Hypoxia inhibits macrophage migration

The chemokine monocyte chemoattractant protein (MCP)-1 plays a role in regu lating the lymphocyte and macrophage infiltrate in ovarian cancer, but macr ophages also accumulate in necrotic areas of the tumors where there is litt le MCP-1 expression (Negus, R. P. M. et al., Am. J. Pathol. 1997. 150: 1723 -1734). Necrotic regions are likely to be hypoxic. In this study we show th at hypoxia inhibits MCP-1-induced migration of THP-1 monocytic cells and hu man macrophages. In contrast, lymphocytes from peripheral blood migrate nor mally to an MCP-1 gradient in hypoxic conditions. The inhibition of monocyt e migration by hypoxia is rapid and reversible. At the exposure times studi ed (30-90 min) hypoxia does not affect expression of the MCP-1 receptor CCR 2B and cells exposed to hypoxia still respond to MCP-1 with an elevation of intracellular calcium. Although hypoxia is known to modulate gene expressi on, the inhibition of migration reported here was not due to the production of soluble factors, and mRNA expression of macrophage migration inhibitory factor was unchanged. Hypoxia-induced inhibition of chemotaxis was not lim ited to MCP-1. Hypoxia also inhibited the chemotactic response to macrophag e inflammatory protein-1 alpha, RANTES and the chemoattractant N-formyl-met -leu-phe, but hypoxic cells were still able to phagocytose opsonized red bl ood cells. We suggest that inhibition of migration by hypoxia is not due to gene regulation but is a reflection of metabolic changes in the cell. Tran sient hypoxia may regulate the distribution of macrophages in tumors and ot her inflammatory conditions.