Heparin-binding Sites in Granulocyte-Macrophage Colony-stimulating Factor

Sebollela, Adriano; Cagliari, Thiago C.; Limaverde, Gabriel S.C.S.; Chapeaurouge, Alex; Sorgine, Marcos Henrique Ferreira; Coelho‐Sampaio, Tatiana; Ramos, Carlos H.I.; Ferreira, Sérgio T.

doi:10.1074/jbc.m505314200

Cited by 39 publications

(38 citation statements)

References 46 publications

(57 reference statements)

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“…5A). A similar mechanism of interaction has been reported for GM-CSF, whereby protonation of two histidine residues in helix C of GM-CSF acts as a pH-dependent switch to control GAG interactions (49). Of particular interest, analogous to IL-18 and in contrast to IL-8, reduced CF BALF levels of GM-CSF have been reported compared with non-CF controls (50).…”

Section: Discussionmentioning

confidence: 83%

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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Section: Discussionmentioning

confidence: 83%

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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“…However, an interaction of GM-CSF with GAGs is only present at a low pH because of protonation of His 83 and His 87 in helix C of GM-CSF, which act as a pH-dependent molecular switch (49). Interaction between GM-CSF and GAGs is absent at a pH of 7 or higher.…”

Section: Discussionmentioning

confidence: 99%

Monocyte Cell Surface Glycosaminoglycans Positively Modulate IL-4-Induced Differentiation toward Dendritic Cells

Dekker

Grefte

Huijs

et al. 2008

The Journal of Immunology

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IL-4 induces the differentiation of monocytes toward dendritic cells (DCs). The activity of many cytokines is modulated by glycosaminoglycans (GAGs). In this study, we explored the effect of GAGs on the IL-4-induced differentiation of monocytes toward DCs. IL-4 dose-dependently up-regulated the expression of DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), CD80, CD206, and CD1a. Monocytes stained positive with Abs against heparan sulfate (HS) and chondroitin sulfate (CS) B (CSB; dermatan sulfate), but not with Abs that recognize CSA, CSC, and CSE. Inhibition of sulfation of monocyte/DC cell surface GAGs by sodium chlorate reduced the reactivity of sulfate-recognizing single-chain Abs. This correlated with hampered IL-4-induced DC differentiation as evidenced by lower expression of DC-SIGN and CD1a and a decreased DC-induced PBL proliferation, suggesting that sulfated monocyte cell surface GAGs support IL-4 activity. Furthermore, removal of cell surface chondroitin sulfates by chondroitinase ABC strongly impaired IL-4-induced STAT6 phosphorylation, whereas removal of HS by heparinase III had only a weak inhibitory effect. IL-4 bound to heparin and CSB, but not to HS, CSA, CSC, CSD, and CSE. Binding of IL-4 required iduronic acid, an N-sulfate group (heparin) and specific O sulfates (CSB and heparin). Together, these data demonstrate that monocyte cell surface chondroitin sulfates play an important role in the IL-4-driven differentiation of monocytes into DCs.

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“…However, pH-dependent interaction between GM-CSF and heparin has been described, and three histidine residues identified as important for binding [42]. In the crystal structures, these residues are not exposed, but it is possible this is not the case for the solution structure at low pH.…”

Section: Short-chain Cytokinesmentioning

confidence: 99%

Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

Mulloy

Forster

2008

Molecular Simulation

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Heparin-binding Sites in Granulocyte-Macrophage Colony-stimulating Factor

Cited by 39 publications

References 46 publications

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

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

Monocyte Cell Surface Glycosaminoglycans Positively Modulate IL-4-Induced Differentiation toward Dendritic Cells

Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

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