Reciprocal regulation of HFE and Nramp2 gene expression by iron in human intestinal cells

The newly identified hemochromatosis gene, HFE, and a candidate iron transp orter gene, Nramp2, have been proposed as key factors responsible for the r egulation of intestinal iron absorption. Although the exact functions of th ese proteins in intestinal iron absorption are unknown, HFE may be required for the down-regulation of iron absorption that occurs with increasing iro n status, and Nramp2 may up-regulate iron absorption when iron status is lo w, Thus, we examined whether the expression of the HFE and Nramp2 genes are regulated by iron status in the human intestinal cell line Caco-2. HFE mRN A and HFE protein were increased and Nramp2 mRNA was decreased by increasin g cellular iron status in Caco-2 cells. This iron-mediated modulation of mR NA levels was specific to icon. Moreover, super-induction of HFE mRNA in th e presence of cycloheximide suggests that HFE gene expression may be contro lled by a short-lived repressor protein. HFE and Nramp2 mRNA levels also ch anged in opposite directions during cellular differentiation. This reciproc al modification of the HFE and Nramp2 gene expression during both iron trea tment and cell differentiation in Caco-2 cells is consistent with an opposi ng role for these proteins in homeostatic regulation of human intestinal ir on absorption.