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Inhibition of angiogenesis in rats by IL-1 receptor antagonist and selected cytokine antibodies

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Abstract

Daily administration of 50 ng recombinant human interleukin 1-alpha (IL-1α), 25 ng IL-8, 50 ng tumor necrosis factor-alpha (TNF-α), or 100 ng basic fibroblast growth factor (bFGF) caused intense neovascularization in a rat sponge model. These cytokine-induced neovascular responses were inhibited by coadministration of IL-1 receptor antagonist (IL-1ra; 50 μg), IL-8 antiserum (IL-8-AS; 1∶1000), TNF-α antibody (TNF-AB; 500 ng), or a monoclonal antibody to bFGF (DG2; 1000 ng), respectively. These data suggest that it is possible to manipulate the angiogenic response elicited by a defined cytokine by its receptor antagonist or neutralizing antibody. In the absence of exogenous cytokines, the sponge-induced angiogenesis was profoundly suppressed by dexamethasone (5μg/day), but not modified by IL-1ra, IL-8-AS, TNF-AB, and DG2 alone. However, the combination of these four reagents was able to inhibit the sponge-induced neovascular response almost completely. These findings provide direct evidence that IL-1α, IL-8, TNF-α and/or bFGF have an intrinsic role in angiogenesis. Further work is necessary to characterize the profile of these cytokines during angiogenesis and to elucidate the nature of their interactions.

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References

  1. Folkman, J., andD. E. Ingber. 1987. Angiostatic steroids: Method of discovery and mechanism of action.Ann. Surg. 206:374–383.

    PubMed  Google Scholar 

  2. Sunderkotter, C., M. Goebeler, K. Schulze-Osthoff, R. Bhardwaj, andC. Sorg. 1991. Macrophage-derived angiogenesis factors.Pharmacol. Ther. 51:195–216.

    PubMed  Google Scholar 

  3. Fan, T.-P. D., andS. Brem. 1992. Angiosuppression.In The Search for New Anti-Cancer Drugs. M. J. Waring and B. J. Ponder, editors. Cancer Biology Series, Vol. 3, Kluwer Academic Publishers, Lancaster, U.K. 185–229.

    Google Scholar 

  4. Hu, D. E., andT.-P. D. Fan. 1993. [Leu8]des-Arg9-bradykinin inhibits the synergistic interaction between bradykinin and interleukin-1 in angiogenesis.Br. J. Pharmacol. 109:14–17.

    PubMed  Google Scholar 

  5. Fan, T.-P. D., Hu, D. E., Guard, S., Gresham, G. A. andK. J. Watling. 1993. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK, or interleukin-1 receptor antagonists.Br. J. Pharmacol. 110:43–49.

    PubMed  Google Scholar 

  6. Henderson, B., andS. Blake. 1992. Therapeutic potential of cytokine manipulation.Trends Pharmacol. Sci. 13:145–152.

    PubMed  Google Scholar 

  7. Hu, D. E., Y.Hori, and T. -P. D.Fan. 1992. Comparative studies on the angiogenic activity of IL-1 and IL-8 in a rat sponge mdodel.Br. J. Pharmacol. 106:103P.

  8. Andrade, S. P., T.-P. D. Fan, andG. P. Lewis. 1987. Quantitative in vivo studies on angiogenesis in a rat sponge model.Br. J. Exp. Pathol. 68:755–766.

    PubMed  Google Scholar 

  9. Fan, T.-P. D., D. E. Hu, R. L. Smither, andG. A. Gresham. 1992. Further studies on angiogenesis in a rat sponge model.In Angiogenesis. R. Steiner, P. B. Weisz, and R. Langer, editors. Brikhauser Verlag, Basel. 308–314.

    Google Scholar 

  10. Fan, T. P. D., D. E. Hu, andC. R. Hiley. 1992. Development and validation of a sponge model for quantitative studies on angiogenesis.In Angiogenesis in Health and Diseases. M. E. Maragoudakis, P. Gullino, and P. I. Lelkes, editors. Plenum Press, New York. 317–332.

    Google Scholar 

  11. Hu, D. E., C. R.Hiley, and T. -P. D.Fan. 1992. Parallel studies of 133Xe clearance and 113Sn microsphere accumulation during sponge-induced angiogenesis and the effects of interleukin-1a.Br. J. Pharmacol. 106:102P.

  12. Hu, D. E., R. L.Smither, T. -P. D.Fan, and G. A.Gresham. 1992. Validation of the rat sponge model for quantitative studies on angiogenesis.Br. J. Pharmacol. 105:211P.

  13. Dinarello, C.A. 1991. Interleukin-1 and interleukin-1 antagonism.Blood 77:1627–1652.

    PubMed  Google Scholar 

  14. Dayer, J. M., C. Zavadil-Grob, C. Ucla, andB. Mach. 1984. Induction of human interleukin-1 mRNA measured by collagenase and prostaglandin E2 stimulating activity in rheumatoid synovial cells.Eur. J. Immunol. 14:898–901.

    PubMed  Google Scholar 

  15. Detmar, M., S. Tenorio, U. Hettmannsperger, Z. Ruszczak, andC. E. Orfanos. 1992. Cytokine regulation of proliferation and ICAM-1 expression of human dermal microvascular endothelial-cells in vitro.Invest. Dermatol. 98:147–153.

    Google Scholar 

  16. Libby, P., S. J. C. Warner, andG. B. Friedman. 1988. Interleukin 1: A mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids.J. Clin. Invest. 81:487–498.

    PubMed  Google Scholar 

  17. Libby, P., D. J. Wyler, M. W. Janicka, andC. A. Dinarello. 1985. Differential effects of human interleukin-1 on growth of human fibroblasts and vascular smooth muscle cells.Arteriosclerosis 5:186–191.

    PubMed  Google Scholar 

  18. Leibovich, S. J., P. J. Polverini, H. M. Shepard, D. M. Wiseman, V. Shively, andN. Niseir. 1987. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α.Nature 329:630–632.

    PubMed  Google Scholar 

  19. Koch, A. E., P. J. Polverini, S. L. Kunkel, L. A. Harlow, A. Dipietro, M. Elner, S. G. Elner, andR. M. Strieter. 1992. Interleukin-8 as a macrophage-derived mediator of angiogenesis.Science 258:1798–1801.

    PubMed  Google Scholar 

  20. Broadley, K. N., A. M. Aquino, S. C. Woodward, A. Buckley-Sturrock, Y. Sato, D. B. Rifkin, andJ. M. Davidson. 1989. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair.Lab. Invest. 61:571–575.

    PubMed  Google Scholar 

  21. Reilly, T. M., D. S. Taylor, W. F. Herblin, M. J. Thoolen, A. T. Chiu, D. W. Watson, andP. B. M. W. M. Timmermans. 1989. Monoclonal antibodies directed against basic fibroblast growth factor which inhibit its biological activity in vitro and in vivo.Biochem. Biophys. Res. Commun. 164:736–743.

    PubMed  Google Scholar 

  22. Ford, H. R., R. A. Hoffman, E. J. Wing, D. M. Magee, L. McIntyre, andR. L. Simmons. 1989. Characterization of wound cytokines in the sponge matrix model.Arch. Surg. 124:1422–1428.

    PubMed  Google Scholar 

  23. Ford, H. R., R. A. Hoffman, E. J. Wing, D. M. Magee, L. A. McIntyre, andR. L. Simmons. 1990. Tumor necrosis factor, macrophage colony-stimulating factor, and interleukin 1 production within sponge matrix allografts.Transplantation 50:460–466.

    PubMed  Google Scholar 

  24. Smither, R. L., andT.-P. D. Fan. 1991. Role of arachidonic acid metabolites in angiogenesis in a rat sponge model.Int. J. Radiat. Biol. 60(1/2):48.

    Google Scholar 

  25. Folkman, J., andM. Klagsbrun. 1987. Angiogenic factors.Science 235:442–447.

    PubMed  Google Scholar 

  26. Ziche, M., M. Ruggiero, F. Pasquali, andV. P. Chiarugi. 1985. Effects of cortisone with and without heparin on angiogenesis induced by prostaglandin E1 and by S180 cells, and on the growth of murine transplantable tumors.Int. J. Cancer 35:549–552.

    PubMed  Google Scholar 

  27. Inoue, K., H. Korenaga, N. G. Tanaka, N. Sakamoto, andS. Kadoya. 1988. The sulfated polysaccharide-peptidoglycan complex potently inhibits embryonic angiogenesis and tumor growth in the presence of cortisone acetate.Carbohydr. Res. 181:135–142.

    PubMed  Google Scholar 

  28. Maragoudakis, M. E., M. Sarmonika, andM. Panoutsacopoulou. 1989. Antiangiogenic action of heparin plus cortisone is associated with decreased collagenous protein synthesis in the chick chorioallantoic membrane.J. Pharmacol. Exp. Ther. 25:679–682.

    Google Scholar 

  29. Wilks, J. W., P. S. Scott, L. K. Vrba, andJ. M. Cocuzza. 1991. Inhibition of angiogenesis with combination treatments of angiostatic steroids and suramin.Int. J. Radiat. Biol. 60:73–77.

    PubMed  Google Scholar 

  30. Hori, Y., D. E.Hu., T.-P. D.Fan, and G. A.Gresham. 1992. Effects of glucocorticoids and angiostatic steroids on sponge-induced angiogenesis in rats.Br. J. Pharmacol. 105:212P.

  31. Lee, S. W., A.-P. Tsou, H. Chan, J. Thomas, K. Petrie, E. M. Eugui, andA. C. Allison. 1988. Glucocorticoids selectively inhibit the transcription of the interleukin 1β gene and decrease the stability of interleukin 1β mRNA.Proc. Natl. Acad. Sci. U.S.A. 85:1204–1208.

    PubMed  Google Scholar 

  32. Gay, C. G., andJ. A. Winkles. 1991. Interleukin 1 regulates heparin-binding growth factor 2 gene expression in vascular smooth muscle cells.Proc. Natl. Acad. Sci. U.S.A. 88:296–300.

    PubMed  Google Scholar 

  33. Folkman, J., R. Langer, R. J. Linhardt, C. Haudenschild, andS. Taylor. 1983. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone.Science 221:719–725.

    PubMed  Google Scholar 

  34. Hu, D. E., and T. -P. D.Fan. 1992. The combined use of dehydroepiandrosterone and dexamethasone inhibits angiogenesis in the rat without causing immunosuppression.Br. J. Pharmacol. 107:260P.

  35. Hu, D. E., Y. Hori, andT.-P. D. Fan. 1993. Interleukin 8 stimulates angiogenesis in rats.Inflammation 17:135–143.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, University of Cambridge, Tennis Court Road, CB2 1QJ, Cambridge, UK

    D. E. Hu, Y. Hori & T. P. Fan

  2. Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy

    M. Presta

  3. Department of Histopathology, Addenbrooke's Hospital, CB2 2QQ, Cambridge, UK

    G. A. Gresham

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  1. D. E. Hu
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  2. Y. Hori
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  4. G. A. Gresham
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  5. T. P. Fan
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Hu, D.E., Hori, Y., Presta, M. et al. Inhibition of angiogenesis in rats by IL-1 receptor antagonist and selected cytokine antibodies. Inflammation 18, 45–58 (1994). https://doi.org/10.1007/BF01534597

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