Regulation of interleukin-8 expression by reduced oxygen pressure in humanglioblastoma

Oxygen deprivation is an important biological feature of tumor growth. We p reviously showed that in glioma, anoxia increases expression of IL-8, a che mokine and angiogenic factor. Here, we analysed for the first time the bioc hemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are i nduced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), on ly the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the inducti on is due to the anoxic stress per se. Furthermore, in LN-229 and Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift as says show increased protein binding to the AP-I site on the IL-8 promoter f ollowing anoxia treatment. Finally, in situ hybridization on glioblastoma s ections shows that the ill vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essentia l to appropriately target them for antitumoral therapy.