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

Abstract

SUMMARYHeparan 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-°), but not of tumour necrosis factor-alpha (TNF-®), 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-°. Furthermore, it was shown that heparin blocked the enhanced adhesion of T lymphocytes to IFN-°-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-°. 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-°, thereby reducing effective biological activity.Keywords glycosaminoglycan interferon-gamma endothelium class II MHC antigen intercellular adhesion molecule-1 lymphocyte adhesion

Examination of the mechanism by which heparin antagonizes activation of a model endothelium by interferon-gamma (IFN-γ)

“…The capacity of heparin and of HS to antagonize the induction of class II MHC antigens by IFN-g-treated EAhy.926 is entirely consistent with the results of previous studies using cultured HUVEC [19,20]. Furthermore, this effect was not produced by the galactosamine-containing molecules CS-A or CS-C.…”

“…For example, the proadhesive activity of chemokines such as RANTES and MCP-1 is blocked by heparin [18]. Previous studies by this group [19,20] and others [21] have shown that heparin can also antagonize the activity of IFN-g.…”

Host Defense Peptides in Wound Healing

“…Both play important roles in wound healing by activating epidermal cells and fibroblasts to form granulation tissue, mediate angiogenesis, and chemoattract macrophages and fibroblasts (133)(134)(135). In a feedback mechanism, cathelicidin from activated leukocytes in pigs (PR-39) has shown a direct influence on dermal fibroblasts by increasing synthesis of the extracellular matrix proteoglycans, syndecan-1 and -4 (136), which are required for the activity of many growth factors (137)(138)(139)(140). In an animal model, syndecan production was delayed and ineffective wound repair (141,142) was reported.…”

Is human placenta proteoglycan remodeling involved in pre-eclampsia?

“…HS, the constituent of up to 50% of the total expressed GAG in endothelial cells [17], is unique among GAGs in the ability to bind a large number of different proteins with complex role in the extracellular matrix, regulating a wide variety of biological process, including hemostasis, inflammation, angiogenesis, growth factors, cell adhesion [18], as well as serine proteinase-mediated tissue remodeling [19]. In the placenta, the endothelium functions as the interface between blood and the tissues and must be able to respond dynamically to its microenvironment in order to regulate the passage of cells into sub-endothelial tissues [20]. Therefore, the regulation (up or down) of the extent of HS sulfation within the endothelial microenvironment might represent a mechanism for balanced homeostasis in the developing placenta.…”