Heparin inhibits lipopolysaccharide (LPS) binding to leukocytes and LPS-induced cytokine production.
The glycosaminoglycan heparin is known to exhibit anti-inflammatory properties unrelated to its anticoagulant activity. However, in a generalized inflammatory response with implanted or extracorporeal devices, the beneficial effect of heparin coating and/or systemic administration is still unclear as well as the precise mechanisms of action. In the present study, we have first studied the effect of heparin on lipopolysaccharide (LPS)-induced cytokine production by human blood monocytes. Our results indicated that the production of interleukin-1alpha, tumor necrosis factor-alpha, and interleukin-8 was significantly decreased when heparin was simultaneously incubated with Escherichia coli LPS. Because the modulation of heparin on monocyte activation could be mediated by its binding via CD14, the main LPS receptor on monocytes, we then studied the binding of LPS and heparin to leukocytes from human blood and to Chinese hamster ovary cells transfected with the human CD14 gene. The data by flow cytometry showed the binding of biotinylated heparin to leukocytes. Moreover, the experiments performed on leukocytes and on CD14-positive Chinese hamster ovary cells indicated that heparin inhibited LPS binding. From our results, we conclude that: 1. heparin is an effective inhibitor of LPS-induced monocyte activation, and 2. heparin inhibits the binding of LPS to cells via a CD14-independent pathway. This study suggests a potentially important therapeutic application for heparin or heparin analogs to prevent inflammation with biomaterials.
Anastase-Ravion
Sylvie
S
INSERM ERIT-M 0204, X Bichat Hospital, Bât INSERM 13, Universities Paris VII & XIII, 46 rue H Huchard, 75877 Paris Cedex 18, France.
Blondin
Catherine
C
Cholley
Béatrice
B
Haeffner-Cavaillon
Nicole
N
Castellot
John J
JJ
Letourneur
Didier
D
D016207:Cytokines / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D006493:Heparin