Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13.
Macrophage effector functions are influenced by their iron status and by shifts in the balance between type 1 Th1 and Th2 cells. To elucidate the influence of the Th2 cytokines IL-4 and IL-13 on macrophage iron metabolism, we investigated activated primary mouse macrophages and the murine macrophage cell line J774. Stimulation of J774 cells and primary macrophages with IFN-gamma/LPS activates the RNA binding affinities of iron regulatory protein-1 (IRP-1) and IRP-2 for iron-responsive elements, leading to translational repression of the iron storage protein ferritin. Activation of IRP-1 and IRP-2 is caused by increased formation of nitric oxide (NO) via stimulation of the inducible NO synthase by IFN-gamma/LPS. Treatment of macrophages with IL-4 and/or IL-13 before stimulation with IFN-gamma/LPS suppresses NO formation and IRP activation, with concomitantly enhanced ferritin synthesis despite a small reduction in ferritin heavy chain mRNA levels. The mRNA levels for the membrane receptor for iron uptake, transferrin receptor (TfR), decrease following stimulation with IFN-gamma/LPS, although IRP-mediated stabilization of the TfR mRNA would have been expected. This as yet unidentified proximal inhibitory signal by IFN-gamma/LPS is antagonized by IL-4 and/or IL-13, which leads to increased TfR mRNA expression in an IRP-independent manner. Thus, IL-4 and IL-13 regulate the iron metabolism of activated macrophages by at least two different pathways: first, by opposing NO-mediated IRP activation, thereby increasing ferritin translation; and second, by an IRP-independent augmentation of TfR mRNA expression. We suggest that IL-4 and IL-13 may enhance iron uptake and storage in activated macrophages and thereby contribute to down-regulation of macrophage effector functions.
Weiss
G
G
European Molecular Biology Laboratory, Gene Expression Program, Heidelberg, Germany.
Bogdan
C
C
Hentze
M W
MW
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins / Q000494:pharmacology; D011990:Receptors, Transferrin / Q000378:metabolism
D018793:Interleukin-13; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D015847:Interleukin-4; D009569:Nitric Oxide; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2