Role of glycosaminoglycans (GAGs) in regulation of the immunogenicity of human vascular endothelial cells.
Heparan sulphate is a common glycosaminoglycan component of proteoglycans present on the luminal surface of vascular endothelium. It has been proposed that an important function of these molecules is the sequestration of a range of proinflammatory and proadhesive cytokines. Such cytokines play a vital role during lymphocyte recruitment from the blood at sites of inflammation. In this study it is shown that the effects of interferon-gamma (IFN-gamma), but not of tumour necrosis factor-alpha (TNF-alpha), are inhibited by treatment with soluble heparin. Specifically, heparin was shown to inhibit the induction of class II MHC antigens and the up-regulation of intercellular adhesion molecule-1 (ICAM-1) produced by treatment of cultured human endothelial cells with IFN-gamma. Furthermore, it was shown that heparin blocked the enhanced adhesion of T lymphocytes to IFN-gamma-treated endothelial cells. Investigation of the inhibitory effects of other GAG molecules demonstrated a requirement for heparin-like structural domains as chondroitin sulphate was unable to inhibit the function of IFN-gamma. These results may explain reported immunosuppressive properties of heparin, and are consistent with the model that heparin may compete with cell surface GAGs to bind IFN-gamma, thereby reducing effective biological activity.
Rix
D A
DA
Transplant Immunology Unit, Department of Surgery, The Medical School, University of Newcastle, Newcastle upon Tyne, UK.
Douglas
M S
MS
Talbot
D
D
Dark
J H
JH
Kirby
J A
JA
D002448:Cell Adhesion; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology*; D006025:Glycosaminoglycans / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D006025:Glycosaminoglycans; D006681:HLA-D Antigens; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D006493:Heparin