Pathways for the regulation of macrophage iron metabolism by the anti- inflammatory cytokines IL-4 and IL-13

• Published in: The Journal of immunology (1950) Vol. 158; no. 1; pp. 420 - 425
• Main Authors: Weiss, G, Bogdan, C, Hentze, MW
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.01.1997
• Subjects: Animals; Base Sequence; Cell Line; Interleukin-13 - pharmacology; Interleukin-4 - pharmacology; Iron - metabolism; Iron Regulatory Protein 1; Iron Regulatory Protein 2; Iron-Regulatory Proteins; Iron-Sulfur Proteins - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice; Molecular Sequence Data; Nitric Oxide - antagonists & inhibitors; Receptors, Transferrin - metabolism; RNA-Binding Proteins - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.158.1.420

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.