Heparin inhibits the antiparasitic and immune modulatory effects of human recombinant interferon‐γ

Däubener, Walter; Nockemann, Susanne; Gutsche, Marc; Hadding, U.

doi:10.1002/eji.1830250309

Cited by 36 publications

(14 citation statements)

References 23 publications

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“…In conclusion, results presented in this study appear to demonstrate that IFN-g binds initially to endothelial cells by interaction between basic amino acids located within the C-terminal region of the molecule and HS-containing PG on the cell surface, confirming the theory proposed previously by several groups, including ourselves [19,21,34]. This interaction is shown to be necessary for optimal proinflammatory activation of endothelial cells.…”

Section: Discussionsupporting

confidence: 91%

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

Douglas

Rix

Dark

et al. 1997

Clinical and Experimental Immunology

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SUMMARYIFN-g increases the potential immunogenicity of vascular endothelial cells by up-regulation of intercellular adhesion molecule-1 (ICAM-1) and class I MHC antigen expression and by induction of class II MHC antigens and certain chemokines. In this study the mechanism by which the glycosaminoglycan (GAG) heparin antagonizes the activation of a model endothelium by IFN-g was investigated. Radioligand binding assays demonstrated that total binding of 125 I-IFN-g to the EAhy.926 endothelial hybridoma cell line was reduced in the presence of heparin or heparan sulphate (HS); the structurally dissimilar GAG chondroitin sulphate had no effect. Treatment of the cells with chlorate, a metabolic inhibitor of GAG sulphation, was found to reduce both the subsequent binding of IFN-g and its ability to induce expression of class II MHC antigens. Treatment with heparinase II dramatically reduced the binding of IFN-g, while chondroitin ABC lyase had no effect. A cationic peptide from the C-terminal region of IFN-g was also found to reduce binding of intact IFN-g to the cells. These results appear to demonstrate that IFN-g is sequestered at the surface of endothelial cells by electrostatic interaction between specific basic amino acid residues and sulphated domains on HS, the most abundant endothelial GAG. This interaction is competitively inhibited by heparin, which is structurally related to HS. These observations are consistent with the model that IFN-g is bound by membrane-associated HS before engagement with the high-affinity receptor and signal transduction. Inhibition of the interaction between proinflammatory cytokines and membrane-associated GAG molecules may provide a mechanism for inducing clinically useful immunosuppression.

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Section: Discussionsupporting

confidence: 91%

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

Douglas

Rix

Dark

et al. 1997

Clinical and Experimental Immunology

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“…However, tight adhesion to endothelium can also be regulated by changes in the expression of ICAM-1 induced by cytokines such as IFN-and TNF-which are produced during the development of inflammatory lesions. It has been reported previously by this group [19], and others [20], that heparin can antagonize the induction of class II MHC molecules by IFN-. In this study it is shown for the first time that heparin can also antagonize the up-regulation of ICAM-1 by IFN--treated HUVEC.…”

Section: Discussionmentioning

confidence: 69%

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

Rix

Douglas

Talbot

et al. 1996

Clinical and Experimental Immunology

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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

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“…Soluble GAG were found to interfere with the activity of IL-10 or IFN-γ [9,10,114,173]. Heparin can also neutralize chemoattractants released from platelets such as PF-4 and RANTES [174].…”

Section: Blockade Of Cytokine Chemokine or Growth Factor Activitiesmentioning

confidence: 99%

Proteoglycan Involvement in Inflammatory Diseases. New Developments in GAG-Based Therapies

Delehedde¹,

Lortat‐Jacob²,

Gallagher³

et al. 2005

MCRO

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Proteoglycans (PG) are complex macromolecules which consist structurally of a core protein and associated glycosaminoglycan (GAG) chains. The different GAG chains of PG, heparan sulfate/heparin, dermatan/chondroitin sulfate, keratan sulfate are synthesized as polymers of repeating disaccharide units. The structures of GAG chains are highly diverse and confer to them a variety of structures and functions. Without covering PG complexity in structures and roles, the most usual classification for PG is based on their localization: being at the cell membrane or in the extracellular matrix, being intracellular or circulating in the blood. By virtue of the multiplicity of protein binding partners (e.g. growth factors, chemokines), PG have been shown to be involved in the regulation of a large number of pathophysiological processes. They are strongly implicated in the different stages of inflammation from the recruitment of inflammatory cells to the release of mediators of inflammation by infiltrating leukocytes and the turnover of extracellular matrix. The overarching theme of PG in inflammation is the regulation of the inflammatory microenvironment, which has to change continuously and dynamically during the progression of the inflammatory response. These changes include the modulation of the activity of GAG-binding cytokines, growth factors, proteases and protease inhibitors. The interactions of regulatory proteins with GAGs provide much of the focus for GAG-based therapeutic targets and the development of GAG mimetics could have in the near future, clinical applications as modulators of cytokine or enzyme functions in inflammatory diseases.

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Heparin inhibits the antiparasitic and immune modulatory effects of human recombinant interferon‐γ

Cited by 36 publications

References 23 publications

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

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

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

Proteoglycan Involvement in Inflammatory Diseases. New Developments in GAG-Based Therapies

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