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Heparin Inhibits IFN-γ-Induced Fractalkine/CX3CL1 Expression in Human Endothelial Cells

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Abstract

Heparin is primarily used as an anticoagulant but has many biological functions as well. It binds with high affinity to a range of cytokines including interferon-γ (IFN-γ) and members of chemokine superfamily. IFN-γ is a proinflammatory cytokine that plays a pivotal role in immune and inflammatory responses; and in endothelial cells, it regulates the expression of fractalkine/CX3CL1 that is a potent agonist for the chemotaxis and adhesion of monocytes and lymphocytes. We have investigated the effect of heparin on the fractalkine expression in human umbilical vein endothelial cells (HUVEC) in culture. HUVEC were treated with ∼100 μg/mL heparin and the expression of the IFN-γ-induced fractalkine mRNA and protein were measured by reverse transcription-PCR and western blotting. The IFN-γ-induced expressions of fractalkine mRNA and protein were inhibited by heparin in a concentration-dependent manner. Heparin also inhibited adhesion of mononuclear cells (MNC) to HUVEC monolayers stimulated with IFN-γ, but it did not inhibit the MNC adhesion to the monolayers stimulated with interleukin-1β. Electrophoretic analysis demonstrated direct binding of heparin to IFN-γ and heparin was found to partially block the binding of IFN-γ to IFN-γ receptor (IFN-γ R). Heparin may play a regulatory role in inflammatory and immune responses by modulating the interaction between leukocytes and the vascular endothelium.

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REFERENCES

  1. Matzner, Y., G. Marx, R. Drexler, and A. Eldor. 1984. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb. Haemost. 52: 134-137.

    Google Scholar 

  2. Strunk, R. and H. R. Colten. 1976. Inhibition of the enzymatic activity of the first component of complement (C1) by heparin. Clin. Immunol. Immunopathol. 6: 248-255.

    Google Scholar 

  3. Miller, M. D. and M. S. Krangel. 1992. Biology and biochemistry of the chemokines: A family of chemotactic and inflammatory cytokines. Crit. Rev. Immunol. 12: 17-46.

    Google Scholar 

  4. Skinner, M. P., C. M. Lucas, G. F. Burns, C. N. Chesterman, and M. C. Berndt. 1991. GMP-140 binding to neutrophils is inhibited by sulfated glycans. J. Biol. Chem. 266: 5371-5374.

    Google Scholar 

  5. Watt, S. M., J. Williamson, H. Genevier, J. Fawcett, and D. L. Simmonds. 1993. The heparin binding PECAM-1 adhesion molecule is expressed by CD34+ hematopoietic precursor cells with early myeloid and B-lymphoid cell phenotypes. Blood 82: 2649-2663.

    Google Scholar 

  6. Diamond, M. S., R. Alon, C. A. Parkos, M. T. Quinn, and T. M. Springer. 1995. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J. Cell. Biol. 130: 1473-1482.

    Google Scholar 

  7. Koenig, A., K. Norgard-Sumnicht, R. Linhardt, and A. Varki. 1998. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J. Clin. Invest. 101: 877-889.

    Google Scholar 

  8. Bazan, J. F., K. B. Bacon, G. Hardiman, W. Wang, and K. Soo. 1997. A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640-644.

    Google Scholar 

  9. Imaizumi, T., T. Matsumiya, K. Fujimoto, K. Okamoto, and X. Cui. 2000. Interferon-γ stimulates the expression of CX3CL1/fractalkine in cultured human endothelial cells. Tohoku J. Exp. Med. 192: 127-139.

    Google Scholar 

  10. Imai, T., K. Hieshima, C. Haskell, M. Baba, and M. Nagira. 1997. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91: 521-530.

    Google Scholar 

  11. Sadir, R., E. Forest, and H. L. Jacob. 1998. The heparan sulfate binding sequence of interferon-γ increased the on rate of the interferon-γ-interferon-γ receptor complex formation. J. Biol. Chem. 273: 10919-10925.

    Google Scholar 

  12. Camejo, E. H., B. Rosengren, G. Camejo, P. Sartipy, and G. Fager. 1995. Interferon-γ binds to extracellular matrix chondroitin-sulfate proteoglycans, thus enhancing its cellular response. Arterioscler. Thromb. Vasc. Biol. 15: 1456-1465.

    Google Scholar 

  13. Zimmerman, G. A., R. E. Whatley, T. M. McIntyre, D. E. Benson, and S. M. Prescott. 1990. Endothelial cells for studies of platelet-activating factor and arachidonate metabolites. Methods Enzymol. 187: 520-535.

    Google Scholar 

  14. Imaizumi, T., H. Itaya, K. Fujita, D. Kudoh, and S. Kudoh. 2000. Expression of tumor necrosis factor-α in cultured human endothelial cells stimulated with lipopolysaccharide or interleukin-1α. Arterioscler. Thromb. Vasc. Biol. 20: 410-415.

    Google Scholar 

  15. Imaizumi, T., H. Itaya, S. Nasu, H. Yoshida, and Y. Matsumiya. 2000. Expression of vascular endothelial growth factor in human umbilical vein endothelial cells stimulated with interleukin-1α: An autocrine regulation of angiogenesis and inflammatory reactions. Thromb. Haemost. 83: 949-955.

    Google Scholar 

  16. Matsumiya, T., T. Imaizumi, K. Fujimoto, X. Cui, and T. Shibata. 2001. Soluble interleukin-6 receptor α inhibits the cytokine-Induced fractalkine/CX3CL1 expression in human vascular endothelial cells in culture. Exp. Cell Res. 269: 35-41.

    Google Scholar 

  17. Marx, N., G. K. Sukhova, T. Collins, P. Libby, and J. Plutzky. 1999. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99: 3125-3131.

    Google Scholar 

  18. Böyum, A. 1968. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand. J. Clin. Lab. Invest. Suppl. 97: 77-89.

    Google Scholar 

  19. Kjellen, L. and U. Lindahl. 1991. Proteoglycans: Structures and interactions. Annu. Rev. Biochem. 60: 443-475.

    Google Scholar 

  20. Salmivirta, M., K. Lidholt, and U. Lindahl. 1996. Heparan sulfate: A piece of information. FASEB J. 10: 1270-1279.

    Google Scholar 

  21. Taipale, J. and J. Keski-Oja. 1997. Growth factors in the extracellular matrix. FASEB J. 11: 51-59.

    Google Scholar 

  22. Burgess, W. H. and T. Maciag. 1989. The heparin-binding (fibroblast) growth factor family of proteins. Annu. Rev. Biochem. 58: 575-606.

    Google Scholar 

  23. Gitay-Goren, H., S. Soker, I. Vlodavsky, and G. Neufeld. 1992. The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules. J. Biol. Chem. 267: 6093-6098.

    Google Scholar 

  24. Ramsden, L. and C. C. Rider. 1992. Selective and differential binding of interleukin (IL)-1 alpha, IL-1 beta, IL-2 and IL-6 to glycosaminoglycans. Eur. J. Immunol. 22: 3027-3031.

    Google Scholar 

  25. Roberts, R., J. Gallagher, E. Spooncer, T. D. Allen, and F. Bloomfield. 1988. Heparan sulphate bound growth factors: A mechanism for stromal cell mediated haemopoiesis. Nature 332: 376-378.

    Google Scholar 

  26. Lortat-Jacob, H., P. Garrone, J. Banchereau, and J. A. Grimaud. 1997. Human interleukin 4 is a glycosaminoglycan-binding protein. Cytokine 9: 101-105.

    Google Scholar 

  27. Clarke, D., O. Katoh, R. V. Gibbs, S. D. Griffiths, and M. Y. Gordon. 1995. Interaction of interleukin 7 (IL-7) with glycosaminoglycans and its biological relevance. Cytokine 7: 325-330.

    Google Scholar 

  28. Webb, L. M., M. U. Ehrengruber, I. Clark-Lewis, M. Baggiolini, and A. Rot. 1993. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc. Natl. Acad. Sci. U. S. A. 90: 7158-7162.

    Google Scholar 

  29. Lortat-Jacob, H. and J. A. Grimaud. 1992. Binding of interferon-gamma to heparan sulfate is restricted to the heparin-like domains and involves carboxylic—but not N-sulfated—groups. Biochim. Biophys. Acta. 1117: 126-130.

    Google Scholar 

  30. Daubener, W., S. Nockemann, M. Gutsche, and U. Hadding. 1995. Heparin inhibits the antiparasitic and immune modulatory effects of human recombinant interferon-γ. Eur. J. Immunol. 25: 688-692.

    Google Scholar 

  31. Garcia, G. E., Y. Xia, S. Chen, Y. Wang, and R. D. Ye. 2000. NF-κB-dependent fractalkine induction in rat aortic endothelial cells stimulated by IL-1β, TNF-α, and LPS. J. Leukoc. Biol. 67: 577-584.

    Google Scholar 

  32. Young, H. A. and K. J. Hardy. 1995. Role of interferon-γ immune cell regulation. J. Leukoc. Biol. 58: 373-381.

    Google Scholar 

  33. Lee, Y. J. and E. N. Benveniste. 1996. Stat1α expression is involved in IFN-γ induction of the class II transactivator and class II MHC genes. J. Immunol. 157: 1559-1568.

    Google Scholar 

  34. Rebecca, H. L., J. K. Girish, A. H. Lawrence, A. W. Mark, and E. J. David. 1999. Dextran sulfate inhibits IFN-γ-induced Jak–Stat pathway in human vascular endothelial cells. Cell. Immunol. 192: 140-148.

    Google Scholar 

  35. Baba, M., E. De Clercq, D. Schols, R. Pauwels, and R. Snoeck. 1990. Novel sulfated polysaccharides: Dissociation of anti-human immunodeficiency virus activity from antithrombin activity. J. Infect. Dis. 161: 208-213.

    Google Scholar 

  36. Lopalco, L., F. Ciccomascolo, P. Lanza, G. Zoppetti, and I. Caramazza. 1994. Anti-HIV type 1 properties of chemically modified heparins with diminished anticoagulant activity. AIDS Res. Hum. Retroviruses 10: 787-793.

    Google Scholar 

  37. Vandana, B. and R. Murai. 2000. Glycosaminoglycans alter the conformation of interferon-γ. Cytokine 12: 466-471.

    Google Scholar 

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Authors and Affiliations

  1. Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki, Japan

    Masaharu Hatakeyama, Tadaatsu Imaizumi, Wakako Tamo, Koji Yamashita, Hidemi Yoshida & Kei Satoh

  2. The First Department of Surgery, Hirosaki University School of Medicine, Hirosaki, Japan

    Ikuo Fukuda

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  1. Masaharu Hatakeyama
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  2. Tadaatsu Imaizumi
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Correspondence to Tadaatsu Imaizumi.

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Hatakeyama, M., Imaizumi, T., Tamo, W. et al. Heparin Inhibits IFN-γ-Induced Fractalkine/CX3CL1 Expression in Human Endothelial Cells. Inflammation 28, 7–13 (2004). https://doi.org/10.1023/B:IFLA.0000014706.49598.78

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  • DOI: https://doi.org/10.1023/B:IFLA.0000014706.49598.78

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