SULFATION-DEPENDENT DOWN-REGULATION OF INTERFERON-GAMMA-INDUCED MAJORHISTOCOMPATIBILITY COMPLEX CLASS-I AND CLASS-II AND INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION ON TUBULAR AND ENDOTHELIAL-CELLS BY GLYCOSAMINOGLYCANS

Background. Previously. it has been demonstrated that heparin inhibits major histocompatibility complex (MHC) class II and intercellular adh esion molecule-1. (ICAM-1) expression on interferon-gamma (IFN-gamma)- stimulated human umbilical vein endothelial cells (HUVECs). Inasmuch a s proximal tubular epithelial cells (PTECs) are prime targets in acute renal allograft rejection, we investigated whether there is a differe nce in the ability of heparin to influence MHC and ICAM-1 expression o n PTECs as compared to HUVECs, We also studied whether the degree of s ulfation of heparin is of relevance for the binding to IFN-gamma and i nhibition of MHC and ICAM-1 expression after IFN-gamma stimulation. Me thods. 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 s orting. Results. Heparin was able to inhibit the up-regulation of MHC and ICAM-1 in a dose-dependent fashion on both IFN-gamma-stimulated HU VECs and PTECs. In PTEC cultures, higher concentrations of heparin wer e required for the inhibition of MHC class I. Heparin and supersulfate d glycosaminoglycans (GAGs) were able to bind to IFN-gamma, whereas N- desulfated N-acetylated GAGs with a low amount of sulfate were not. In hibition of cell-bound heparan sulfate proteoglycan sulfation with NaC IO3 resulted in an impaired MHC and ICAM-1 expression after IFN-gamma stimulation. Conclusion. We postulate that IFN-gamma binds to cell-bou nd heparan sulfate proteoglycan in a sulfation-dependent fashion. This binding mag facilitate the interaction of IFN-gamma with its receptor . Supersulfated GAGs with low anti-coagulant, activity could be used t herapeutically to decrease MBC and ICAM-1 expression on organ grafts.