title: Sulfation-dependent down-regulation of interferon-gamma-induced major histocompatibility complex class I and II and intercellular adhesion molecule-1 expression on tubular and endothelial cells by glycosaminoglycans.
abstract: BACKGROUND
  Previously, it has been demonstrated that heparin inhibits major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1) expression on interferon-gamma (IFN-gamma)-stimulated human umbilical vein endothelial cells (HUVECs). Inasmuch as proximal tubular epithelial cells (PTECs) are prime targets in acute renal allograft rejection, we investigated whether there is a difference in the ability of heparin to influence MHC and ICAM-1 expression on PTECs as compared to HUVECs. We also studied whether the degree of sulfation of heparin is of relevance for the binding to IFN-gamma and inhibition of MHC and ICAM-1 expression after IFN-gamma stimulation.
  
  
  METHODS
  Cultured HUVECs and PTECs were stimulated with IFN-gamma for 72 hr in the presence or absence of various heparinoids. MHC and ICAM-1 expression were thereafter determined by fluorescence-activated cell sorting.
  
  
  RESULTS
  Heparin was able to inhibit the up-regulation of MHC and ICAM-1 in a dose-dependent fashion on both IFN-gamma-stimulated HUVECs and PTECs. In PTEC cultures, higher concentrations of heparin were required for the inhibition of MHC class I. Heparin and supersulfated glycosaminoglycans (GAGs) were able to bind to IFN-gamma, whereas N-desulfated N-acetylated GAGs with a low amount of sulfate were not. Inhibition of cell-bound heparan sulfate proteoglycan sulfation with NaClO3 resulted in an impaired MHC and ICAM-1 expression after IFN-gamma stimulation.
  
  
  CONCLUSIONS
  We postulate that IFN-gamma binds to cell-bound heparan sulfate proteoglycan in a sulfation-dependent fashion. This binding may facilitate the interaction of IFN-gamma with its receptor. Supersulfated GAGs with low anti-coagulant activity could be used therapeutically to decrease MHC and ICAM-1 expression on organ grafts.
authors.affiliation: V. Medizinische Klinik, Klinikum Mannheim, University of Heidelberg, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Yard
authors.forename: C P
authors.initials: CP
authors.lastname: Lorentz
authors.forename: D
authors.initials: D
authors.lastname: Herr
authors.forename: F J
authors.initials: FJ
authors.lastname: van der Woude
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D013431:Sulfates