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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2383-2389
Regulation of Iron Metabolism in Murine J774 Macrophages: Role of
Nitric Oxide-Dependent and -Independent Pathways Following Activation
With Gamma Interferon and Lipopolysaccharide
Victoriano Mulero and
Jeremy H. Brock
From the Department of Immunology and Bacteriology, Western
Infirmary, University of Glasgow, Glasgow, UK; and the Department of
Cell Biology, Faculty of Biology, University of Murcia, Murcia, Spain.
To elucidate the pathways by which nitric oxide (NO) influences
macrophage iron metabolism, the uptake, release, and intracellular distribution of iron in the murine macrophage cell line J774 has been
investigated, together with transferrin receptor (TfR) expression and
iron-regulatory protein (IRP1 and IRP2) activity. Stimulation of
macrophages with interferon- (IFN-) and/or lipopolysaccharide (LPS) decreased Fe uptake from transferrin (Tf), and there was a
concomitant downregulation of TfR expression. These effects were
mediated by NO-dependent and NO-independent mechanisms. Addition of the
NO synthase (NOS) inhibitor N-monomethyl arginine (NMMA) partially restored Fe uptake but either had no effect on or
downregulated TfR expression, which suggests that NO by itself is able
to affect iron availability. Analysis of the intracellular distribution of incorporated iron revealed that in IFN-/LPS-activated macrophages there was a decreased amount and proportion of ferritin-bound iron and
a compensatory increase in insoluble iron, which probably consists
mainly of iron bound to intracellular organelles. Finally, although NO
released by IFN-/LPS-activated macrophages increased the
iron-responsive element (IRE)-binding activity of both IRP1 and IRP2,
IFN- treatment decreased IRP2 activity in an NO-independent manner.
This study demonstrates that the effect of IFN- and/or LPS on
macrophage iron metabolism is complex, and is not entirely due to
either NO-or to IRP-mediated mechanisms. The overall effect is to
decrease iron uptake, but not its utilization.
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