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

Douglas, Michael S.; Rix, D.; Dark, J.H.; Talbot, David; Kirby, John A.

doi:10.1046/j.1365-2249.1997.3141206.x

Cited by 53 publications

(43 citation statements)

References 30 publications

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“…33,36,37 They also express large amounts of both N-and O-sulfated heparan sulfate on their cell surface as detected by immunofluorescence flow cytometry (data not shown) and have been used previously by this group and others to model endothelial/cytokine interactions. [38][39][40] Importantly, immunofluorescence microscopy demonstrated that they lack cell surface expression of CCR2, the cognate receptor for MCP-1 (data not shown).…”

Section: Resultsmentioning

confidence: 95%

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration

et al. 2003

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It is proposed that a chemokine concentration gradient promotes vectorial leukocyte migration across the vascular endothelium during inflammation. In this study, monocyte migration across a model endothelial monolayer was assessed at defined time-points after the addition of MCP-1 (CCL2). At each time-point transendothelial migration was quantified, medium from the apical and basal surface was collected for ELISA and monolayers were stained to detect both heparan sulfate and MCP-1. Statistically significant monocyte migration was observed within 60 min of chemokine addition to the basal surface of the endothelium and an asymmetric distribution of MCP-1 across the monolayer was observed at all time-points. Dual color immunofluorescence analysis demonstrated that MCP-1 was focused into heparan sulfate-containing domains on the apical surface of some of the endothelial cells. Furthermore, no uniform concentration gradient of chemokine was observed within the space between adjacent endothelial cells with apical MCP-1 application resulting in a staining pattern identical to that observed after basal application. The addition of a functional, monomeric form of MCP-1 produced a staining pattern identical to that observed using the wild-type protein, suggesting that localized chemokine oligomerization is not responsible for generating the focal chemokine distribution. Together, these data suggest that apical presentation of concentrated, chemokine-containing domains provides sufficient stimulus to promote transendothelial leukocyte migration in the absence of the formation of a formal haptotactic concentration gradient between endothelial cells.

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Section: Resultsmentioning

confidence: 95%

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration

et al. 2003

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“…A large body of work has been carried out in this area, and blocking interactions between IFN-g and endothelial GAGs was suggested as a clinical method of immunosuppression (66), whereas mutation of the GAG binding site of RANTES has revealed a novel anti-inflammatory strategy (67). Moreover, anti-inflammatory properties of a cationic-derived peptide of mouse IFN-g was shown to inhibit the GAG binding capacity of IL-8 (68).…”

Section: Discussionmentioning

confidence: 99%

IL-8 Dictates Glycosaminoglycan Binding and Stability of IL-18 in Cystic Fibrosis

Reeves

Williamson

Byrne

et al. 2009

The Journal of Immunology

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Dysregulation of airway inflammation contributes to lung disease in cystic fibrosis (CF). Inflammation is mediated by inflammatory cytokines, including IL-8, which illustrates an increase in biological half-life and proinflammatory activity when bound to glycosaminoglycans (GAGs). The aim of this project was to compare IL-8 and IL-18 for their relative stability, activity, and interaction with GAGs, including chondroitin sulfate, hyaluronic acid, and heparan sulfate, present in high quantities in the lungs of patients with CF. Bronchoalveolar lavage fluid was collected from patients with CF (n = 28), non-CF controls (n = 14), and patients with chronic obstructive pulmonary disease (n = 12). Increased levels of IL-8 and reduced concentrations of IL-18 were detected in bronchial samples obtained from CF individuals. The low level of IL-18 was not a defect in IL-18 production, as the pro- and mature forms of the molecule were expressed and produced by CF epithelial cells and monocytes. There was, however, a marked competition between IL-8 and IL-18 for binding to GAGs. A pronounced loss of IL-18 binding capacity occurred in the presence of IL-8, which displaced IL-18 from these anionic-matrices, rendering the cytokine susceptible to proteolytic degradation by neutrophil elastase. As a biological consequence of IL-18 degradation, reduced levels of IL-2 were secreted by Jurkat T lymphocytes. In conclusion, a novel mechanism has been identified highlighting the potential of IL-8 to determine the fate of other inflammatory molecules, such as IL-18, within the inflammatory milieu of the CF lung.

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“…Utilizing endothelial cell layers and immobilized purified GAGs, others have shown that human IFN-␥ binds to heparin, heparan sulfate, and chondroitin sulfate, sulfation of the GAGs being essential for in this interaction (12)(13)(14)(15)(16)39). Binding is thought to be an ionic interaction between positively charged basic amino acids near the C terminus of IFN-␥ and the negatively charged sugar residues on GAGs (16).…”

Section: Discussionmentioning

confidence: 99%

“…One possible candidate is cell surface proteoglycans. In common with other cytokines and growth factors, human IFN-␥ has been shown to bind to proteoglycans of the extracellular matrix, and more specifically to the glycosaminoglycans (GAGs) heparin, heparan sulfate, and chondroitin sulfate (12)(13)(14)(15)(16). The binding interaction between human IFN-␥ and heparan sulfate has been well characterized: it involves two groups of carboxyl-terminal basic amino acids on the cytokine and two sulfated domains of heparan sulfate, such that the two domains of the GAG directly bind the two carboxyl-terminals of an IFN-␥ dimer (13,(17)(18)(19).…”

mentioning

confidence: 99%

Presentation of IFN-γ to Nitric Oxide-Producing Cells: A Novel Function for Mast Cells

Brooks¹,

Briggs²,

Eastmond³

et al. 2000

The Journal of Immunology

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We report that mast cells can bind and present IFN-γ in a functionally active form to macrophages. Flow-cytometric analysis revealed that biotinylated IFN-γ bound equally well to purified peritoneal mast cells from both IFN-γR knockout and wild-type mice, indicating a non-IFN-γR binding site. Purified peritoneal mast cells, loaded with IFN-γ for 30 min and washed, were able to induce NO synthesis by peritoneal macrophages. This response required cell contact and expression of IFN-γR on the responding macrophages, but not the mast cells. Human HMC-1 mast cells were also able to present IFN-γ to mouse macrophages. Enzyme treatment of mouse mast cells revealed that binding of IFN-γ was predominantly to chondroitin sulfate B (dermatan sulfate). Binding of IFN-γ to dermatan sulfate was confirmed by inhibition ELISA. This study demonstrates for the first time that mast cells can present IFN-γ to other cells via glycosaminoglycans. Mast cells may act as a reservoir of surface-stored functionally active cytokines.

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

Cited by 53 publications

References 30 publications

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration

IL-8 Dictates Glycosaminoglycan Binding and Stability of IL-18 in Cystic Fibrosis

Presentation of IFN-γ to Nitric Oxide-Producing Cells: A Novel Function for Mast Cells

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