title: The small molecule ferristatin II induces hepatic hepcidin expression in vivo and in vitro.
abstract: Previous studies have shown that administration of ferristatin II to rats is associated with decreased serum iron, reduced transferrin saturation, and increased hepatic hepcidin expression. BMP and IL-6 signaling act via Smad and Stat3 transcription factors, respectively, to increase expression of hepcidin, the master regulator of iron metabolism. In this study, we aimed to explore the underlying mechanism of ferristatin II action on hepcidin production. We found that ferristatin II greatly increased hepcidin expression both in vivo and in vitro. In the rat liver, ferristatin II treatment decreased expression of Smad downstream targets Smad7 and Id1 and increased expression of Stat3 downstream targets α-2-macroglobulin, α-1-acid glycoprotein, and C-reactive peptide. Ferristatin II also increased Stat3 phosphorylation in the rat liver without affecting serum or hepatic IL-6 levels. It is unclear whether the Stat3 activation observed in vivo is a cause or a consequence to hepcidin induction. Reporter gene expression studies demonstrated that ferristatin II synergized with BMP6 and IL-6 to enhance hepcidin expression in vitro. However, this synergy was not due to activation of either Smad or Stat3 signaling, raising the possibility that ferristatin II may activate a novel pathway for hepcidin regulation.
authors.affiliation: Department of Genetic and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Alkhateeb
authors.affiliation: Department of Genetic and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Peter D
authors.initials: PD
authors.lastname: Buckett
authors.affiliation: Department of Genetic and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gardeck
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts; and.
authors.forename: Jonghan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Genetic and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Shaina L
authors.initials: SL
authors.lastname: Byrne
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Fraenkel
authors.affiliation: Department of Genetic and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts; wessling@hsph.harvard.edu.
authors.forename: Marianne
authors.initials: M
authors.lastname: Wessling-Resnick
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001713:Biphenyl Compounds; D055418:Bone Morphogenetic Protein 6; D064451:Hepcidins; D015850:Interleukin-6; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; D013450:Sulfones; C588093:ferristatin II
keywords: BMP6; IL-6; hemochromatosis; iron transport