Ferritin translation by interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes

Interleukin-1beta (IL-1beta) elevates H- and L-ferritin subunit synthesis in both human hepatoma cells (HepG2) and primary human umbilical vein endothelial cells. Ferritin induction is greater than the increase in total HepG2 protein synthesis in response to IL-1. IL-6 causes a moderate increase in L-subunit synthesis. The levels of the mRNAs for the ferritin H-subunits (H-mRNA) and light subunits (L-mRNA) remain unchanged, indicating that expression of the iron storage protein, ferritin, is regulated by translational mechanisms during inflammation. We have found a translational enhancer region in the L- ferritin mRNA 5′UTR that confers two-fold baseline and twofold IL-1- dependent translational regulation to a CAT reporter message. The L- mRNA motif is related to a 61 nucleotide (nt) G+C-rich translational enhancer within 70 nt of the H-ferritin start codon. Sequences upstream of the start codons (SUS elements) in both H-mRNA and L-mRNAs confer IL- 1beta but not IL-6-dependent translation to hybrid ferritin/CAT reporter mRNAs. The H- and L-ferritin mRNA SUS elements contain a motif similar to a consensus reported for the 5′ leaders of other acute phase response mRNAs. Transfected hybrid H-mRNA SUS/CAT mRNAs with a three nucleotide deleted version of the H-mRNA SUS displays an eightfold reduced level of translation and no longer confer IL-1beta-dependent translation.