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J. Biol. Chem., Vol. 278, Issue 45, 44018-44024, November 7, 2003

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Role of Ceruloplasmin in Macrophage Iron Efflux during Hypoxia^*

Joydeep Sarkar, Vasudevan Seshadri, Nicholas A. Tripoulas, Michael E. Ketterer¶, and Paul L. Fox||

From the Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, the Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, and the ^¶Department of Chemistry, Northern Arizona University, Flagstaff, Arizona 86011

The reticuloendothelial system has a central role in erythropoiesis and iron homeostasis. An important function of reticuloendothelial macrophages is phagocytosis of senescent red blood cells. The iron liberated from heme is recycled for delivery to erythrocyte precursors for a new round of hemoglobin synthesis. The molecular mechanism by which recycled iron is released from macrophages remains unresolved. We have investigated the mechanism of macrophage iron efflux, focusing on the role of ceruloplasmin (Cp), a copper protein with a potent ferroxidase activity that converts Fe²⁺ to Fe³⁺ in the presence of molecular oxygen. As shown by others, Cp markedly increased iron binding to apotransferrin at acidic pH; however, the physiological significance of this finding is uncertain because little stimulation was observed at neutral pH. Introduction of a hypoxic atmosphere resulted in marked Cp-stimulated binding of iron to apotransferrin at physiological pH. The role of Cp in cellular iron release was examined in U937 monocytic cells induced to differentiate to the macrophage lineage. Cp added at its normal plasma concentration increased the rate of ⁵⁵Fe release from U937 cells by about 250%. The stimulation was absolutely dependent on the presence of apotransferrin and hypoxia. Cp-stimulated iron release was confirmed in mouse peritoneal macrophages. Stimulation of iron release required an intracellular "labile iron pool" that was rapidly depleted in the presence of Cp and apotransferrin. Ferroxidase-mediated loading of iron into apotransferrin was critical for iron release because ferroxidase-deficient Cp was inactive and because holotransferrin could not substitute for apotransferrin. The extracellular iron concentration was critical as shown by inhibition of iron release by exogenous free iron, and marked enhancement of release by an iron chelator. Together these data show that Cp stimulates iron release from macrophages under hypoxic conditions by a ferroxidase-dependent mechanism, possibly involving generation of a negative iron gradient.

Received for publication, May 12, 2003 , and in revised form, July 29, 2003.

^* This work was supported by National Institutes of Health Grants HL29582 and HL67725 (to P. L. F.) and by National Science Foundation Award CHE-0116804 (to M. E. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-8053; Fax: 216-444-9404; E-mail: foxp{at}ccf.org.

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