Autocrine formation of hepcidin induces iron retention in human monocytes.
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 toward cellular iron metabolism. Monocyte hepcidin mRNA expression was significantly induced within 3 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 using a ferroportin/EmGFP fusion protein construct demonstrated that LPS inducible hepcidin expression in THP-1 monocytes resulted in internalization and degradation of ferroportin. Transfection of monocytes with siRNA directed against hepcidin almost fully reversed this lipopolysaccharide-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.
Theurl
Igor
I
Department of General Internal Medicine, Medical University, Innsbruck, Innsbruck, Austria.
Theurl
Milan
M
Seifert
Markus
M
Mair
Sabine
S
Nairz
Manfred
M
Rumpold
Holger
H
Zoller
Heinz
H
Bellmann-Weiler
Rosa
R
Niederegger
Harald
H
Talasz
Heribert
H
Weiss
Günter
G
D000740:Anemia / Q000097:blood* / Q000209:etiology; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D002097:C-Reactive Protein / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D012333:RNA, Messenger; D002097:C-Reactive Protein; D007501:Iron