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Pathways for the regulation of interferon‐γ‐inducible genes by iron in human monocytic cells
Author(s) -
Oexle Horst,
Kaser Arthur,
Möst Johannes,
BellmannWeiler Rosa,
Werner Ernst R.,
WernerFelmayer Gabriele,
Weiss Günter
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0802420
Subject(s) - biology , signal transduction , gtp' , interferon , guanosine , effector , receptor , microbiology and biotechnology , gene expression , guanosine triphosphate , cytokine , gene , biochemistry , immunology , enzyme
To elucidate iron‐regulated interferon‐γ (IFN‐γ) effector functions, we investigated three IFN‐γ‐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‐γ 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‐γ binding to its receptor nor IFN‐γ receptor surface expression. IFN‐γ‐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‐γ alone. Thus, iron perturbations regulate IFN‐γ effector pathways by transcriptional and post‐transcriptional mechanisms, indicating that iron rather interferes with IFN‐γ signal‐transduction processes.