Interleukin-6 stimulates motility of vascular endothelium

  • Eliot M. Rosen
  • David Liu
  • Eva Setter
  • Madhu Bhargava
  • Itzhak D. Goldberg
Part of the Experientia Supplementum book series (EXS, volume 59)


Interleukin-6 (IL-6) is a cytokine which regulates host response to injury. Various preparations of recombinant human IL-6 stimulated migration of bovine brain and bovine aortic endothelial cells, with maximal responses at 100-600 ng/ml. The migration response was inhibited by anti-IL-6 monoclonal antibody. IL-6 also inhibited endothelial cell proliferation in a dose-dependent fashion. Combinations of IL-6 and tumor necrosis factor induced additive stimulation of migration. Studies with inhibitors and stimulators of various metabolic processes suggest that IL-6-induced motility: 1) does not require a pertussis toxin-sensitive G-protein, protein kinase C, or DNA synthesis; and 2) is regulated differently from the motility induced by scatter factor. A possible role for IL-6 in the regulation of physiologic angiogenesis is discussed.


Scatter Factor Bovine Aortic Endothelial Cell Human Breast Carcinoma Cell Line Microcarrier Bead Endothelial Cell Motility 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ashendel, C. L. (1985) The phorbol ester receptor: A phospholipid-regulated protein kinase. Biochim. Biophys. Acta 822: 219–242.Google Scholar
  2. Creasey, A. A., Doyle, L. V., Reynolds, M. T., Jung, T., Lin, L. S., and Vitt, C. R. (1987) Biological effects of recombinant human tumor necrosis factor and its novel muteins on tumor and normal cell lines. Cancer Res. 47: 145–149.Google Scholar
  3. Daviet, I., Herbert, J. M., and Maffrand, J. P. (1990) Involvement of protein kinase C in the mitogenic and Chemotaxis effects of basic fibroblast growth factor on bovine cerebral cortex capillary endothelial cells. FEBS Lett. 259: 315–317.CrossRefGoogle Scholar
  4. Frater-Schroder, M., Risan, W., Hallmann, R., Gautschi, P., and Bohlen, P. (1987) Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro is angiogenic in vivo. PNAS USA 84: 5277–5281.CrossRefGoogle Scholar
  5. Gherardi, E., Grey, J., Stoker, M., Perryman, M., and Furlong, R. (1989) Purification of scatter factor, a fibroblast-derived basic protein which modulates epithelial interactions and movement. PNAS USA 86: 5844–5848.CrossRefGoogle Scholar
  6. Gherardi, E., and Stoker, M. (1990) Hepatocytes and scatter factor. Nature 346: 228 (Correspondence).Google Scholar
  7. Gilman, A. G. (1984) Guanine nucleotide-binding regulating proteins and dual control of adenylate cyclase. J. Clin. Invest. 73: 1–4.CrossRefGoogle Scholar
  8. Gohda, E., Tsubouchi, H., Nakagama, H., Hirono, S., Sakiyama, O., Takahashi, K., Miyazaka, H., Hashimoto, S., and Daikuhara, Y. (1988) Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J. Clin. Invest. 81: 414–419.CrossRefGoogle Scholar
  9. Jaken, S., Feldman, H., Blumberg, P. M., and Tashjian, A. H. Jr. (1983) Association of phorbol ester receptor down modulation with a cryptic receptor state. Cancer Res. 43: 5795–5800.Google Scholar
  10. Kase, H., Iwanashi, K., and Matsuda, Y. (1986) K-252a, a potent inhibitor of protein kinase C from bacterial origin. J. Antibiotics (Tokyo) 39: 1059–1065.CrossRefGoogle Scholar
  11. Küpper, T. S., Min, K., Sehgal, P., Mizutani, H., Birchall, N., Ray, A., and May, L. (1989) Production of IL-6 by keratinocytes. Ann. NY Acad. Sci. 557: 454–465.CrossRefGoogle Scholar
  12. Leibovich, S. J., Polverini, P. J., Shepard, H. M., Wiseman, D. M., Shively, V., and NuScir, N. (1987) Macrophage-induced angiogenesis is mediated by tumor necrosis factor-a. Nature 239: 630–632.CrossRefGoogle Scholar
  13. May, L. T., Santhanam, U., Tatter, S. B., Ghrayeb, J., and Sehgal, P. B. (1989a) Multiple forms of human interleukin-6. Phosphoglycoproteins secreted by many different tissues. Ann. NY Acad. Sci. 557: 114–121.CrossRefGoogle Scholar
  14. May, L. T., Torcia, G., Cozzolino, F., Ray, A., Tatter, S. B., Santhanam, U., Sehgal, P. B., and Stern, D. (1989b) Interleukin-6 gene expression in human endothelial cells: RNA start sites, multiple IL-6 proteins and inhibition of proliferation. Biochem. Biophys. Res. Commun. 159: 991–998.CrossRefGoogle Scholar
  15. Motro, B., Itin, A., Sachs, L., and Keshet, E. (1990) Pattern of interleukin-6 gene expression in vivo suggests a role for this cytokine in angiogenesis. PNAS USA 87: 3092–3096.CrossRefGoogle Scholar
  16. Nakadate, T., Jeng, A. Y., and Blumberg, P. M. (1988) Comparison of protein kinase C functional assays to clarify mechanisms of inhibitor action. Biochem. Pharmacol. 37: 1541–1545.CrossRefGoogle Scholar
  17. Nakamura, T., Nawa, K., Ichihara, A., Kasire, A., and Nishino, T. (1987) Subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett. 224: 331–338.CrossRefGoogle Scholar
  18. Nakuno, H., Kobayashi, E., Takahashi, I., Tamaoki, T., Kuzuu, Y., and Iba, H. (1987) Staurosporine inhibits tyrosine-specific protein kinase activity of Rous sarcoma virus transforming protein p60. Antibiot 40: 706–708.CrossRefGoogle Scholar
  19. Presta, M., Maier, J. A. M., and Ragnotti, G. (1989) The mitogenic signalling pathway but not the plasminogen activator-inducing pathway of basic fibroblast growth factor is mediated through protein kinase C in fetal bovine aortic endothelial cells. J. Cell Biol. 109: 1877–1884.CrossRefGoogle Scholar
  20. Rosen, E. M., Meromsky, L., Setter, E., Vinter, D. W., and Goldberg, I. D. (1990a) Quantitation of cytokine-stimulated migration of endothelium and epithelium by a new assay using microcarrier beads. Exp. Cell Res. 186: 22–31.CrossRefGoogle Scholar
  21. Rosen, E. M., Meromsky, L., Setter, E., Vinter, D. W., and Goldberg, I. D. (1990b) Purification and migration-stimulating activities of scatter factor. Proc. Soc. Exp. Biol. Med. 195: 34–43.Google Scholar
  22. Rosen, E. M., Meromsky, L., Setter, E., Vinter, D. W., and Goldberg, I. D. (1990c) Smooth muscle-derived factor stimulates mobility of human tumor cells. Invas. Metastasis 10: 49–64.Google Scholar
  23. Rosen, E. M., Meromsky, L., Romero, R., Setter, E., and Goldberg, I. (1900d) Human placenta contains an epithelial scatter protein. Biochem. Biophys. Res. Comm. 168: 1082–1088.CrossRefGoogle Scholar
  24. Rosen, E. M., Jaken, S., Carley, W., Setter, E., Bhargava, M., and Goldberg, I. D. (1991) Regulation of motility in bovine brain endothehal cells. J. Cell Physiol. 146: 325–335.CrossRefGoogle Scholar
  25. Sehgal, P. B. (1990a) Minireview. Interleukin 6 in infection and cancer. J. Exp. Med. 90: 183–211.Google Scholar
  26. Sehgal, P. B. (1990b) Interleukin-6: A regulator of plasma protein gene expression in hepatic and non-hepatic tissues. Mol. Biol. Med. 7: 117–130.Google Scholar
  27. Sehgal, P. B., and Tamm, I. (1991) Interleukin-6 enhances motility of breast carcinoma cells, in: Cell Motility Factors, Eds I. D. Goldberg. Birkhauser Verlag, Basel, pp. 178–193. (this volume)Google Scholar
  28. Sholley, M. M., Ferguson, G. P., Scibel, H. R., Montour, J. L., and Wilson, J. D. (1984) Mechanisms of neovascularization. Vascular sprouting can occur without proHferation of endothelial cells. Lab Invest 54: 624–634.Google Scholar
  29. Stoker, M., and Perryman, M. (1985) An epithelial scatter factor released by embryo fibroblasts. J. Cell Sci. 77: 209–223.Google Scholar
  30. Stoker, M., Gherardi, E., Perryman, M., and Gray, J. (1987) Scatter factor is a fibroblast- derived modulator of epithehal cell mobility. Nature 327: 239–242.CrossRefGoogle Scholar
  31. Stoker, M. (1989) Effect of scatter factor on motility of epithelial cells and fibroblasts. J. Cell Physiol. 139: 565–569.CrossRefGoogle Scholar
  32. Stracke, M. L., Guirguis, R., Liotta, L. A., and Schiffman, E. (1987) Pertussis toxin inhibits stimulated motility independently of the adenylate cyclase pathway in human melanoma cells. Biochem. Biophys. Res. Comm. 146: 339–345.CrossRefGoogle Scholar
  33. Takai, Y., Wong, G. G., Clark, S. C., Burakoff, S. J., and Herrmann, S. H. (1988) B cell stimulating factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J. Immunol. 140: 508.Google Scholar
  34. Tamaoki, K., Nomoto, H., Takahashi, I., Kato, Y., Morimoto, M., and Tomita, F. (1986) Staurosporine, a potent inhibitor of phospholipid-calcium dependent protein kinase. Biochem. Biophys. Res. Comm. 135: 397–402.CrossRefGoogle Scholar
  35. Tamm, I. (1989) IL-6. Current research and new questions. Ann. NY Acad. Sci. 557: 478–488.CrossRefGoogle Scholar
  36. Tamm, I., Cardinale, I., Krueger, J., Murphy, J. S., May, L. T., and Sehgal, P. B. (1989) Interleukin-6 decreases cell-cell association and increases motility of ductal breast carcinoma cells. J. Exp. Med. 170: 1649–1669.CrossRefGoogle Scholar
  37. Thomas, K. A. (1987) Fibroblast growth factors. FASEB J1: 434–440.Google Scholar
  38. Valles, A. M., Boyer, B., Badet, J., Tucker, G. C., Barritault, D., and Thiery, J. P. (1990) Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. PNAS USA 87: 1124–1128.CrossRefGoogle Scholar
  39. Weidner, K. M., Behrens, J., Vandekerckhove, J., and Birchmeier, W. (1990) Scatter factor: Molecular characteristics and effect on invasiveness of epithelial cells. J. Cell Biol. 111: 2097–2108.CrossRefGoogle Scholar
  40. Zarnegar, R., and Michalopoulos, G. (1989) Purification and biological characterization of human hepatopoietin A; a polypeptide growth factor hepatocytes. Cancer Res 49: 3314–3320.Google Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 1991

Authors and Affiliations

  • Eliot M. Rosen
    • 1
  • David Liu
    • 2
  • Eva Setter
    • 1
  • Madhu Bhargava
    • 3
  • Itzhak D. Goldberg
    • 3
  1. 1.Department of Therapeutic RadiologyYale University School of MedicineNew HavenUSA
  2. 2.Cetus CorporationEmeryvilleUSA
  3. 3.Department of Radiation OncologyLong Island Jewish Medical CenterNew Hyde ParkUSA

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