The
chemokine monocyte chemoattractant protein (MCP)-1 plays a role in regulating the lymphocyte and macrophage infiltrate in
ovarian cancer, but macrophages also accumulate in necrotic areas of the
tumors where there is little 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 that
hypoxia inhibits MCP-1-induced migration of THP-1 monocytic cells and human macrophages. In contrast, lymphocytes from peripheral blood migrate normally to an MCP-1 gradient in hypoxic conditions. The inhibition of monocyte migration by
hypoxia is rapid and reversible. At the exposure times studied (30-90 min)
hypoxia does not affect expression of the
MCP-1 receptor CCR2B and cells exposed to
hypoxia still respond to MCP-1 with an elevation of intracellular
calcium. Although
hypoxia is known to modulate gene expression, 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 limited to MCP-1.
Hypoxia also inhibited the chemotactic response to macrophage inflammatory protein-1alpha,
RANTES and the
chemoattractant N-formyl-
met-leu-phe, but hypoxic cells were still able to phagocytose opsonized red blood 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. Transient
hypoxia may regulate the distribution of macrophages in
tumors and other inflammatory conditions.