Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.
Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms.
Yoshida
S
S
Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
Ono
M
M
Shono
T
T
Izumi
H
H
Ishibashi
T
T
Suzuki
H
H
Kuwano
M
M
D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007158:Immunologic Techniques; D016209:Interleukin-8 / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D009024:Morphogenesis / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology; D018919:Neovascularization, Physiologic; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D011817:Rabbits; D016329:Sp1 Transcription Factor / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2