PMID- 18327406
OWN - NLM
STAT- MEDLINE
DCOM- 20080515
LR  - 20080310
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 99
IP  - 3
DP  - 2008 Mar
TI  - Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced 
      activation of mononuclear cells in whole blood.
PG  - 570-5
LID - 10.1160/TH07-06-0424 [doi]
AB  - 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)-1beta, IL-6, IL-8, and TNF-alpha) 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-1beta, IL-6, IL-8, and TNF-alpha) in response to LPS-stimulation 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-1beta 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.
FAU - Hochart, Helene
AU  - Hochart H
AD  - Thrombosis and Haemostasis Research Group, Institute of Molecular Medicine, 
      Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.
FAU - Jenkins, P Vincent
AU  - Jenkins PV
FAU - Preston, Roger J S
AU  - Preston RJ
FAU - Smith, Owen P
AU  - Smith OP
FAU - White, Barry
AU  - White B
FAU - O'Donnell, James
AU  - O'Donnell J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Acute-Phase Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (IL6 protein, human)
RN  - 0 (Immunologic Factors)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (lipopolysaccharide-binding protein)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Acute-Phase Proteins/*metabolism
MH  - Carrier Proteins/*metabolism
MH  - Cell Line
MH  - Cells, Cultured
MH  - Culture Media, Serum-Free
MH  - Dose-Response Relationship, Drug
MH  - Heparin/*pharmacology
MH  - Heparin, Low-Molecular-Weight/pharmacology
MH  - Humans
MH  - Immunologic Factors/*pharmacology
MH  - Inflammation/immunology/*metabolism
MH  - Inflammation Mediators/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Interleukin-6/metabolism
MH  - Interleukin-8/metabolism
MH  - Leukocytes, Mononuclear/*drug effects/immunology/metabolism
MH  - Lipopolysaccharides/*pharmacology
MH  - Membrane Glycoproteins/*metabolism
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2008/03/11 09:00
MHDA- 2008/05/16 09:00
CRDT- 2008/03/11 09:00
PHST- 2008/03/11 09:00 [pubmed]
PHST- 2008/05/16 09:00 [medline]
PHST- 2008/03/11 09:00 [entrez]
AID - 08030570 [pii]
AID - 10.1160/TH07-06-0424 [doi]
PST - ppublish
SO  - Thromb Haemost. 2008 Mar;99(3):570-5. doi: 10.1160/TH07-06-0424.