Abstract
To test the hypothesis that the cytokines interleukin-6 (IL-6) and IL-8 may play regulatory roles in the aberrant neovascularization in chronic inflammatory diseases, we examined their effects in a rat sponge model and compared their actions with those of IL-1 and lumor necrosis factor-α (TNF-α). Daily doses of 3 pmol IL-8, IL-1, TNF-α, but nol IL-6, significantly accelerated the sponge-induced angio-genesis. Although lower doses (0.3 pmol) of these cytokines were inactive, IL-1 acted synergistically with subthreshold daily doses (10 pmol) of substance P (SP) and bradykinin (BK) to produce an intense angiogenic response. In contrast, IL-8 only interacted positively with IL-1, but not TNF-α, SP, or BK. There was no synergism or antagonism between IL-6 and SP. These results demonstrate the discrete interactions between angiogenic factors and cytokines in chronic inflammation and suggest that the sponge model is a good means for the study of such interactions.
Similar content being viewed by others
References
Folkman, J., andM. Klagsbrun. 1987. Angiogenic factors.Science 235:442–447.
Brown, R., J. B. Weiss, I. W. Tomlinson, P. Phillips, andS. Kumar. 1980. Angiogenic factor from synovial fluid resembling that from tumors.Lancet 1:682–685.
Fontana, A., H. Hengartner, E. Weber, K. Fehr, P. J. Grob, andG. Cohen. 1982. Interleukin-1 activity in the synovial-fluid of patients with rheumatoid-arthritis.Rheumatol. Int. 2:9.
Hopkins, S. J., andA. Meager. 1988. Cytokines in synovial fluid. 2. The presence of tumor necrosis factor and Interferon.Clin. Exp. Immunol. 73:88–92.
Hirano, T., S. Akira, T. Taga, andT. Kishimoto. 1990. Biological and clinical aspects of interleukin-6.Immunol. Today 11:443–449.
Koch, A. E., S. L. Kunkel, J. C. Burrows, H. L. Evanoff, G. K. Haines, R. M. Pope, andR. M. Strieter. 1991. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8.J. Immunol. 147:2187–2195.
Leibovich, S. J., P. J. Polverini, H. M. Shepard, D. M. Wiseman, V. Shively, andN. Nuseir. 1987. Macrophage-induced angiogenesis is mediated by tumor necrosis factor-alpha.Nature 329:630–632.
Mahadevan, V., I. R. Hart, andG. P. Lewis. 1989. Factors influencing blood-supply in wound granuloma qantitated by a new in vivo technique.Cancer Res. 49:415–419.
May, L. T., G. Torcia, F. Cozzolino, A. Ray, S. B. Tatter, U. Santhanam, P. B. Sehgal, andD. Stern. 1989. 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.
Oppenheim, J. J., C. O. C. Zachariae, N. Mukaida, andK. Matsushima. 1991. Properties of the novel proinflammatory supergene “intercrine” cytokine family.Annu. Rev. Immunol. 9:617–648.
Kristensen, M. S., K. Paludan, C. G. Larsen, C. O. C. Zachariae, B. W. Deleuran, P. K. A. Jensen, P. Jorgensen, andK. Thestrup-Pedersen. 1991. Quantitative determination of IL-1α-induced IL-8 mRNA levels in cultured human keratinocytes, dermal fibroblasts, endothelial cells, and monocytes.J. Invest. Dermatol. 97:506–510.
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.
Hu, D. E., C. R.Hiley, and T.-P. D.Fan. 1992. Parallel studies of133Xe clearance and113Sn microsphere accumulation during sponge-induced angiogenesis and the effects of interleukin-1α.Br. J. Pharmacol. 106:102P.
Kimura, M., K. Amemiya, T. Yamada, andJ. Suzuki. 1986. Quantitative method for measuring adjuvant-induced granuloma angiogenesis in insulin-treated diabetic mice.J. Pharmacobio-Dyn. 9:442–446.
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. 105:211 P.
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.
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.
Motro, B., A. Itin, L. Sachs, andE. Keshet. 1990. Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis.Proc. Natl. Acad. Sci. U.S.A. 87:3092–3096.
Endo, H., T. Akahoshi, K. Takagishi, S. Kashiwazaki, andK. Matsushima. 1991. Elevation of interleukin-8 levels in joint fluid of patients with rheumatoid-arthritis and the induction by IL-8 of leukocyte infiltration and synovitis in rabbit joints.Lymphokine Cytokine Res. 10:245–252.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hu, D.E., Hori, Y. & Fan, T.P.D. Interleukln-8 stimulates angiogenesis in rats. Inflammation 17, 135–143 (1993). https://doi.org/10.1007/BF00916100
Issue Date:
DOI: https://doi.org/10.1007/BF00916100