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Published online before print May 22, 2003

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0802420

Received for publication August 28, 2002.
Revised March 7, 2003.
Accepted for publication March 13, 2003.

Article

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

Horst Oexle ^*, Arthur Kaser ^*, Johannes Möst ^*, Rosa Bellmann-Weiler ^*, Ernst R. Werner , Gabriele Werner-Felmayer , and Günter Weiss ^*@

*Department of Internal Medicine, University Hospital Innsbruck, Austria; and Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria

^@ To whom correspondence should be addressed. E-mail: guenter.weiss{at}uibk.ac.at.

	Abstract

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. IFN- 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- binding to its receptor nor IFN- receptor 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 post-transcriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFN- alone. Thus, iron perturbations regulate IFN- effector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFN- signal-transduction processes.

Key Words: monocytes/macrophages • gene regulation • cytokines • adhesion molecules

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