Disaccharides generated from heparan sulphate or heparin modulate chemokine‐induced T‐cell adhesion to extracellular matrix

Hershkoviz, Rami; Schor, Hagai; Ariel, Amiram; Hecht, Iris; Cohen, Irun R.; Lider, Ofer; Cahalon, Liora

doi:10.1046/j.1365-2567.2000.00931.x

Cited by 22 publications

(9 citation statements)

References 28 publications

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“…A number of explanations have been put forward to elucidate the mechanism by which the DS molecules inhibit chemokineinduced adhesion and migration. It was suggested that the ability of DS molecules to inhibit CXCL12-induced responses, as shown here and in previous studies [38], might result from their direct interaction with the chemokine, thus affecting the chemokine's function. Indeed, function-altering interactions between glycosaminoglycans and chemokines have been reported previously [39 -42].…”

Section: Discussionsupporting

confidence: 74%

Heparin-disaccharide affects T cells: inhibition of NF-κB activation, cell migration, and modulation of intracellular signaling

Hecht

Hershkoviz

Lapidot

et al. 2004

Journal of Leukocyte Biology

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We previously reported that disaccharides (DS), generated by enzymatic degradation of heparin or heparan sulfate, inhibit T cell-mediated immune reactions in rodents and regulate cytokine [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-8, and IL-1beta] secretion by T cells, macrophages, or intestinal epithelial cells. Here, we investigated the effects of a trisulfated heparin DS (3S-DS) on two aspects of T cell function: secretion of proinflammatory cytokines and migration to an inflamed site. 3S-DS down-regulated nuclear factor-kappaB activity and reduced the secretion of TNF-alpha and interferon-gamma (IFN-gamma) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1alpha)-dependent migration in vitro and in vivo and decreased CXCL12-induced T cell adhesion to the extracellular matrix glycoprotein, fibronectin (FN). This inhibition was accompanied by attenuation of CXCL12-induced Pyk2 phosphorylation but did not involve internalization of the CXCL12 receptor, CXCR4, or phosphorylation of extracellular-regulated kinase. Despite inhibiting CXCL12-induced adhesion, 3S-DS, on its own, induced T cell adhesion to FN, which was accompanied by phosphorylation of Pyk2. A monosulfated DS showed no effect. Taken together, these data provide evidence that 3S-DS can regulate inflammation by inducing and modulating T cell-signaling events, desensitizing CXCR4, and modulating T cell receptor-induced responses.

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Section: Discussionsupporting

confidence: 74%

Heparin-disaccharide affects T cells: inhibition of NF-κB activation, cell migration, and modulation of intracellular signaling

Hecht

Hershkoviz

Lapidot

et al. 2004

Journal of Leukocyte Biology

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“…In most examples, these saccharides share no common structural elements with GXM, and sulfation or phosphorylation appears essential for their effects. However, smaller nonsulfated or phosphorylated sugars, such as L-fucose, D-mannose, and disaccharides derived from heparin, also affect leukocyte adhesion (67,68). Although heparin has been shown to bind CD11b/CD18 and P-selectin (69,70), no specific receptors on leukocytes have been identified for the other carbohydrates.…”

Section: Discussionmentioning

confidence: 99%

O-Acetylation of Cryptococcal Capsular Glucuronoxylomannan Is Essential for Interference with Neutrophil Migration

Ellerbroek

Lefeber

Veghel

et al. 2004

The Journal of Immunology

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The capsular polysaccharide glucuronoxylomannan (GXM) of Cryptococcus neoformans has been shown to interfere with neutrophil migration. Although several receptors have been implied to mediate this process, the structural perspectives are unknown. Here, we assess the contribution of 6-O-acetylation and xylose substitution of the (1→3)-α-d-mannan backbone of GXM, the variable structural features of GXM, to the interference with neutrophil migration. We compare chemically deacetylated GXM and acetyl- or xylose-deficient GXM from genetically modified strains with wild-type GXM in their ability to inhibit the different phases of neutrophil migration. Additionally, we verify the effects of de-O-acetylation on neutrophil migration in vivo. De-O-acetylation caused a dramatic reduction of the inhibitory capacity of GXM in the in vitro assays for neutrophil chemokinesis, rolling on E-selectin and firm adhesion to endothelium. Genetic removal of xylose only marginally reduced the ability of GXM to reduce firm adhesion. In vivo, chemical deacetylation of GXM significantly reduced its ability to interfere with neutrophil recruitment in a model of myocardial ischemia (65% reduction vs a nonsignificant reduction in tissue myeloperoxidase, respectively). Our findings indicate that 6-O-acetylated mannose of GXM is a crucial motive for the inhibition of neutrophil recruitment.

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“…Growing evidence has supported that heparin could modulate immune responses (27)(28)(29), and there are specific binding sites for heparin on monocytes (30). However, there has been no report regarding the effect of heparin on the differentiation of DCs from monocytes.…”

Section: Discussionmentioning

confidence: 99%

Heparin Induces Differentiation of CD1a+ Dendritic Cells from Monocytes: Phenotypic and Functional Characterization

Xia

Kao

2002

The Journal of Immunology

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Dendritic cells (DCs) play important roles in initiation and regulation of immune responses. DCs derived from human monocytes can be classified according to presence of CD1a molecules. Although CD1a+ DCs can be prepared from monocytes in media containing GM-CSF, IL-4, and FCS, it has been reported that CD1a+ DCs could not be easily obtained from monocytes using media containing human serum or plasma. In this study, we demonstrate for the first time that heparin can reliably induce differentiation of CD1a+ DCs from monocytes with or without autologous serum or plasma. The development of CD1a+ DCs is heparin concentration dependent (0–50 U/ml). Comparing with CD1a− DCs developed without heparin, CD1a+ DCs express higher CD40 and CD80 and lower CD86. Both CD1a+ and CD1a− DCs express similar levels of HLA-DR. CD80, CD86, HLA-DR, and CD40 are proportionally up-regulated when both types of DCs are stimulated with LPS or LPS plus IFN-γ. The effect of heparin is neutralized by heparin-binding proteins, such as protamine sulfate, platelet factor-4, and β-thromboglobulin. Functionally, heparin-treated DCs respond to LPS or LPS plus IFN-γ with higher IL-10 and less IL-12 production than heparin-untreated DCs. Heparin-treated DCs are more potent in priming allogeneic and autologous CD4+ T cells to proliferate and to produce both type 1 and type 2 cytokines. The results of our study show that CD1a+ DCs can be prepared from monocytes ex vivo without using xenogeneic serum and may be used for immunotherapy.

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Disaccharides generated from heparan sulphate or heparin modulate chemokine‐induced T‐cell adhesion to extracellular matrix

Cited by 22 publications

References 28 publications

Heparin-disaccharide affects T cells: inhibition of NF-κB activation, cell migration, and modulation of intracellular signaling

Heparin-disaccharide affects T cells: inhibition of NF-κB activation, cell migration, and modulation of intracellular signaling

O-Acetylation of Cryptococcal Capsular Glucuronoxylomannan Is Essential for Interference with Neutrophil Migration

Heparin Induces Differentiation of CD1a+ Dendritic Cells from Monocytes: Phenotypic and Functional Characterization

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