Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors

Abstract: Monocyte chemoattractant protein 1 (MCP-1) is likely to contribute to the macrophage infiltrate in human ovarian carcinomas. Although MCP-1 is predominantly expressed by the tumor parenchyma, macrophages accumulate at highest density in necrotic regions, which are associated with low oxygen tensions. Tumor necrosis factor a (TNF-a) can stimulate MCP-1 production and is also present within ovarian carcinomas. We have investigated the effect of hypoxia both on MCP-1 expression in ovarian cancer cell lines and mono-cyte migration. Hypoxia down-regulated TNF-a-induced MCP-1 mRNA and protein production by ovarian cancer cells. The effect was mimicked by cobalt chloride and desferrioxamine, consistent with a specific oxygen-sensing mechanism. Unlike antioxidants, hypoxia did not inhibit nuclear factor kB mobilization. Monocyte migration in response to MCP-1 was also diminished under hypoxic condi-tions. Down-regulation of MCP-1 expression and the inhibition of monocyte migration are indepen-dent effects of hypoxia that may contribute to the distribution of macrophages within ovarian tumors