STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation

• Published in: Blood 2007-01, Vol.109 (1), p.353-358
• Main Authors: Verga Falzacappa, Maria Vittoria, Vujic Spasic, Maja, Kessler, Regina, Stolte, Jens, Hentze, Matthias W., Muckenthaler, Martina U.
• Format: Article
• Language: English
• Subjects: Acute-Phase Reaction; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Base Sequence; Binding Sites; Biological and medical sciences; Carcinoma, Hepatocellular - pathology; CCAAT-Enhancer-Binding Protein-alpha - genetics; Cell Line - drug effects; Cell Line - metabolism; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Culture Media, Conditioned - pharmacology; Gene Silencing; Genes, Reporter; Hematologic and hematopoietic diseases; Hepcidins; Humans; Inflammation - genetics; Inflammation - metabolism; Interleukin-6 - pharmacology; Iron - metabolism; Liver Neoplasms - pathology; Luciferases - biosynthesis; Luciferases - genetics; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Molecular Sequence Data; Monocytes - drug effects; Monocytes - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Recombinant Proteins - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Small Interfering - pharmacology; STAT3 Transcription Factor - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-07-033969

Hepcidin is a key iron-regulatory hormone produced by the liver. Inappropriately low hepcidin levels cause iron overload, while increased hepcidin expression plays an important role in the anemia of inflammation (AI) by restricting intestinal iron absorption and macrophage iron release. Its expression is modulated in response to body iron stores, hypoxia, and inflammatory and infectious stimuli involving at least in part cytokines secreted by macrophages. In this study we established and characterized IL6-mediated hepcidin activation in the human liver cell line Huh7. We show that the proximal 165 bp of the hepcidin promoter is critical for hepcidin activation in response to exogenously administered IL6 or to conditioned medium from the monocyte/macrophage cell line THP-1. Importantly, we show that hepcidin activation by these stimuli requires a STAT3 binding motif located at position –64/–72 of the promoter. The same STAT binding site is also required for high basal-level hepcidin mRNA expression under control culture conditions, and siRNA-mediated RNA knockdown of STAT3 strongly reduces hepcidin mRNA expression. These results identify a missing link in the acute-phase activation of hepcidin and establish STAT3 as a key effector of baseline hepcidin expression and during inflammatory conditions.