Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells.
To elucidate iron-regulated interferon-gamma (IFN-gamma) effector functions, we investigated three IFN-gamma-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. IFN-gamma increased 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 IFN-gamma binding to its receptor nor IFN-gamma receptor surface expression. IFN-gamma-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 post-transcriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFN-gamma alone. Thus, iron perturbations regulate IFN-gamma effector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFN-gamma signal-transduction processes.
Oexle
Horst
H
Department of Internal Medicine, University Hospital Innsbruck, Austria.
Kaser
Arthur
A
Möst
Johannes
J
Bellmann-Weiler
Rosa
R
Werner
Ernst R
ER
Werner-Felmayer
Gabriele
G
Weiss
Günter
G
D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000096743:Interferon gamma Receptor
D003676:Deferoxamine; D006136:GTP Cyclohydrolase; D006684:HLA-DR Antigens; D018799:Intercellular Adhesion Molecule-1; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D007501:Iron; D007502:Iron Chelating Agents; D012313:RNA; D017471:Receptors, Interferon; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C079868:gamma interferon activation factor