title: Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes.
abstract: The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-β1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-β1-induced hepcidin expression are still unclear. Here we show that TGF-β1 treatment of mouse and human hepatocytes, as well as ectopic expression of TGF-β1 in mice, increases hepcidin mRNA levels. The hepcidin response to TGF-β1 depends on functional TGF-β1 type I receptor (ALK5) and TGF-β1 type II receptor (TβRII) and is mediated by a noncanonical mechanism that involves Smad1/5/8 phosphorylation. Interestingly, increasing availability of canonical Smad2/3 decreases TGF-β1-induced hepcidin regulation, whereas the BMP6-hepcidin signal was enhanced, indicating a signaling component stoichiometry-dependent cross-talk between the two pathways. Although ALK2/3-dependent hepcidin activation by BMP6 can be modulated by each of the three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and TfR2 (transferrin receptor 2), these proteins do not control the ALK5-mediated hepcidin response to TGF-β1. TGF-β1 mRNA levels are increased in mouse models of iron overload, indicating that TGF-β1 may contribute to hepcidin synthesis under these conditions. In conclusion, these data demonstrate that a complex regulatory network involving TGF-β1 and BMP6 may control the sensing of systemic and/or hepatic iron levels.
authors.affiliation: From the Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69117 Heidelberg, Germany, the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany, the Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany, and.
authors.forename: Simeng
authors.initials: S
authors.lastname: Chen
authors.affiliation: the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Teng
authors.initials: T
authors.lastname: Feng
authors.affiliation: From the Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69117 Heidelberg, Germany, the Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany, and.
authors.forename: Maja
authors.initials: M
authors.lastname: Vujić Spasić
authors.affiliation: From the Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69117 Heidelberg, Germany, the Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany, and.
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.affiliation: the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.affiliation: the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Altenöder
authors.affiliation: Center for Liver Cell Research, Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, 93053 Regensburg, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.affiliation: the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany, Steven.Dooley@medma.uni-heidelberg.de.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: From the Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69117 Heidelberg, Germany, the Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany, and Martina.Muckenthaler@med.uni-heidelberg.de.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism*; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D064451:Hepcidins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: ALK5; HJV; SMAD transcription factor; bone morphogenetic protein (BMP); hepcidin; iron; liver; transforming growth factor beta (TGF-β)