Hepcidin expression and iron transport in alveolar macrophages.
Alveolar macrophages express many proteins important in iron homeostasis, including the iron importer divalent metal transport 1 (DMT1) and the iron exporter ferroportin 1 (FPN1) that likely participate in lung defense. We found the iron regulatory hormone hepcidin (HAMP) is also produced by alveolar macrophages. In mouse alveolar macrophages, HAMP mRNA was detected at a low level when not stimulated but at a high level when exposed to lipopolysaccharide (LPS). LPS also affected the mRNA levels of the iron transporters, with DMT1 being upregulated and FPN1 downregulated. However, iron had no effect on HAMP expression but was able to upregulate both DMT1 and FPN1 in alveolar macrophages. IL-1 and IL-6, which are important in HAMP augmentation in hepatocytes, also did not affect HAMP expression in alveolar macrophages. In fact, the LPS-induced alterations in the expression of HAMP as well as DMT1 and FPN1 were preserved in the alveolar macrophages isolated from IL-1 receptor or IL-6-deficient mice. When alveolar macrophages were loaded with transferrin-bound (55)Fe, the subsequent release of (55)Fe was inhibited significantly by LPS. In addition, treatment of these cells with either LPS or HAMP caused the diminishment of the surface FPN1. These findings are consistent with the current model that HAMP production leads to a decreased iron efflux. Our studies suggest that iron mobilization by alveolar macrophages can be affected by iron and LPS via several pathways, including HAMP-mediated degradation of FPN1, and that these cells may use unique regulatory mechanisms to cope with iron imbalance in the lung.
Nguyen
Ngoc-Bich
NB
Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, 78229, USA.
Callaghan
Kimberly D
KD
Ghio
Andrew J
AJ
Haile
David J
DJ
Yang
Funmei
F
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001693:Biological Transport, Active; D027682:Cation Transport Proteins / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D004731:Endotoxins; D064451:Hepcidins; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D015854:Up-Regulation; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D016207:Cytokines; D004731:Endotoxins; D064451:Hepcidins; D007501:Iron; D033862:Iron-Binding Proteins; D008070:Lipopolysaccharides; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C579599:Hamp protein, mouse