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1 Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
2 Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States; Human Studies Division, US Environmental Protection Agency, Chapel Hill, North Carolina, United States
3 Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States; Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
* To whom correspondence should be addressed. E-mail: yangf{at}uthscsa.edu.
Alveolar macrophages express many proteins important in iron homeostasis including the iron importer DMT1 and the iron exporter 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 up-regulated and FPN1 down-regulated. However, iron had no effect on HAMP expression but was able to up-regulate 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 55Fe, the subsequent release of 55Fe was significantly inhibited by LPS. In addtion, 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 suggests 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.
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