Involvement of Interleukin-8, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor in Tumor Necrosis Factor Alpha-Dependent Angiogenesis

• DOI: 10.1128/mcb.17.7.4015
• Publication Date: 2015-10-09T18:08:17Z
• Authors: Shigeo Yoshida; Mayumi Ono; Tadahisa Shono; Hiroto Izumi; Tatsuro Ishibashi; Hideo Suzuki; Michihiko Kuwano
• Keywords: Lymphokines; 0303 health sciences; Proto-Oncogene Proteins c-jun; Sp1 Transcription Factor; Tumor Necrosis Factor-alpha; Interleukin-8; NF-kappa B; Gene Expression Regulation, Developmental; Neovascularization, Physiologic; Endothelial Growth Factors; Oligonucleotides, Antisense; Transforming Growth Factor alpha; 3. Good health; Cornea; 03 medical and health sciences; Immunologic Techniques; Morphogenesis; Animals; Humans; Fibroblast Growth Factor 2; Endothelium, Vascular; Rabbits; Cells, Cultured

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.