Pathways for the regulation of interferon- -inducible genes by iron in human monocytic cells

To elucidate iron-regulated interferon(IFN) effector functions, we investigated three IFN-inducible genes [intercellular adhesion molecule-1 (ICAM-1), human leukocyte antigen (HLA)-DR, guanosine 5 -triphosphate-cyclohydrolase I (GTP-CH)] in primary human monocytes and the cell line THP-1. IFNincreased the surface expression of ICAM-1 and HLA-DR and stimulated GTP-CH activity. Addition of iron before cytokine stimulation resulted in a dose-dependent reduction of these pathways, and iron restriction by desferrioxamine (DFO) enhanced ICAM-1, HLA-DR, and GTP-CH expression. Iron neither affected IFNbinding to its receptor nor IFNreceptor surface expression. IFN-inducible mRNA expression of ICAM-1, HLA-DR, and GTP-CH was reduced by iron and increased by DFO by a transcriptional mechanism. Moreover, ICAM-1 and to a lesser extent, GTP-CH and HLA-DR mRNA expression were regulated posttranscriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFNalone. Thus, iron perturbations regulate IFNeffector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFNsignaltransduction processes. J. Leukoc. Biol. 74: 000–000; 2003.