Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy.

Macrophages accumulate in ischemic areas of such pathological tissues as solid tumors, atherosclerotic plaques and arthritic joints. Studies have suggested that hypoxia alters the phenotype of macrophages in a way that promotes these lesions. However, the genes up-regulated by macrophages in such hypoxic tissues are poorly characterized. Here, we have used cDNA array hybridization to investigate the effects of hypoxia on the mRNAs of 1185 genes in primary human monocyte-derived macrophages. As shown previously in other cell types, mRNA levels for vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1) were up-regulated by hypoxia. However, the mRNAs of other genes were also up-regulated including matrix metalloproteinase-7 (MMP-7), neuromedin B receptor, and the DNA-binding protein inhibitor, Id2. The promoters of GLUT-1 and MMP-7 confer hypoxic inducibility on a reporter gene in RAW 264.7 macrophages, indicating that the hypoxic up-regulation of these mRNAs may occur, at least in part, at the transcriptional level. GLUT-1 and MMP-7 mRNA were also shown to be up-regulated in hypoxic macrophages in vitro by real-time RT-PCR, and these proteins were elevated in hypoxic macrophages in vitro and in hypoxic areas of human breast tumors. The hypoxia up-regulated genes identified could be important for the survival and functioning of macrophages in hypoxic diseased tissues, and their promoters could prove useful in macrophage-delivered gene therapy.