Polyvalent cationic metals induce the rate of transferrin-independent iron acquisition by HL-60 cells

The trivalent metals iron, aluminum, and gallium greatly increase the rate of iron acquisition from low molecular weight chelates by human myeloid cells. The present study explores the mechanism responsible. Gallium-induced iron acquisition was shown to lead to stable cellular association of iron, the magnitude of which varied with the chelate to which the iron was bound. The majority of this iron initially associated with the plasma membrane. Cellular depletion of ATP did not affect the response to gallium nor did it require the continued presence of extracellular gallium. However, continued cell association of gallium was needed as subsequent cellular exposure to metal chelators resulted in a rapid loss of the "induced" phenotype. Other trivalent metals (lanthanum and gadolinium) and tetravalent metals (tin and zirconium) but not divalent metals also induced iron acquisition. Neither enhanced iron reduction nor protein kinase C or tyrosine kinases appeared involved in gallium-mediated induction of iron acquisition. Exposure of HL-60 cells to polyvalent cationic metals results in a dramatic and sustained increase in the rate of iron acquisition from low molecular weight chelating agents. This could be important for the rapid clearance of iron by phagocytes from the extracellular environment at sites of local tissue damage.