Role of glycosaminoglycans (GAGs) in regulation of the immunogenicity of human vascular endothelial cells

Authors


John A. Kirby Transplant Immunology Unit, Department of Surgery, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.

Abstract

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-γ), but not of tumour necrosis factor-alpha (TNF-α), 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-γ. Furthermore, it was shown that heparin blocked the enhanced adhesion of T lymphocytes to IFN-γ-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-γ. 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-γ, thereby reducing effective biological activity.

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