Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 May;85(5):522–529. doi: 10.1111/j.1349-7006.1994.tb02390.x

Interaction of Interleukin‐1 and Interferon‐γ on Fibroblast Growth Factor‐induced Angiogenesis

Ken‐ichi Norioka 1,✉, Toshihiro Mitaka 1, Yohichi Mochizuki 1, Masako Hara 2,†, Mitsuhiro Kawagoe 2, Haruo Nakamura 2
PMCID: PMC5919500  PMID: 7516930

Abstract

The interaction of interleukin‐1 (IL‐1) and interferon‐γ (IFN‐γ) actions on several aspects of angiogenesis in vitro and in vivo was studied. The proliferation and migration of human umbilical vein endothelial cells cultured with basic fibroblast growth factor (bFGF) were synergistically inhibited by cotreatment with IL‐1 and IFN‐γ. Endothelial cell adhesion to collagen was suppressed by IL‐1 and the effect was slightly enhanced by the combination of IL‐1 and IFN‐γ. Local administration of IL‐1 (10,000 U) and IFN‐γ (1,000 U) inhibited bFGF‐induced angiogenesis in the skin of mice, and synergistic inhibitory activity of the combination was demonstrated. Expression of FGF receptors was strongly downregulated by the combination, whereas expressions of epidermal growth factor (EGF) receptors, integrin β1 and integrin β3 were not. EGF partially abrogated the growth‐inhibitory effects of IL‐1 and IFN‐γ. These findings indicate that IL‐1 and IFN‐γ are each able to act an angiogenesis inhibitor in a situation where FGF plays a major role in angiogenesis, and the activity is synergistically enhanced when they are used in combination.

Keywords: Interleukin‐1, Interferon‐γ, Fibroblast growth factor, Vascular endothelial cell, Angiogenesis

Full Text

The Full Text of this article is available as a PDF (517.0 KB).

REFERENCES

  • 1. ) Folkman , J. and Klagsbrun , M.Angiogenic factors . Science , 235 , 442 – 447 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Folkman , J.Angiogenesis, retrospect and outlook . In “ Angiogenesis ,” ed. Steiner R. , Weisz P. B. , and Langer R. , pp. 4 – 13 ( 1992. ). Birkhäuser Verlag; , Basel . [Google Scholar]
  • 3. ) Friesel , R. , Komoriyama , A. and Maciag , T.Inhibition of endothelial cell proliferation by gamma‐interferon . J. Cell Biol. , 104 , 689 – 696 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Tsuruoka , N. , Sugiyama , M. , Tawaragi , Y. , Tsujimoto , M. , Nishihara , T. , Goto , T. and Sato , N.Inhibition of in vitro angiogenesis by lymphotoxin and interferon‐γ . Biochem. Biophys. Res. Commun. , 155 , 429 – 435 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Sidky , Y. A. and Borden , E. C.Inhibition of angiogenesis by interferons: effects on tumor‐ and lymphocyte‐induced vascular responses . Cancer Res. , 47 , 5155 – 5161 ( 1987. ). [PubMed] [Google Scholar]
  • 6. ) Norioka , K. , Hara , M. , Kitani , A. , Hirose , T. , Hirose , W. , Harigai , M. , Suzuki , K. , Kawakami , M. , Tabata , H. , Kawagoe , M. and Nakamura , H.Inhibitory effect of human recombinant interleukin‐1 α and β on growth of human vascular endothelial cells . Biochem. Biophys. Res. Commun. , 145 , 969 – 975 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Sato , N. , Goto , T. , Haranaka , K. , Satomi , N. , Nariuchi , H. , Mano‐Hirano , Y. and Sawasaki , Y.Actions of tumor necrosis factor on cultured vascular endothelial cells . J. Natl. Cancer Inst. , 76 , 1113 – 1121 ( 1986. ). [PubMed] [Google Scholar]
  • 8. ) Cozzolino , F. , Torcia , M. , Aldinucci , D. , Ziche , M. , Almerigogna , F. , Bani , D. and Stern , D. M.Interleukin 1 is an autocrine regulator of human endithelial cell growth . Proc. Natl. Acad. Sci. USA , 87 , 6487 – 6491 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Dunn , C. J. , Hardee , M. M. and Staite , N. D.Acute and chronic inflammatory responses to local administration of recombinant IL‐lα, IL‐1β, TNFα, IL‐2 and Ifnγ, in mice . Agents Actions , 27 , 290 – 293 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) BenEzra , D. , Hemo , H. and Mafzir , G.In vivo angiogenic activity of interleukins . Arch. Ophthalmol. , 108 , 573 – 576 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Fajardo , L. F. , Kwan , H. H. , Kowalski , J. , Prionas , S. D. and Allison , A. C.Dual role of tumor necrosis factor‐α in angiogenesis . Am. J. Pathol. , 140 , 539 – 544 ( 1992. ). [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Blood , C. H. and Zetter , B. R.Tumor interactions with the vasculature: angiogenesis and tumor metastasis . Biochim. Biophys. Acta , 1032 , 89 – 118 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Norioka , K. , Borden , E. C. and Auerbach , R.Inhibitory effects of cytokines on vascular endothelial cells: synergistic interactions among interferon‐γ, tumor necrosis factor‐α, and interleukin‐1 . J. Immunother. , 12 , 13 – 18 ( 1992. ). [PubMed] [Google Scholar]
  • 14. ) Norioka , K. , Hara , M. , Harigai , M. , Kitani , A. , Hirose , T. , Suzuki , K. , Kawakami , M. , Tabata , H. , Kawagoe , M. and Nakamura , H.Production of B cell stimulatory factor‐2/interleukin‐6 activity by human endothelial cells . Biochem. Biophys. Res. Commun. , 153 , 1045 – 1050 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Defilippi , P. , Truffa , G. , Stefanuto , G. , Altruda , F. , Silengo , L. and Tarone , G.Tumor necrosis factor α and interferon γ modulate the expression of the vitronectin receptor (integrin β3) in human endothelial cells . J. Biol. Chem. , 266 , 7638 – 7645 ( 1991. ). [PubMed] [Google Scholar]
  • 16. ) Asakura , S. , Hurley , R. W. , Skorstengaard , K. , Ohkubo , I. and Mosher , D. F.Inhibition of cell adhesion by high molecular weight kininogen . J. Cell Biol. , 116 , 465 – 476 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Weckbecker , G. , Liu , R. and Tolcsvai , L.Intradermal angiogenesis in nude mice induced by human tumor cells or b‐FGF . In “ Angiogenesis ,” ed. Steiner R. , Weisz P. B. and Langer R. , pp. 296 – 301 ( 1992. ). Birkhäuser Verlag; , Basel . [DOI] [PubMed] [Google Scholar]
  • 18. ) Sidky , Y. A. and Auerbach , R.Lymphocyte‐induced angiogenesis: a quantitative and sensitive assay of the graft‐vs.‐host reaction . J. Exp. Med. , 141 , 1084 – 1100 ( 1975. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Wallenstein , S. , Zucker , C. L. and Fleiss , J. L.Some statistical methods useful in circulation research . Circ. Res. , 47 , 1 – 9 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Berenbaum , M. C.Criteria for analyzing interactions between biologically active agents . Adv. Cancer Res. , 35 , 269 – 335 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Soncin , F.Angiogenin supports endothelial and flbroblast cell adhesion . Proc. Natl. Acad. Sci. USA , 89 , 2232 – 2236 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Gospodarovicz , D. , Brown , K. D. , Birdwell , C. R. and Zetter , B. R.Control of proliferation of human vascular endothelial cells . J. Cell Biol. , 77 , 774 – 788 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Moscatelli , D. , Presta , M. and Rifkin , D. B.Purification of a factor from human placenta that stimulates capillary cell protease production, DNA synthesis, and migration . Proc. Natl. Acad. Sci. USA , 83 , 2091 – 2095 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Baird , A. , Schubert , D. , Ling , N. and Guillemin , R.Receptor‐ and heparin‐binding domains of basic fibroblast growth factor . Proc. Natl. Acad. Sci. USA , 85 , 2324 – 2328 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. ) Montesano , R. , Orci , L. and Vassalli , P.Human endothelial cell cultures: phenotypic modulation by leukocyte interleukins . J. Cell Physiol. , 122 , 424 – 434 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Doukas , J. and Pober , J. S.IFN‐γ enhances endothelial cell activation induced by tumor necrosis factor but not IL‐1 . J. Immunol. , 145 , 1727 – 1733 ( 1990. ). [PubMed] [Google Scholar]
  • 27. ) Seppä , H. , Grotendorst , G. , Seppä , S. , Schiffmann , E. and Martin , G. R.Platelet‐derived growth factor is chemotactic for fibroblasts . J. Cell Biol. , 92 , 584 – 588 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Takikawa , O. , Kuroiwa , T. , Yamazaki , F. and Kido , R.Mechanism of interferon‐γ action . J. Biol. Chem. , 263 , 2041 – 2048 ( 1988. ). [PubMed] [Google Scholar]
  • 29. ) Detmar , M. , Tenorio , S. , Hettmannsperger , U. , Ruszczak , Z. and Orfanos , C. E.Cytokine regulation of proliferation and ICAM‐1 expression of humann dermal microvascular endothelial cells in vitro . J. Invest. Dermatol. , 98 , 147 – 153 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Meyskens , F. L. , Kopecky , K. , Samson , M. , Hersh , E. , Macdonald , J. , Jaffe , H. , Crowley , J. and Coltman , C.Recombinant human interferon γ: adverse effects in high‐risk stage I and II cutaneous malignant melanoma . J. Natl. Cane. Inst. , 82 , 1071 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Kandel , J. , Bossy‐Wetzel , E. , Radvanyi , F. , Klagsbrun , M. , Folkman , J. and Hanahan , D.Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma . Cell , 66 , 1095 – 1104 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Plate , K. H. , Breier , G. , Weich , H. A. and Risau , W.Vascular endothelial cell growth factor is a potent tumor angiogenesis factor in human gliomas in vivo . Nature , 359 , 845 – 848 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Bassukas , I. D. , Vester , G. and Maurer‐Schultze , B.Cell kinetic studies of endothelial cells in the adenocarcinoma EO771 and the effect of cyclophosphamide. Virchows Arch . B Cell Pathol. , 59 , 251 – 256 ( 1990. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES