Regulation of interleukin‐8 binding and function by heparin and α<sub>2</sub>‐macroglobulin

Ramdin, Lara S.P.; Perks, Beatrice; Sheron, Nick; Shute, Janis K.

doi:10.1046/j.1365-2222.1998.00283.x

Cited by 51 publications

(46 citation statements)

References 41 publications

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“…Subsequently, it was shown that the binding of IL-8 to HUVECs was competed with GAGs in the order of efficacy, heparin Ͼ HS Ͼ dermatan sulfate Ͼ chondroitin sulfate, indicating the relative affinity of IL-8 for heparin and HS (9). Functionally, soluble GAGs had an inhibitory effect on target cell responses, heparin and HS inhibiting IL-8-induced neutrophil calcium fluxes (9), in line with our previous observation that heparin inhibits IL-8-induced neutrophil chemotaxis (21).…”

Section: Discussionsupporting

confidence: 73%

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

Marshall

Ramdin

Brooks³

et al. 2003

The Journal of Immunology

124

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The endothelium is the primary barrier to leukocyte recruitment at sites of inflammation. Neutrophil recruitment is directed by transendothelial gradients of IL-8 that, in vivo, are bound to the endothelial cell surface. We have investigated the identity and function of the binding site(s) in an in vitro model of neutrophil transendothelial migration. In endothelial culture supernatants, IL-8 was detected in a trimolecular complex with heparan sulfate and syndecan-1. Constitutive shedding of IL-8 in this form was increased in the presence of a neutralizing Ab to plasminogen activator inhibitor-1 (PAI-1), indicating a role for endothelial plasminogen activator in the shedding of IL-8. Increased shedding of IL-8/heparan sulfate/syndecan-1 complexes was accompanied by inhibition of neutrophil transendothelial migration, and aprotinin, a potent plasmin inhibitor, reversed this inhibition. Platelets, added as an exogenous source of PAI-1, had no effect on shedding of the complexes or neutrophil migration. Our results indicate that IL-8 is immobilized on the endothelial cell surface through binding to syndecan-1 ectodomains, and that plasmin, generated by endothelial plasminogen activator, induces the shedding of this form of IL-8. PAI-1 appears to stabilize the chemoattractant form of IL-8 at the cell surface and may represent a therapeutic target for novel anti-inflammatory strategies.

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Section: Discussionsupporting

confidence: 73%

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

Marshall

Ramdin

Brooks³

et al. 2003

The Journal of Immunology

124

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“…While binding does not necessarily imply an effect on function, we showed an inhibitory effect of heparin on IL-8-induced neutrophil chemotaxis in microBoyden chambers (43). These observations have since been confirmed and extended to the inhibitory effect of heparin on IL-8 bound to endothelial cell surface heparan sulfate proteoglycans (44).…”

Section: Discussionsupporting

confidence: 63%

IL-8 Released Constitutively by Primary Bronchial Epithelial Cells in Culture Forms an Inactive Complex with Secretory Component

Marshall

Perks

Ferkol

et al. 2001

The Journal of Immunology

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The bronchial epithelium is a source of both α and β chemokines and, uniquely, of secretory component (SC), the extracellular ligand-binding domain of the polymeric IgA receptor. Ig superfamily relatives of SC, such as IgG and α2-macroglobulin, bind IL-8. Therefore, we tested the hypothesis that SC binds IL-8, modifying its activity as a neutrophil chemoattractant. Primary bronchial epithelial cells were cultured under conditions to optimize SC synthesis. The chemokines IL-8, epithelial neutrophil-activating peptide-78, growth-related oncogene α, and RANTES were released constitutively by epithelial cells from both normal and asthmatic donors and detected in high m.w. complexes with SC. There were no qualitative differences in the production of SC-chemokine complexes by epithelial cells from normal or asthmatic donors, and in all cases this was the only form of chemokine detected. SC contains 15% N-linked carbohydrate, and complete deglycosylation with peptide N-glycosidase F abolished IL-8 binding. In micro-Boyden chamber assays, no IL-8-dependent neutrophil chemotactic responses to epithelial culture supernatants could be demonstrated. SC dose-dependently (IC50 ∼0.3 nM) inhibited the neutrophil chemotactic response to rIL-8 (10 nM) in micro-Boyden chamber assays and also inhibited IL-8-mediated neutrophil transendothelial migration. SC inhibited the binding of IL-8 to nonspecific binding sites on polycarbonate filters and endothelial cell monolayers, and therefore the formation of haptotactic gradients, without effects on IL-8 binding to specific receptors on neutrophils. The data indicate that in the airways IL-8 may be solubilized and inactivated by binding to SC.

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“…Furthermore, heparin has displayed a diverse range of in vitro antiinflammatory and immunomodulatory effects, including inhibitory effects upon leukocyte recruitment [15], neutrophil chemotaxis [16], neutrophil elastase [17] and chemokines, such as IL-8 [18]. Excess neutrophil elastase activity plays a key role in contributing to airway obstruction in CF by multiple mechanisms, including stimulating IL-8 production [19] and mucus secretion [20], impairing ciliary function [21], and potentially desiccating airway secretions by activating epithelial sodium channels [22].…”

mentioning

confidence: 99%

Inhaled heparin in cystic fibrosis

Serisier

Shute²,

Hockey³

et al. 2006

European Respiratory Journal

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Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possible in vivo mucolytic and anti-inflammatory outcomes.A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean¡SD age 23¡7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1¡15.56%) completed the study protocol.Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers.The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.

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Regulation of interleukin‐8 binding and function by heparin and α₂‐macroglobulin

Abstract: These results point to an anti-inflammatory role for heparin and a novel, potentially, pro-inflammatory role for alpha2-macroglobulin which together indicate the importance of cytokine-binding macromolecules in determining net cytokine function.

Cited by 51 publications

References 41 publications

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

IL-8 Released Constitutively by Primary Bronchial Epithelial Cells in Culture Forms an Inactive Complex with Secretory Component

Inhaled heparin in cystic fibrosis

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Regulation of interleukin‐8 binding and function by heparin and α2‐macroglobulin

Abstract: These results point to an anti-inflammatory role for heparin and a novel, potentially, pro-inflammatory role for alpha2-macroglobulin which together indicate the importance of cytokine-binding macromolecules in determining net cytokine function.

Cited by 51 publications

References 41 publications

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

IL-8 Released Constitutively by Primary Bronchial Epithelial Cells in Culture Forms an Inactive Complex with Secretory Component

Inhaled heparin in cystic fibrosis

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Regulation of interleukin‐8 binding and function by heparin and α₂‐macroglobulin