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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2392-2399.
Prepublished online as a Blood First Edition Paper on December 11, 2007; DOI 10.1182/blood-2007-05-090019.
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Submitted May 15, 2007
Accepted November 25, 2007
Autocrine formation of hepcidin induces iron retention in human monocytes
Igor Theurl, Milan Theurl, Markus Seifert, Sabine Mair, Manfred Nairz, Holger Rumpold, Heinz Zoller, Rosa Bellmann-Weiler, Harald Niederegger, Heribert Talasz, and Guenter Weiss*
Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Medical University, Innsbruck, Austria
Department of Hematology and Oncology, Medical University, Innsbruck, Austria
Department of Gastroenterology and Hepatology, Medical University, Innsbruck, Austria
Tyrolean Cancer Research Institute, Medical University, Innsbruck, Austria
Biocenter, Division of Clinical Biochemistry, Medical University, Innsbruck, Austria
* Corresponding author; email: guenter.weiss{at}i-med.ac.at.
Hepcidin, a master regulator of iron homeostasis, is produced in small amounts by inflammatory monocytes/macrophages. Chronic immune activation leads to iron retention within monocytes/macrophages and the development of anemia of chronic disease (ACD). We questioned whether monocyte derived hepcidin exerts autocrine regulation of cellular iron metabolism.
Monocyte hepcidin mRNA expression was significantly induced within three hours after stimulation with LPS or IL-6, and hepcidin mRNA expression was significantly higher in monocytes of ACD patients than in controls. In ACD patients monocyte hepcidin mRNA levels were significantly correlated to serum IL-6 concentrations, and increased monocyte hepcidin mRNA levels were associated with decreased expression of the iron exporter ferroportin and iron retention in these cells. Transient transfection experiments employing a ferroportin/EmGFP fusion protein construct demonstrated that LPS inducible hepcidin expression in THP-1 monocytes resulted in internalisation and degradation of ferroportin. Transfection of monocytes with siRNA directed against hepcidin almost fully reversed this LPS mediated effect. Using ferroportin mutation constructs we found that ferroportin is mainly targeted by hepcidin when expressed on the cell surface.
Our results suggest that ferroportin expression in inflammatory monocytes is negatively affected by autocrine formation of hepcidin, thus contributing to iron sequestration within monocytes as found in ACD.
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