Thromb Haemost 2008; 99(03): 570-575
DOI: 10.1160/TH07-06-0424
Wound Healing and Inflammation/Infection
Schattauer GmbH

Concentration-dependent roles for heparin in modifying liopolysaccharide-induced activation of mononuclear cells in whole blood

Helene Hochart
1   Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin
,
Vincent P. Jenkins
1   Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin
2   National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin
,
Roger J. S. Preston
1   Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin
,
Owen P. Smith
3   Department of Paediatric Haematology and Oncology, Our Lady’s Hospital for Sick Children, Dublin; Ireland
,
Barry White
1   Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin
2   National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin
,
James O’Donnell
1   Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin
2   National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin
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Publikationsverlauf

Received: 25. Juni 2007

Accepted after major revision: 16. Januar 2008

Publikationsdatum:
07. Dezember 2017 (online)

Summary

In addition to their anticoagulant activity,unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have important immunomodulatory properties. However, different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear.It was the objective of this study to determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide- binding protein (LBP) in mediating this effect. Whole blood was pre-treated with UFH or LMWH (0.1–200 IU/ml), prior to stimulation with LPS (10 ng/ml). After six hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1β, IL-6, IL-8, and TNF-α) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of LBP (50–100 nM). Under serum-free conditions, heparin demonstrated dose-dependent anti-inflammatory effects,significantly reducing secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) in response to LPSstimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1β and IL-8 following LPS-stimulation) of heparin were also observed,but only at supra-therapeutic doses (10–200 IU/ml). Our data demonstrate that in the absence of LBP, the direct effect of heparin on LPS-stimulated monocytes is anti-inflammatory. However in whole blood, the immunomodulatory effects of heparin are significantly more complex, with either pro- or anti-inflammatory effects dependent upon heparin concentration.

 
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