title: Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3).
abstract: The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 μM), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of >50 μM. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2)-mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism.
authors.affiliation: Center for Alcohol Research, University of Heidelberg and Salem Medical Center, 69120 Heidelberg, Germany. gunda.millonig@uni-heidelberg.de
authors.forename: Gunda
authors.initials: G
authors.lastname: Millonig
authors.forename: Ingo
authors.initials: I
authors.lastname: Ganzleben
authors.forename: Teresa
authors.initials: T
authors.lastname: Peccerella
authors.forename: Guillem
authors.initials: G
authors.lastname: Casanovas
authors.forename: Lidia
authors.initials: L
authors.lastname: Brodziak-Jarosz
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.forename: Tobias P
authors.initials: TP
authors.lastname: Dick
authors.forename: Helmut-Karl
authors.initials: HK
authors.lastname: Seitz
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mueller
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D055418:Bone Morphogenetic Protein 6 / Q000502:physiology; D045744:Cell Line, Tumor; D016166:Free Radical Scavengers / Q000494:pharmacology; D064451:Hepcidins; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology*; D015850:Interleukin-6 / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D023181:Antimicrobial Cationic Peptides; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D016166:Free Radical Scavengers; C578702:HAMP protein, human; D064451:Hepcidins; D018836:Inflammation Mediators; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D006861:Hydrogen Peroxide; D000111:Acetylcysteine