Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor (∗)

Angiogenesis, the formation of new blood vessels, is induced by various growth factors and cytokines that act either directly or indirectly. Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells and therefore has a central role in physiological events of angiogenesis. Interleukin-6 (IL-6) expression on the other hand is elevated in tissues that undergo active angiogenesis but does not induce proliferation of endothelial cells. We demonstrate using Northern analysis that treatment of various cell lines with IL-6 for 6-48 h results in a significant induction of VEGF mRNA. The level of induction is comparable to the documented induction of VEGF mRNA by hypoxia or cobalt chloride, an activator of hypoxia-induced genes. In addition, it is demonstrated by transient transfection assays that the effect of IL-6 is mediated not only by DNA elements at the promoter region but also through specific motif(s) located in the 5′-untranslated region (5′-UTR) of VEGF mRNA. Our results imply that IL-6 may induce angiogenesis indirectly by inducing VEGF expression. It is also shown that the 5′-UTR is important for the expression of VEGF. The 5′-UTR of VEGF is exceptionally long (1038 base pairs) and very rich in G + C. This suggests that secondary structures in the 5′-UTR might be essential for VEGF expression through transcriptional and post-transcriptional control mechanisms.