|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1994 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Oxygen radicals are generated under various pathologic condition including inflammation, ischemia reperfusion, sepsis and ultraviolet light irradiation, The vascular endothelium is one of the prime targets for oxidant injury in a variety of inflammatory conditions. It is reported that hypoxic or hyperoxic stress induces angiogenic signaling in human glioma cells. Among angiogenic factors, we especially focused on the mechanism of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) induction under various stress.
1) The expression of VEGF has been implicated in brain tumor angiogenesis and the promoter region for VEGF gene conditions several SP-1 and AP-1 (c-fos/c-jun) binding motifs. Among 8 human glioma cell lines, cellular mRNA levels of transcription factors, SP-1 and AP-1 (c-fos/c-jun), were found to be closely correlated with those of VEGF.Our data indicate that VEGF gene expression by bFGF or TNF-alpha is mediated in part through the transcription factor SP-1, and that by hypoxia is mediated through the transcription factor AP-1.
2) Another angiogeic factor is the cytokine, IL-8, that is produced at high levels in monocytes, macrophages and also human brain tumors. IL-8 induces cell migration of human umbilical endothelial cells, angiogenesis in rat cornea and tubular morphogenesis by microvascular endothelilal cells. Recent studies demonstrate that the IL-8 gene promoter region contains binding sites for AP-1 and NFxB.Moreover, co-administration of anti-IL-8 antibody inhibited tubular morphogenesis enhanced by H_2O_2, and IL-8 itself also enhanced formation of tube-like structures. H_2O_2 increased production of IL-8 in endothelial cells. Treatment with antisense NFkB oligonucleotide completely blcked the H_2O_2-dependent IL-8 production. Transcription factors SP-1, AP-1 and NFxB appeared to be involved in VEGF or IL-8 induction in glioma cells under various stress.