm of and its translocation into the nucleus of with 6.9-kDa fragmented hyaluronan We the induction of the DNA binding of YB-1 by 6.9-kDa fragmented hyaluronan by we from and with 6.9-kDa fragmented hyaluronan, and with a YB-1 binding We in the of oligonucleotides and from with 6.9-kDa fragmented hyaluronan results imply that of with 6.9-kDa fragmented hyaluronan resulted in a of including activation of factor YB-1, its and the binding of activated YB-1 to the of the MDR-1 results with in the expression of P-glycoprotein in YB-1 P-glycoprotein on YB-1 is directly with fragmented hyaluronan-induced MDR-1 gene we the expression of P-glycoprotein on with YB-1 antisense expression or and the levels of P-glycoprotein expression on with or 6.9-kDa fragmented hyaluronan. In with the of YB-1 antisense the expression of P-glycoprotein on Fragmented hyaluronan the expression of P-glycoprotein on cells, but such induction by of YB-1 antisense Fragmented Hyaluronan of P-glycoprotein on CD4+ T the expression of P-glycoprotein on lymphocytes in we and and P-glycoprotein expression on of lymphocytes. that P-glycoprotein expression by 6.9-kDa fragmented hyaluronan on CD4+ but not cells in in we CD4+ T cells from We first the expression of P-glycoprotein on CD4+ T cells a with 6.9-kDa fragmented hyaluronan. of P-glycoprotein on CD4+ T cells induced by the addition of the fragmented hyaluronan P-glycoprotein expression the of MDR-1 gene expression in response to fragmented hyaluronan, we the expression of MDR-1 by a in MDR-1 to in CD4+ T cells with 6.9-kDa fragmented hyaluronan, with CD4+ T cells the Fragmented Hyaluronan of CD4+ T and of studies from our that soluble factors, which lymphocytes such as YB-1 activation followed by P-glycoprotein expression in lymphocytes (13Tsujimura S. Saito K. Nakayamada S. Nakano K. Tsukada J. Kohno K. Tanaka Y. Genes Cells. 2004; 9: 1265-1273Crossref PubMed Scopus (55) Google Scholar). In the we of P-glycoprotein expression by fragmented hyaluronan with activation of lymphocytes. We used the cell CD69, a well activation of T cells M.R. PubMed Scopus Google Scholar), to CD4+ T cell that expression on CD4+ T cells by the 6.9-kDa fragmented hyaluronan expression of P-glycoprotein on high CD4+ T cells, and the of P-glycoprotein expression on high CD4+ T cells by the 6.9-kDa fragmented hyaluronan and results imply that expression of P-glycoprotein is closely associated with activation of CD4+ T cells and that of P-glycoprotein by the 6.9-kDa fragmented hyaluronan on high CD4+ T cells. of P-glycoprotein of in CD4+ T the expression of P-glycoprotein on CD4+ T cell and of drugs through P-glycoprotein, the intracellular and extracellular of dexamethasone Stimulation with fragmented hyaluronan resulted in a significant of intracellular dexamethasone of CD4+ T cells the functional of P-glycoprotein in the of intracellular we added A, a competitive of P-glycoprotein, to fragmented CD4+ T cells. of dexamethasone in CD4+ T cells inhibited by Anti-CD44 of MDR-1 in CD4+ T of the principal for hyaluronan is CD44 (19Aruffo A. Stamenkovic I. Melnick M. Underhill C.B. Seed B. Cell. 1990; 61: 1303-1313Abstract Full Text PDF PubMed Scopus (2144) Google Scholar). we used a to the for of MDR-1 gene expression in CD4+ T cells by fragmented hyaluronan. We found that fragmented hyaluronan markedly induced the translocation of YB-1 and the expression of cell P-glycoprotein by and The by with the of CD44 molecules in fragmented hyaluronan-induced P-glycoprotein expression In of of hyaluronan with cell functional of CD44 have CD44 and cells of as well as epithelial cells and tumor cells to In CD44 is on T cells, and is not to hyaluronan such as M. P. J. Immunol. Google Scholar). Fragmented hyaluronan but not native hyaluronan has to the expression of and cell adhesion molecules through a CD44 in endothelial cells, various malignant cells, and macrophages P. P. J.D. J. S. J. Cancer. PubMed Scopus Google Scholar, M. C. J. 1996; PubMed Scopus Google Scholar). In we a physiological of fragmented hyaluronan on CD4+ T cells. The findings of the as Fragmented hyaluronan, but not the native high molecular weight hyaluronan, to transcriptional regulation of the MDR-1 gene, YB-1 activation followed by P-glycoprotein in CD4+ T cells. of P-glycoprotein on CD4+ T cells induced by fragmented hyaluronan on activated CD4+ T cells. Overexpression of P-glycoprotein resulted in dexamethasone excretion from CD4+ T cells, which inhibited by the competitive A. induction of MDR-1 gene by fragmented hyaluronan through CD44 molecules on CD4+ T cells. have reported that fragmented hyaluronan binding to cell CD44 in with from to and that fragmented hyaluronan J. M. J. Biol. Chem. Full Text Full Text PDF PubMed Google Scholar), the 6.9-kDa fragmented hyaluronan CD44 as well as tumor cell certain and in a hyaluronan to T. H. H. H. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). evidence with our results that 6.9-kDa fragmented hyaluronan induced expression of P-glycoprotein on lymphocytes In to our S. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google reported that fragmented hyaluronan MDR-1 expression in human cells. The for the on the of fragmented hyaluronan are to the of of fragmented hyaluronan. used of that only we used of which binding J. M. J. Biol. Chem. Full Text Full Text PDF PubMed Google Scholar). The of hyaluronan and CD44 by signals a not S. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the other we that the of with CD44 molecules on the CD4+ T cells and that the induces activation of CD4+ T cells and expression of reported that induced of cells CD44 J. U. T. P. J. Immunol. 165: PubMed Scopus Google Scholar). of hyaluronan the on In addition to hyaluronan of hyaluronan have biological cells hyaluronan and high molecular hyaluronan into and L. 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CD4+ T cells by P-glycoprotein-mediated chemotherapy resistance. for the that expression of P-glycoprotein on CD4+ T cells is in accordance with activation of CD4+ T cells induced by fragmented hyaluronan In we that the in fragmented CD4+ T cells, of CD44 MDR-1 P-glycoprotein and of P-glycoprotein that inhibited by P-glycoprotein Our findings that a characteristic of extracellular matrix in a specific directly the Our findings also our of the tumors, chronic inflammation, and the We T. for the
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