Abstract
We analyzed the influence of heparins (unfractionated heparin, UFH and low molecular weight heparin certoparin) on the generation of IL-1ra, IL-6, IL-10, and IL-12p40 and from leukocyte fractions in vitro. Polymorphonuclear neutrophil leukocytes (PMN) and peripheral blood mononuclear cells (PBMC) from 16 different healthy donors were isolated and adjusted to 1 × 106 cells/ml supplemented RPMI 1640. Leukocyte fractions were differentially stimulated (PMN with 1 μg and 5 μg LPS, PBMC with 10 ng TSST-1 or 2 μg ConA) in the presence or absence of heparins (1 U/ml, 2 U/ml, and 4 U/ml) for 24 h at 37°C. Cytokine release was analyzed by ELISA. Certoparin but not UFH led to a dose-dependent increase in IL-6 from non-stimulated PBMC. In contrast, the release of IL-1ra, IL-10, and IL-12p40 was not modulated by heparins in a dose-dependent fashion. Increases in these cytokines occurred only as single incidents at intermediate heparin levels. An influence of the heparins on the apoptosis of PMN (measured as DNA-fragmentation in non-stimulated or LPS-stimulated cell-fractions) was not observed.
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References
Fareed, J., D. A. Hoppensteadt, and R. L. Bick. 2000. An update on heparins at the beginning of the new millennium. Semin. Thromb. Hemost. 26(Suppl 1):5–21
Weitz, J. I. 1997. Low-molecular-weight heparins. New Engl. J. Med. 337:688–698.
Lever, R., J. R. Hoult, and C. P. Page. 2000. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro. Br. J. Pharmacol. 129: 533–540.
Donata, P., T. Qutob, W. Hamouda, F. Bakri, A. Aljada, and Y. Kumbkarni. 1999. Heparin inhibits reactive oxygen species generation by polymorphonuclear and mononuclear leucocytes. Thromb. Res. 96:437–443.
Nelson, R. M., O. Cecconi, W. G. Roberts, A. Aruffo, R. J. Linhardt, and M. P. Bevilacqua. 1993. Heparin oligosaccharides bind L-and P-selectin and inhibit acute inflammation. Blood 82:3253–3258.
McBride, W. T., M. A. Armstrong, and T. J. McMurray. 1996. An investigation of the effects of heparin, low molecular weight heparin, protamine, and fentanyl on the balance of pro-and antiinflammatory cytokines in in-vitro monocyte cultures. Anaesthesia 51:634–640.
Heinzelmann, M., M. Miller, A. Platz, L. E. Gordon, D. O. Herzig, H. C. Polk Jr. 1999. Heparin and enoxaparin enhance endotoxininduced tumor necrosis factor-alpha production in human monocytes. Ann. Surg. 229:542–550.
Call D. R., and D. G. Remick. 1998. Low molecular weight heparin is associated with greater cytokine production in a stimulated whole blood model. Shock 10:192–197.
Baram, D., M. Rashkovsky, R. Hershkoviz, I. Drucker, T. Reshef, S. Ben-Shitrit, and Y. A. Mekori. 1997. Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation. Clin. Exp. Immunol. 110:485–491.
Engstad, C. S., T. J. Gutteberg, and B. Osterud. 1997. Modulation of blood cell activation by four commonly used anticoagulants. Thromb. Haemost. 77:690–696.
English, D., and B. R. Andersen. 1974. Single step separation of red blood cells, granulocytes and mononuclear leukocytes on discontinuous density gradient of ficoll-hypaque. J. Immunol. Methods 5:249–252.
Köller, M., P. Wachtler, A David, G. Muhr, and W. König. 1997. Arachidonic acid induces DNA-fragmentation in human polymorphonuclear neutrophil granulocytes. Inflammation 21:463–474.
Altstaedt, J., H. Kirchner, and L. Rink. 1996. Cytokine production of neutrophils is limited to interleukin-8. Immunology 89:563–568.
Sweeney, J. F., P. K. Nguyen, G. M. Omann, and D. B. Hinshaw. 1997. Ultraviolet irradiation accelerates apoptosis in human polymorphonuclear leukocytes: protection by LPS and GM-CSF. J. Leuko. Biol. 62:517–523.
Esmon, C. T., K. Fukudome, T. Mather, W. Bode, L. M. Regan, D. J. Stearns-Kurosawa, and S. Kurosawa. 1999. Inflammation, sepsis, and coagulation. Haematologica 84:254–259.
Hoffman, M., and S. T. Cooper. 1995. Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. Blood Cells Mol. Dis. 21:156–167.
Dinarello, C. A. 1998. Interleukin-1. In: The Cytokine Handbook. Ed. A. Thomson. Academic Press, San Diego, pp. 35–72.
Tilg, H., C. A. Dinarello, and J. W. Mier. 1997. IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol. Today 9:428–432.
De Waal Malefyt, R., H. Yssel, M. G. Roncarolo, H. Spits, and J. E. De Vries. 1992. Interleukin-10. Curr. Opinion Immunol. 4:314–320.
Storkus, W. J., H. Tahara, and M. T Lotze. 1998. Interleukin-12. In: The Cytokine Handbook. Ed. A. Thomson. Academic Press, San Diego, pp. 391–426.
Darien, B. J., J. Fareed, K. S. Centgraf, A. P. Hart, P. S. MacWilliams, M. K. Clayton, H. Wolf, and K. T. Kruse-Elliott. 1998. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 9:274–281.
Schwartz, D., D. Engelhard, R. Gallily, I. Matoth, and T. Brenner. 1998. Glial cells production of inflammatory mediators induced by Streptococcuspneumoniae: inhibition by pentoxifylline, lowmolecular-weight heparin and dexamethasone. J. Neurol. Sci. 18:13–22.
Mummery, R. S., and C. C. Rider. 2000. Characterization of the heparin-binding properties of IL-6. J. Immunol. 165:5671–5679.
Balasubramanian, V., and M. Ramanathan. 2000. Glycosaminoglycans alter the conformation of interferon-gamma. Cytokine 12:466–471.
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Köller, M., Kutscha-Lissberg, F., Brom, J. et al. Influence of Low Molecular Weight Heparin (Certoparin) and Unfractionated Heparin on the Release of Cytokines from Human Leukocytes. Inflammation 25, 331–337 (2001). https://doi.org/10.1023/A:1012883916991
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DOI: https://doi.org/10.1023/A:1012883916991