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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-06-1736. This Article Full Text (PDF) All Versions of this Article: 2002-06-1736v1 101/2/602    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dimitroff, C. J Articles by Sackstein, R. Search for Related Content PubMed PubMed Citation Articles by Dimitroff, C. J Articles by Sackstein, R. Social Bookmarking                   What's this? Submitted June 27, 2002 Accepted August 23, 2002 Glycosylation-dependent inhibition of cutaneous lymphocyte-associated antigen expression: implications in modulating lymphocyte migration to skin Charles J Dimitroff, Ralph J Bernacki, and Robert Sackstein* Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA * Corresponding author; email: rsackstein{at}rics.bwh.harvard.edu. Constitutive E-selectin expression on dermal microvascular endothelial cells plays a critical role in mediating rolling adhesive interactions of human skin-homing T-cells and in pathologic accumulation of lymphocytes in skin. The major E-selectin ligand on human skin-homing T-cells is cutaneous lymphocyte-associated antigen (CLA), a specialized glycoform of P-selectin glycoprotein ligand-1 (PSGL-1) defined by monoclonal antibody HECA-452. Since HECA-452 reactivity, and not PSGL-1 polypeptide itself, confers the specificity of human T-cells to enter dermal tissue, inhibition of HECA-452 expression is a potential strategy for modulating lymphocyte migration to skin. In this study, we examined the efficacy of several well-characterized metabolic inhibitors of glycosylation and of a novel fluorinated analog of N-acetylglucosamine (4-F-GlcNAc) to alter HECA-452 expression on human CLA+ T-cells and prevent cell tethering and rolling on selectins under shear stress. At concentrations that did not affect PSGL-1 expression, we found that swainsonine (inhibitor of complex-type N-glycan synthesis) had no affect on HECA-452 expression and selectin ligand activity, whereas benzyl-O-N-acetylgalactosamide (BAG; inhibitor of O-glycan biosynthesis) ablated HECA-452 expression on PSGL-1 and significantly lowered selectin ligand activity. 4-F-GlcNAc (putative inhibitor of poly-N-acetyllactosamine biosynthesis) was more potent than BAG at lowering HECA-452 expression and selectin-binding. In addition, we show that 4-F-GlcNAc was incorporated directly into native CLA expressed on T-cells, indicating direct inhibition on poly-N-acetyllactosamine elongation and selectin-binding determinants on PSGL-1 O-glycans. These observations establish a potential treatment approach for targeting pathologic lymphocyte trafficking to skin and indicate that 4-F-GlcNAc may be a promising agent for treatment of dermal tropism associated with malignancies and inflammatory disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. C. Kerr, C. B. Fieger, K. R. Snapp, and S. D. Rosen Endoglycan, a Member of the CD34 Family of Sialomucins, Is a Ligand for the Vascular Selectins J. Immunol., July 15, 2008; 181(2): 1480 - 1490. [Abstract] [Full Text] [PDF] M. E. Gainers, L. Descheny, S. R. Barthel, L. Liu, M.-A. Wurbel, and C. J. Dimitroff Skin-Homing Receptors on Effector Leukocytes Are Differentially Sensitive to Glyco-Metabolic Antagonism in Allergic Contact Dermatitis J. Immunol., December 15, 2007; 179(12): 8509 - 8518. [Abstract] [Full Text] [PDF] P. V. Cabrera, M. Amano, J. Mitoma, J. Chan, J. Said, M. Fukuda, and L. G. 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