Published ahead of print on June 5, 2003, doi:10.1165/rcmb.2003-0070OC Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 653-660 A more recent version of this article appeared on December 1, 2003
Submitted on March 6, 2003 Superoxide-dependent iron uptake: A new role for anion exchange protein 2Andrew J Ghio1,1 Medicine, Duke University Medical Center, Durham, NC, USA; National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Durham, NC, USA, 2 Pediatrics, Duke University Medical Center, Durham, NC, USA, 3 Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, NC, USA, 4 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA, 5 Medicine, Duke University Medical Center, Durham, NC, USA * To whom correspondence should be addressed. E-mail: piant001{at}mc.duke.edu.
Lung cells import iron across the plasma membrane as ferrous (Fe2+) ion by incompletely understood mechanisms. We tested the hypothesis that human bronchial epithelial (HBE) cells import non-transferrin-bound iron (NTBI) using superoxide-dependent ferri-reductase activity involving anion exchange protein 2 (AE2) and extracellular bicarbonate (HCO3-). HBE cells that constitutively express AE2 mRNA by rt-PCR and AE2 protein by Western analysis avidly transported NTBI after exposure to either Fe2+ or Fe3+ but reduction of Fe3+ to Fe2+ was first required. The ability of HBE cells to reduce Fe3+ and transport Fe2+ was inhibited by active extracellular superoxide dismutase (SOD). Similarly HBE cells that over-express Cu,Zn SOD after adenoviral infection with AdSOD1 showed diminished iron uptake. The role of AE2 in iron uptake was indicated by three lines of evidence: lack of both iron reduction and iron transport in bicarbonate-free buffer at controlled pH, failure of HBE cells treated with stilbene AE inhibitors to reduce Fe3+ or transport iron, and inhibition of iron uptake in HBE cells by inhibition of AE2 protein expression with antisense oligonucleotides. We thus disclose a novel ferri-reductase mechanism of NTBI uptake by human lung cells that employs superoxide exchange for HCO3- by AE2 protein in the plasma membrane.
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